TUGAS KELOMPOK

MATA KULIAH PATOFIOLOGI KASUS KEBIDANAN

PENYAKIT GINEKOLOGI PADA ANAK PEREMPUAN USIA 12-17
TAHUN “POLYCYSTIC OVARY SYNDROME (PCOS)”

Disusun Oleh:

Kelompok 4
Nurul Faidah Ayu Damayanti
Ulin Nikmah K Sri Wahyuni
Shofi Alimatuzidni Sri Wahyuni, SST
Intan Alya A Fadliana Hidayatu R
Ajeng Aryaningsih Ferry Suciati
Fanni Noor Arafanti Kurnia Ningsih,SST
Venny Nurrotuz Z

KEMENTERIAN KESEHATAN REPUBLIK INDONESIA

POLITEKNIK KESEHATAN KEMENKES SURABAYA
JURUSAN KEBIDANAN
PROGRAM STUDI PROFESI BIDAN
TAHUN 2021
 KATA PENGANTAR

Puji syukur penulis panjatkan kehadirat Tuhan Yang Maha Esa, karena atas
rahmat dan karunia-Nya penulis dapat menyusun makalah ini dalam tugas
Patofisiologi dalam Kasus Kebidanan

Selama penyusunan makalah ini, penulis menyadari sepenuhnya bahwa

telah mendapatkan banyak bantuan, bimbingan, dorongan, dan doa dari berbagai
pihak. Oleh karena itu, tidak lupa penulis menyampaikan terimakasih yang
sebesar-besarnya kepada:
1. Novita Eka Kusuma Wardani,SST,M.keb selaku Dosen Pembimbing Mata
Kuliah Patofisiologi dalam Kasus Kebidanan atas segala bimbingan,
kesempatan, dan ide serta masukan-masukan dalam penyusunan dan
pembuatan makalah ini.
2. Semua pihak yang tidak dapat penulis sebutkan satu-persatu.
Kami menyadari bahwa masih banyak kekurangan yang mendasar pada
makalah ini. Oleh karena itu, penulis mengharapkan saran dan kritik yang sifatnya
membangun dari pembaca untuk penyempurnaan makalah selanjutnya. Semoga
makalah ini dapat memberikan manfaat bagi kita semua dan memberikan inspirasi
pengembangan yang lebih baik untuk menghasilkan suatu karya yang lebih
optimal.

Surabaya, 5 September 2021

Penyusun
 BAB 1
PENDAHULUAN

1.1 Latar Belakang

Sindrom ovarium polikistik (PCOS) merupakan gangguan endokrin yang
paling umum terjadi pada wanita dengan konsekuensi luas yang memengaruhi
setiap aspek kehidupan wanita sekitar 6-10%, termasuk kesehatan reproduksi,
mental, kardiovaskular, dan metabolisme. Lebih dari 50% pasien SOPK dikaitkan
dengan sindrom metabolik termasuk obesitas, resistensi insulin, dan dislipidemia.
Insiden kejadian SOPK pada remaja ± sebesar 11-26%, dan sekitar 50%
diantaranya overweight (Irene, 2019).
Pada penelitian Michelmore et al., (1999) di Inggris didapatkan bahwa
prevalensi SOPK pada rentang usia 18-25 tahun sebesar 33%, sedangkan di
Indonesia pada penelitian yang dilakukan oleh Sumapraja et al., (2011)
didapatkan frekuensi tertinggi pada rentang usia 26- 30 tahun, yaitu sebesar
45,7%. Menurut Profesor Dr. H. Budi Santoso, dr., Sp.OG., (K), prevalensi
perempuan PCOS cenderung mengalami peningkatan. Dalam jurnal tahun 90-an,
ditemukan sekitar 4-6%. Kemudian, pada penelitian yang dilakukannya di
Surabaya tahun 2007, Prof. Bus menemukan hasil sebesar 4,5%. Sementara
penelitian lain sejumlah 8-12%. Bahkan, ada pihak yang mengklaim sebanyak 12-
20% perempuan usia reproduktif.
Penatalaksanaan Polycystic Ovarian Syndrome (PCOS) lini pertama
meliputi modifikasi gaya hidup, seperti diet dan olahraga. Tata laksana
farmakologis dibutuhkan untuk kondisi gangguan metabolik, anovulasi,
hirsutisme, dan ketidakteraturan menstruasi. Obat-obatan untuk kondisi tersebut
mencakup kontrasepsi oral, metformin, prednison, leuprolide, clomiphene, dan
spironolactone. Terapi bedah dilakukan terutama untuk memulihkan ovulasi dan
biasanya digunakan sebagai salah satu terapi infertilitas pada penderita PCOS
yang ingin hamil.
1.2. Rumusan Masalah
1. Apa saja definisi Sindrom ovarium polikistik (PCOS)?
2. Bagaimana gejala klinis pada Sindrom ovarium polikistik (PCOS)?
3. Bagaimana patofisiologis pada Sindrom ovarium polikistik (PCOS)?
4. Bagaimana diagnosis pada Sindrom ovarium polikistik (PCOS?
5. Apa saja treatment/pengobatan pada Sindrom ovarium polikistik (PCOS?

1.3. Tujuan
1. Untuk mengetahui definisi Sindrom ovarium polikistik (PCOS.
2. Untuk mengetahui gejala klinis pada Sindrom ovarium polikistik (PCOS.
3. Untuk mengetahui patofisiologis pada Sindrom ovarium polikistik (PCOS).
4. Untuk mengetahui diagnosis pada Sindrom ovarium polikistik (PCOS.
5. Untuk mengetahui treatment/pengobatan pada Sindrom ovarium polikistik
(PCOS.
 BAB 2
REVIEW JURNAL TENTANG PCOS

2.1 Difinisi

Sindrom ovarium polikistik (PCOS) adalah gangguan familial heterogen

yang kompleks dan dialami dalam jangka panjang.

2.2 Gejala Klinis

Gejala biasanya berkembang selama masa remaja. Lebih lanjut, awitan dini

adrenarke dapat mewakili gambaran klinis awal PCOS untuk beberapa anak

perempuan. Pada saat pasien datang untuk mendapatkan klinis, termasuk

hiperandrogenisme dan anovulasi kronis, perhatian medis, gangguan multisistem

ini sering kali menjadi kekacauan yang berlangsung terus-menerus di mana

identifikasi faktor pemicu menjadi sulit.

2.3 Patofisiologi

Komponen patofisiologis utama PCOS pada remaja adalah konsentrasi

androgen yang meningkat (hirsutisme dan hiperandrogenisme adalah manifestasi

dari produksi androgen yang berlebihan), menekan kadar konsentrasi sex

hormone-binding globulin (SHBG) berkontribusi terhadap konsentrasi testosteron

bebas yang lebih tinggi.

 Gambar 1. Faktor potensial yang terlibat dalam patofisiologi PCOS.

Perubahan pada steroidogenesis, folikulogenesis ovarium, fungsi

neuroendokrin, metabolisme, sekresi insulin, sensitivitas insulin, fungsi sel

adiposa, faktor inflamasi, dan fungsi saraf simpatis berkontribusi pada patogenesis

gangguan ini. Tidak semua faktor berperan dalam individu. Faktor lingkungan

seperti pilihan makanan, olahraga, dan pengganggu endokrin mempengaruhi

perkembangan gambaran klinis. Studi asosiasi genom telah mengidentifikasi lokus

yang menarik dekat gen yang terlibat dalam sekresi gonadotropin, aksi

gonadotropin, perkembangan folikel ovarium, dan sensitivitas insulin.

2.3.1 Patofisiologi Ovarium Primer

Jumlah maksimum folikel ovarium, sekitar 6-7 juta, ada selama pertengahan

kehamilan dan menurun menjadi sekitar 2-3 juta folikel primordial saat lahir.

Selanjutnya, folikel primordial direkrut untuk mempertahankan cadangan ovarium

guna mempertahankan kesuburan. Fase awal pertumbuhan folikel adalah

gonadotropin-independen dan dipengaruhi oleh autokrin, parakrin, dan faktor

endokrin lokal.

Pada PCOS, keseimbangan antara androgen, hormon Anti-Müllerian

(AMH), dan FSH terganggu sehingga menyebabkan penangkapan folikel. LH

yang melimpah mendorong sel teka untuk memproduksi androgen, tetapi

konsentrasi FSH dan konversi androgen menjadi estradiol tidak mencukupi, hal

ini mengakibatkan kegagalan untuk memilih folikel dominan, sehingga terjadi

anovulasi kronis. AMH, disekresikan oleh sel granulosa, memainkan peran utama

dalam mengatur keseimbangan ini karena menghambat transisi dari folikel

primordial ke primer. Oleh karena itu, PCOS ditandai dengan peningkatan

pertumbuhan folikel kecil tetapi penghentian pertumbuhan selanjutnya mengarah

ke morfologi polikistik yang khas. Telah dikemukakan bahwa folikel dalam

ovarium PCOS secara inheren berbeda dari folikel dalam ovarium normal.

2.3.2 Resistensi insulin / Hiperinsulinemia

Resistensi insulin (IR) dan hiperinsulinemia sering ditemukan pada wanita

dengan PCOS, topografi lemak tubuh, dan kadar androgen. Wanita dengan PCOS

memiliki risiko tinggi mengalami gangguan toleransi glukosa dan diabetes

mellitus tipe 2. Patogenesis IR pada PCOS mencerminkan interaksi pengaruh

genetik, faktor lingkungan intra dan ekstrauterin yang tidak dapat diturunkan, dan

adaptasi alternatif terhadap kelebihan energi.

Dalam konteks PCOS, pubertas memainkan peran penting terhadap asal

molekuler IR dan hiperinsulinemia. Selama pubertas, remaja mengalami

penurunan sensitivitas insulin sementara. IR dan hiperinsulinemia ini telah

dikaitkan dengan peningkatan hormon pertumbuhan dan konsentrasi IGF-1 pada

periode pertumbuhan untuk ketersediaan lebih banyak asam amino. IR masa

pubertas selektif pada metabolisme glukosa, sedangkan metabolisme protein

merespon secara normal terhadap kerja insulin.

IR pada wanita dengan PCOS bersifat selektif jaringan. Resistensi terhadap

metabolik insulin terutama terdapat pada otot rangka, jaringan adiposa, dan hati;

sedangkan sensitivitas terhadap kerja insulin pada steroidogenesis di kelenjar

adrenal dan ovarium. Baik penelitian in vivo maupun in vitro menunjukkan

bahwa insulin serta IGF-1 bersinergi dengan LH untuk meningkatkan produksi

androgen sel teka. Insulin dapat menurunkan sintesis hepatik dari SHBG yang

meningkatkan androgen bebas yang bersirkulasi.

Insulin secara langsung merangsang aktivitas enzim P450c17 dan P450scc

ovarium untuk mempromosikan steroidogenesis androgen ovarium. Disfungsi

sekresi sel beta pankreas pada sebagian wanita dengan PCOS, memiliki risiko

tertinggi mengembangkan intoleransi karbohidrat dan diabetes tipe 2.

Mekanisme potensial lainnya, pada masa pubertas terjadi peningkatan dalam

produksi androgen berkontribusi pada IR dan hiperinsulinemia. Hubungan antara

IR dan kelebihan androgen (hiperandrogenik) pada wanita sebagai mutasi reseptor

insulin atau autoantibodi menargetkan reseptor insulin. Insulin juga dapat

mempotensiasi respon steroidogenik terhadap gonadotropin secara langsung,

dengan bekerja pada hipofisis untuk meningkatkan sensitivitas gonadotrop

terhadap GnRH. Peningkatan kadar androgen telah dikaitkan dengan penurunan

sekresi adiponektin oleh adiposit pada wanita PCOS, sehingga mengurangi

sensitivitas insulin dan akibatnya meningkatkan kadar insulin kompensasi.

Obesitas dikaitkan dengan IR dan hiperinsulinemia kompensasi. Di antara

remaja obesitas, IR yang terkait dengan obesitas dapat memperburuk IR yang

terkait dengan pubertas selama periode ini, yang menyebabkan kelompok individu

ini mengembangkan pradiabetes dan diabetes tipe 2. Meskipun mekanisme yang

bertanggung jawab untuk IR terkait obesitas tidak sepenuhnya jelas, akumulasi

asam lemak ektopik di organ dan jaringan yang tidak dimaksudkan untuk

menyimpan sejumlah besar lemak tampaknya berperan.

Peningkatan asam lemak bebas mengalir melalui vena portal ke hati

selanjutnya mempengaruhi sekresi, metabolisme, dan kerja insulin perifer. Wanita

dengan PCOS dilaporkan memiliki tingkat fosforilasi serin lebih tinggi dari

reseptor insulin dan substrat reseptor insulin-1 yang mengakibatkan gangguan

transduksi sinyal insulin dan IR intrinsik independen dari massa tubuh total atau

bebas lemak.

Akumulasi lipid, yaitu diasilgliserol (DAG) dan seramida, otot dan hati

mengganggu pensinyalan insulin. Seramida intraseluler dapat mengganggu

pensinyalan insulin dengan menghalangi translokasi Akt, mediator penting dari

sensitivitas insulin, ke membran plasma.

2.3.3 Obesitas

Pada penelitian Stephanie S, et al tahun 2017 menyatakan bahwa Obesitas

dianggap berkontribusi pada patofisiologi PCOS, yang mengarah ke kondisi yang

lebih parah. Peningkatan adipositas telah dikaitkan dengan disfungsi menstruasi dan
meningkatkan konsentrasi androgen. Obesitas meningkatkan resistensi insulin dan

memperburuk hiperandrogenisme terlihat pada PCOS. Peningkatan konsentrasi

androgen sebagian terkait dengan penurunan globulin pengikat hormon seks terlihat

pada obesitas. Selain itu, adipositas yang berlebihan dapat berkontribusi terhadap

kelebihan androgen karena jaringan adiposa mengandung beberapa enzim

steroidogenik yang mengubah androstenedion menjadi testosteron, dan testosteron

menjadi dihidrotestosteron (DHT), sebuah androgen yang lebih kuat. Dalam beberapa

penelitian tentang gadis remaja obesitas, dengan indeks massa tubuh (BMI)

meningkat, ada peningkatan proporsional dalam konsentrasi testosteron bebas. Dalam

keadaan normal berat badan pasien dengan PCOS, resistensi insulin mungkin ada,

bagaimanapun, resistensi insulin adalah berlebihan jika ada obesitas. Selain itu, gadis

remaja obesitas dengan PCOS menunjukkan resistensi insulin yang lebih signifikan

dan hiperinsulinemia dibandingkan dengan pasien yang mengalami obesitas tetapi

tidak membawa diagnosis PCOS

2.3.4 Perubahan Neuroendokrin

1. Perubahan GnRH dan Sekresi Gonadotropin pada PCOS

Ciri khas PCOS adalah adanya deregulasi sekresi gonadotropin, LH dan

FSH, yang mengontrol steroidogenesis ovarium, dinamika folikel, dan

ovulasi. Perubahan profil sekretorik gonadotropin dapat memengaruhi fitur

utama PCOS, termasuk hiperandrogenisme dan disfungsi ovulasi.

Peningkatan kadar LH yang bersirkulasi, peningkatan rasio LH:FSH,

peningkatan frekuensi dan/atau amplitudo LH, serta kadar FSH yang relatif

menurun biasanya ditemukan pada wanita dengan PCOS. Namun, sebagian

kecil pasien PCOS dengan hiperandrogenisme, bila dikaitkan dengan

obesitas, menunjukkan peningkatan kadar LH basal atau terstimulasi, yang

selanjutnya membuktikan heterogenitas presentasi (dan patofisiologi) dari

sindrom tersebut. Disosiasi antara GnRH dan LH berkontribusi pada sekresi

LH yang lebih rendah pada beberapa wanita obesitas dengan PCOS.

Perubahan profil sekresi gonadotropin sesuai dengan perubahan profil

pulsasi GnRH, mungkin mencerminkan peningkatan aktivitas generator

pulsa GnRH. Memang, studi neuroendokrin klasik menetapkan bahwa pola

sekresi GnRH didefinisikan oleh peningkatan jumlah pulsa nikmat LH atas

sekresi FSH oleh hipofisis [67]. Meskipun ada kemungkinan bahwa

perubahan primer (misalnya, ditentukan secara genetik) pada jaringan

generator GnRHpulse mungkin mendorong perubahan tersebut pada

beberapa pasien, data dari studi klinis dan eksperimental yang berbeda telah

menunjukkan peran kontribusi dari gangguan modulator kunci

neurosecretion GnRH, termasuk insulin dan androgen, yang kadarnya

dilaporkan berubah pada PCOS.

Peningkatan androgen mengganggu kapasitas steroid seks untuk

mengatur sekresi GnRH/LH melalui loop umpan balik klasik,

mengakibatkan berkurangnya tindakan umpan balik negatif dari steroid

ovarium (estrogen dan progesteron) yang berkontribusi hipersekresi LH dari

PCOS.

Berkurangnya umpan balik negatif progesteron dan estrogen, terkait

dengan kelebihan androgen, memiliki peran dalam peningkatan pulsatilitas

LH dilaporkan pada pasien dengan PCOS. Neuron GnRH tidak memiliki

 reseptor steroid seks utama yang bertanggung jawab untuk umpan balik

negatif.

2. Perubahan Sinyal Kisspeptin di PCOS

Neuron aferen ke neuron GnRH, neuron Kiss1, menghasilkan kisspeptin

(dikodekan oleh cium1 gen), sebagai pengatur utama neurosekresi dan

ovulasi GnRH. Kisspeptins adalah salah satu aktivator paling kuat dari

neuron GnRH. Kumpulan neuron KISS1 yang menonjol dan sangat

terkonservasi berada pada nukleus arkuata (ARC) dari hipotalamus

mediobasal, atau regio infundibular .

Neuron Kiss1 di ARC mengekspresikan neurotransmiter (neurokinin B

(NKB) dan dynorphin) lain yang juga memainkan peran utama dalam

kontrol sekresi GnRH/gonadotropin. Reseptor NKB NK3R juga

diekspresikan dalam neuron Kiss1. Neuron yang mengekspres kisspeptins,

NKB, dan dynorphin ini disebut neuron KNDy. Aksi NKB dan dynorphin

secara dominan merangsang dan menghambat sekresi LH, dan interkoneksi

padat neuron KNDy dalam ARC.

3. Perubahan Sinyal GABA dan PCOS

Perubahan multi-faktorial dari sinyal gamma aminobutyric acid (GABA)

setelah androgenisasi awal pada model tikus PCOS. GABA dapat

membangkitkan respon depolarisasi (aktivasi) langsung di neuron GnRH.

Jalur saraf GABA yang berasal dari ARC memainkan peran dalam

mentransmisikan tindakan umpan balik steroid seks.

 Penelitian dalam model PCOS tikus dari paparan prenatal terhadap

dihidrotestosteron (DHT) menyatakan adanya peningkatan dorongan

GABAergik ke neuron GnRH. Input GABA yang meningkat ini berasal dari

ekspresi reseptor progesteron yang ditekan di neuron ARC GABA yang

diproyeksikan ke neuron GnRH, sehingga mengakibatkan berkurangnya

pengekangan pensinyalan GABA ke neuron GnRH dengan konsekuensi

peningkatan neurosekresi GnRH. Metabolit androgenik yang dihasilkan

setelah paparan DHT yang tidak tepat, seperti 3α- dan 3β-androstanediol,

dapat berkontribusi pada aktivasi reseptor GABA-A dan penekanan umpan

balik negatif di neuron GnRH.

Data eksperimental yang mendukung jalur GABA patogen seperti itu

berasal dari model PCOS tikus tunggal, yang tidak meniru fenotipe obesitas

yang biasa terlihat pada setidaknya setengah dari pasien PCOS. Oleh karena

itu, masih belum jelas apakah deregulasi GABAergik biasa terjadi pada

spektrum luas kasus klinis PCOS.

4. Pengubah Endokrin dan Metabolik Sekresi GnRH lainya di PCOS; AMH,

Insulin dan Adiponektin

Injeksi sentral AMH telah terbukti meningkatkan sekresi pulsatil LH

pada tikus betina dengan cara yang bergantung pada dosis. Efek yang

bergantung pada GnRH ini dikaitkan dengan peningkatan penembakan

neuron GnRH, yang mengekspresikan AMH reseptor AMHR2. Namun,

penting untuk dicatat bahwa aksi stimulasi AMH pada neurosekresi GnRH

telah diamati pada tikus kontrol, bukan pada manusia dengan PCOS;
 karenanya, meskipun sangat menarik, peran sentral potensial AMH dalam

disfungsi neuroendokrinyang terkait dengan PCOS masih harus diverifikasi.

Meskipun hiperandrogenisme dan kemungkinan faktor ovarium lainnya

merupakan faktor utama yang berkontribusi terhadap peningkatan sekresi

GnRH/LH, peningkatan kadar insulin dan IRare juga diduga terlibat dalam

perubahan neuroendokrin tersebut. Aksi insulin sentral sangat diperlukan

untuk berfungsinya aksis gonadotropik; kurangnya sinyal insulin otak

menurunkan kadar LH dan mengganggu pematangan folikel. Infus insulin

pada wanita kontrol meningkatkan frekuensi denyut LH. Pasien kurus

dengan PCOS telah terbukti menunjukkan peningkatan kadar LH basal dan

rasio LH:FSH.

Reseptor insulin di neuron GnRH dapat digunakan untuk pematangan

dan kesuburan pubertas yang tepat, oleh karena itu menunjuk ke tindakan

utama insulin pada target otak lainnya, kemungkinan terjadi di hulu neuron

GnRH. Wanita dengan PCOS menunjukkan tingkat adiponektin yang lebih

rendah, yang berkorelasi dengan IR. Manfaat terapeutik dari pemberian

adiponektin dan/atau transplantasi BAT pada wanita dengan PCOS masih

harus dibuktikan.

2.3.5 Genetika

Studi kembar monozigot dan dizigotik telah menunjukkan heritabilitas

moderat PCOS. Pentingnya mempertimbangkan faktor risiko dan proses biologis

yang bekerja sepanjang perjalanan hidup, seperti: berat badan lahir rendah dan

paparan androgen pada janin; penambahan berat badan yang cepat setelah
melahirkan; adrenarke dewasa sebelum waktunya dan usia dini pada

perkembangan pubertas; status berat badan dewasa dan gaya hidup.

Genome-wide association studies (GWAS) pertama untuk PCOS dilakukan

pada populasi Cina Han; sementara lokus genomik yang teridentifikasi dapat

direplikasi dalam populasi itu, perkiraan efeknya secara konsisten lebih kecil pada

kasus PCOS Kaukasia, mungkin karena perbedaan populasi dalam arsitektur

genetik atau bahkan sub-fenotipe PCOS.

Peran transkrip sambungan DENND1A dalam steroidogenesis sel teka

ovarium sedang diselidiki. Kerentanan PCOS dalam gen FSHB juga terkait erat

dengan kadar FSH yang lebih rendah dalam sirkulasi, dan dengan fenotipe lain

yang menunjukkan berkurangnya stimulasi folikel ovarium: onset pubertas yang

lebih lambat, dan risiko yang lebih rendah untuk kembaran dizigotik. Patogenesis

neuroendokrin utama PCOS, di samping kemungkinan penyebabnya adalah pada

ovariumnya. Studi genetik dan studi farmakologis yang melibatkan antagonis

NK3R mendorong penyelidikan lebih lanjut pada neuroendokrin PCOS. Temuan

GWAS juga menunjukkan pentingnya penelitian di masa depan tentang

kemungkinan peran reseptor faktor pertumbuhan epidermal pada perkembangan

folikel ovarium / steroidogenesis

Analisis Mendelianrandomization menunjukkan peran kausal dalam etiologi

PCOS pada BMI yang lebih tinggi, IR yang lebih tinggi, dan konsentrasi serum

SHBG yang lebih rendah, yang dapat bertindak meningkatkan bioaktivitas

androgen atau steroid seks lainnya.

 Menurut studi yang dilakukan oleh Stephanie S, et al tahun 2017

menyatakan Sampai saat ini, lebih dari 100 gen kandidat telah terlibat dalam

patofisiologi PCOS, dengan fokus khusus pada gen yang mempengaruhi biosintesis

dan fungsi reproduksi hormon, metabolisme sel dan peradangan kronis. Beberapa gen

kunci yang terkait dengan steroidogenesis terlibat, termasuk CYP17A1, CYP19,

CYP21, HSD17B5 dan HSD17B6. Hormon seks dan reseptornya juga terlibat. PCOS

juga merupakan gangguan metabolisme, dengan hubungan yang kuat dengan diabetes

tipe 2, hiperlipidemia, obesitas, dan sindrom metabolik. Gen kandidat metabolik

terkait termasuk gen yang terkait dengan biosintesis insulin dan fungsi (INS (gen

insulin), INSR (reseptor insulin), IRS1 (substrat reseptor insulin 1), IRS2, IGF,

PPAR-g dan CAPN10) serta gen terkait obesitas (FTO (lemak dan obesitas terkait

gen)). Akhirnya, mengingat hubungan PCOS dengan keadaan proinflamasi, gen

terkait dengan peradangan kronis juga terlibat, terutama sitokin inflamasi seperti

tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1A, IL-1B dan aktivator

plasminogen penghambat (PAI).

2.3.5 Epigenetik

Sejumlah GWAS serta studi replikasi pada subjek Cina dan Kaukasia telah

mengidentifikasi reseptor LH/choriogonadotropin (LHCGR) sebagai gen

kerentanan untuk PCOS. Peningkatan aktivitas LH adalah ciri umum pada PCOS

dan dapat berkontribusi pada folikulogenesis yang rusak dan hiperandrogenisme

yang biasa terlihat pada pasien. Hipometilasi LHCGR pertama kali dijelaskan

dalam model tikus PCOS dan baru-baru ini dikonfirmasi dalam sel darah tepi

manusia dan sel granulosa dari subjek PCOS. Penurunan metilasi LHCGR

diketahui meningkatkan ekspresi gen. Hipometilasi LHCGR, oleh menyebabkan

hipersensitivitas terhadap denyut LH, dengan demikian mungkin merupakan

mekanisme yang masuk akal yang mendasari kerentanan terhadap PCOS.

Aromatase, dikodekan oleh CYP19A1, adalah gen kandidat pada PCOS.

Karena estrogen diperlukan untuk seleksi dan pertumbuhan folikel, penurunan

aromatase dapat berkontribusi pada folikulogenesis yang rusak yang diamati pada

pasien PCOS. Pada wanita Cina dengan PCOS, CYP19A1 mengalami

hipermetilasi dalam jaringan ovarium, yang berkorelasi dengan penurunan kadar

mRNA dan protein.

Metilasi luas genom penelitian pada ovarium wanita dengan PCOS telah

mengungkapkan perubahan dalam metilasi DNA dan ekspresi gen di jalur seperti

jalur diabetes mellitus tipe 1, jalur pensinyalan p53 dan jalur pensinyalan reseptor

mirip NOD (terlibat dalam respons imun), serta di jalur metabolisme terliSelain

studi bertarget gen, studi metilasi luas genom di ovarium wanita dengan PCOS.

Dalam sel darah perifer, metilasi diferensial diamati pada jalur yang terkait

dengan respons imun dan jalur kanker (kelangsungan hidup seluler, proliferasi,

pluripotensi, invasi, metastasis, dan angiogenesis. Menghubungkan PCOS dengan

perubahan epigenetik dalam jalur yang terlibat dalam penyakit autoimun dan

alergi, seperti diabetes mellitus tipe 1, penyakit tiroid, dan asma, dan konsisten

dengan hasil yang disebutkan di atas pada jaringan ovarium.

Selain ovarium dan sel darah tepi, studi metilasi luas genom telah dilakukan

di jaringan adiposa dari wanita dengan PCOS dan pada model primata PCOS.

Pada wanita, metilasi diferensial diamati pada gen yang terlibat dalam

metabolisme steroid (CYP1B1), fungsi hati (GPT), dalam gen kandidat untuk
PCOS (RAB5B, yang berpartisipasi dalam transportasi vesikel intraseluler),

dalam dua gen yang terkait dengan diabetes mellitus tipe 2 ( PPARG, SVEP1) dan

dalam satu gen yang terlibat dalam metilasi DNA (DMAP1).

Regulasi ekspresi gen oleh microRNAs (mi RNAs) dianggap sebagai

lapisan tambahan regulasi epigenetik. Profil ekspresi miRNA yang beredar di

seluruh genom mengidentifikasi sejumlah miRNA yang tidak diatur pada wanita

dengan PCOS. Spesies miRNA ini terlibat dalam glikometabolisme dan jalur

pengembangan folikel ovarium. Menariknya, miRNA-592 telah terbukti

diturunkan regulasi dan berbanding terbalik dengan kadar LHCGR pada pasien

PCOS.

2.3.6 Perubahan Aktifitas Saraf Simpatik

Perubahan aktivitas saraf simpatis telah diusulkan untuk berkontribusi pada

etiologi PCOS. Banyak gejala klinis PCOS yang umum, termasuk obesitas sentral,

hiperinsulinemia, dan hiperandrogenemia, terkait dengan peningkatan aktivitas

kronis sistem saraf simpatik. Penilaian langsung aktivitas simpatis pada wanita

PCOS mengungkapkan hubungan antara aktivitas saraf simpatis otot yang tinggi

dan PCOS secara independen dari BMI. Penanda tidak langsung tambahan dari

aktivitas otonom termasuk variabilitas detak jantung dan pemulihan detak jantung

setelah berolahraga telah menunjukkan bahwa wanita PCOS muda menunjukkan

peningkatan simpatik dan penurunan respons parasimpatis terhadap tantangan ini.

Peningkatan tonus simpatis ovarium pada PCOS didukung oleh penemuan

densitas yang lebih besar dari serat saraf katekol aminergik di ovarium polikistik

dan studi tambahan pada model PCOS tikus yang menunjukkan peningkatan
aliran simpatis sebelum munculnya ovarium. kista. Studi tambahan pada model

tikus ini menunjukkan hubungan antara perkembangan kista folikel dan

peningkatan produksi faktor pertumbuhan saraf kronis di ovarium, ciri

hiperaktivitas simpatis. Hubungan antara neurotropin dan PCOS diperkuat oleh

temuan bahwa produksi faktor pertumbuhan saraf ovarium meningkat pada wanita

PCOS.

2.3.7 Paparan Lingkungan

Menurut studi yang dilakukan oleh Stephanie S, et al tahun 2017

menyatakan Menambah kompleksitas patofisiologi PCOS adalah kontribusi potensial

dari paparan lingkungan dan faktor gaya hidup. Bahan kimia pengganggu endokrin

(EDC) adalah didefinisikan sebagai "zat dalam lingkungan kita, makanan, dan produk

konsumen yang mengganggu" biosintesis, metabolisme, atau aksi hormon yang

mengakibatkan penyimpangan dari homeostatis normal kontrol atau reproduksi”.

EDC adalah kelas molekul yang luas yang mencakup plasticizer seperti: seperti

phthlates dan bisphenol A (BPA), serta produk akhir glikasi lanjutan (AGEs).

sebagian besar paparan manusia adalah melalui kemasan makanan, namun molekul

ini juga digunakan dalam produksi alat kesehatan. EDC telah terlibat dalam banyak

gangguan yang melibatkan gangguan reproduksi pria dan wanita, perkembangan

payudara abnormal dan kanker, prostat kanker, neuroendokrinologi, tiroid,

metabolisme dan obesitas, dan kardiovaskular endokrinologi.

Waktu paparan sangat penting, dengan bukti bahwa janin dan anak kecil yang

paling rentan terhadap efek buruk dari EDC.Penelitian pada hewan telah

menunjukkan bahwa paparan prenatal terhadap androgen tingkat tinggi selama titik-

titik kunci dalam kehamilan menghasilkan pemrograman sifat PCOS. Oleh karena itu,
paparan terhadap EDC seperti androgen dapat menyebabkan disfungsi metabolik di

masa dewasa, seperti PCOS. Paparan EDC juga dapat berkontribusi terhadap

gangguan endokrin pada wanita dengan PCOS. Wanita dengan PCOS telah

ditemukan memiliki tingkat EDC yang lebih tinggi dibandingkan dengan ovulasi

perempuan.

2.4 Diagnosa

1. Fitur Klinis PCOS

a. Hirsutisme sedang hingga berat merupakan bukti klinis kelebihan

androgen (Level B).

b. Hirsutisme ringan mungkin merupakan tanda kelebihan androgen bila

dikaitkan dengan ketidakteraturan menstruasi (Tingkat C).

c. Jerawat inflamasi sedang atau berat yang tidak responsif terhadap terapi

topikal mungkin memerlukan pemeriksaan kelebihan androgen (Level C).

d. Jerawat dan/atau alopecia yang terisolasi tidak boleh dianggap sebagai

kriteria diagnostik untuk PCOS pada masa remaja (Lev el C).

e. Gangguan menstruasi yang persisten (oligomenore dan amenore

sekunder) lebih dari 2 tahun setelah menarche atau amenore primer pada

anak perempuan dengan pubertas lengkap dapat menunjukkan kelebihan

androgen (Level B).

f. Hiperandrogenisme biokimia harus didefinisikan berdasarkan metodologi

yang digunakan, karena tidak ada batasan yang jelas untuk konsentrasi

testosteron untuk remaja (Level A).

 g. Bukti biokimia hiperandrogenisme berdasarkan peningkatan testosteron

total dan/atau testosteron bebas yang diukur dalam referensi laboratorium

yang andal mendokumentasikan hiperandrogenemia pada remaja

bergejala (Level B).

2. Morfologi Polikistik Ovarium

a. Adanya PCOM pada remaja yang tidak mengalami hiperandrogenisme/

oligo-anovulasi tidak menunjukkan diagnosis PCOS (Level A).

b. Pengukuran volume ovarium, jumlah dan ukuran folikel, dan dimensi

uterus mungkin berguna dalam evaluasi amenore, tetapi tidak diperlukan

untuk diagnosis PCOS pada remaja (Level A).

3. Biomarker untuk PCOS

Penggunaan rasio AMH, T/DHT, dan protein spesifik atau microRNA

sebagai biomarker PCOS belum divalidasi pada remaja (Level C.).

4. IR dalam kontek PCOS

IR, hiperinsulinemia kompensasi, atau obesitas tidak boleh dianggap

sebagai kriteria diagnostik untuk PCOS pada remaja (Level A).

a. Diagnosis PCOS Pada Remaja

Menurut penelitian dari Stephanie S, et al tahun 2017 Seperti disebutkan

di atas, diagnosis PCOS ditegakkan dengan adanya dua dari tiga kriteria

berikut:

(1) tanda-tanda hiperandrogenisme klinis atau biokimia (HA)

(2)disfungsi ovulasi kronis (OD)

(3)morfologi ovarium polikistik (PCOM).

 Namun,populasi remaja memerlukan pertimbangan khusus, karena

kriteria ini dikembangkan untuk diagnosis pada orang dewasa; selama masa

remaja, PCOS dapat muncul secara berbeda.

Karakteristik yang paling umum terlihat pada remaja adalah

hiperandrogenisme. Berlawanan dengan populasi orang dewasa, satu

satunya keberadaan jerawat dan/atau hirsutisme tidak boleh dianggap bukti

klinis hiperandrogenisme pada gadis remaja. Namun, temuan kasus klinis

yang lebih parah bisa menjadi indikasi hiperandrogenisme. Misalnya jerawat

komedo dan jerawat ringan hirsutisme umum terjadi pada semua wanita

remaja. Jerawat inflamasi sedang-berat (didefinisikan sebagai: lebih dari 11

lesi inflamasi) tidak responsif terhadap obat topikal dan hirsutisme sedang-

berat (berdasarkan sistem penilaian Ferriman-Gallwey) akan menjadi

indikasi untuk memulai pengujian untuk hiperandrogenisme.MANUS

b. Evaluasi Laboratorium

Dalam penelitian dari Stephanie S, et al tahun 2017, Penilaian biokimia

hiperandrogenisme membutuhkan tes yang andal dengan potongan yang

terdefinisi dengan baik. Pengukuran kadar testosteron serum

direkomendasikan sebagai langkah awal dalam mengevaluasi

hiperandrogenisme. Testosteron bebas adalah bagian bioaktif dari total

serum testosteron, menjadikannya indikator paling sensitif untuk

peningkatan kadar androgen. Tingkat sirkulasi testosteron bebas diatur oleh

globulin pengikat hormon seks (SHBG) yang dipengaruhi oleh beberapa

kondisi fisiologis. Androgen serum lainnya seperti androstenedion dan

DHEA-S secara luas diukur, tetapi efektivitas biaya secara rutin mengukur
 beragam androgen belum dibuktikan dengan baik. Tak lama setelah

menarche, testosteron serum mencapai tingkat dewasa, memanfaatkan

rentang referensi dewasa sesuai. Ada beberapa faktor yang membuat

interpretasi hasil lab ini menantang. Ini termasuk kurangnya standarisasi

pengujian testosteron di antara rumah sakit dan laboratorium serta

kurangnya sensitivitas, spesifisitas, dan akurasi tes yang digunakan.

2.5 Pemeriksaan Radiologi

Dalam penelitian dari Stephanie S, et al tahun 2017 menyatakan Pada

populasi orang dewasa, peran pencitraan dalam mendiagnosis PCOS telah ditetapkan

dengan baik. Secara histopatologis, morfologi ovarium polikistik (PCOM) disebabkan

oleh kelebihan jumlah sel kecil folikel yang berhenti sebelum tahap perkembangan

praovulasi. PCOM didefinisikan sebagai antral jumlah 12 folikel (folikel berukuran 2-

9mm) dalam setidaknya satu ovarium atau volume ovarium >10,0 cm³. Namun,

ovarium dengan banyak folikel adalah normal dan biasanya terlihat di sekitar waktu

menarche; sekitar 50% remaja normal akan memenuhi kriteria: morfologi ovarium

polikistik. Selanjutnya, siklus anovulasi karena tidak konsisten perekrutan folikel

dominan pada tahun-tahun awal pasca menarche dapat berkontribusi pada penampilan

multifollicular ovarium yang khas terlihat selama masa pubertas. Pada populasi

remaja, diagnosis PCOS tidak boleh hanya didasarkan pada gejala anovulasi dan

ovarium yang tampak polikistik pada ultrasound, terutama di dalam dua tahun

menarche. Pedoman Endocrine Society memperingatkan terhadap penggunaan

PCOM sebagai kriteria diagnostik untuk remaja. Namun, pencitraan dapat digunakan
sebagai tes konfirmasi untuk remaja di mana diagnosis PCOS masih belum pasti

setelah klinis dan laboratorium evaluasi.

1. USG

Ultrasonografi transvaginal (TVUS) adalah modalitas pilihan untuk evaluasi

anatomi panggul pada populasi wanita dewasa. Meskipun optimal untuk

mengevaluasi anatomi panggul, pertimbangan hati-hati harus diambil sebelum

mencoba USG transvaginal di remaja, terutama jika dia masih perawan. Atau,

melakukan USG transabdominal (TAUS) pada remaja obesitas secara teknis

menantang dan seringkali tidak memberikan hasil yang dapat diandalkan untuk

pencitraan ovarium. Akibatnya, jumlah folikel antral sulit ditentukan dengan ini.

2. MRI (Resonansi Magnetik)

Dibandingkan dengan USG, MRI pada remaja memberikan pandangan

ovarium yang paling akurat. MRI memiliki keuntungan yang dapat diakses

untuk segala usia mengingat sifatnya yang non-invasif. Dalam sebuah studi

yang membandingkan remaja obesitas dengan PCOS hingga remaja obesitas

tanpa PCOS, ditunjukkan bahwa temuan MRI menggunakan kriteria Rotterdam

memiliki spesifisitas 77-82%. Pada pasien dengan ketidakpastian temuan klinis

dan laboratorium, MRI dapat dianggap sebagai pencitraan diagnostik yang

akurat pengandaian. Namun, MRI secara signifikan lebih mahal daripada USG

transvaginal.
2.6 Treatment / Pengobatan

Tidak ada pengobatan farmakologis yang telah disetujui sejauh ini oleh

FDA/EMA untuk digunakan pada remaja dengan PCOS; namun, beberapa

intervensi farmakologis telah digunakan untuk mengelola gejala PCOS. Pada

bagian berikut, perawatan farmakologis dasar dan aditif dan potensi manfaatnya,

serta pekt reproduksi pada remaja PCOS dibahas. Dosis dan urutan kombinasi

intervensi perlu diindividualisasikan.

2.6.1. Perawatan Dasar

1. Intervensi Gaya Hidup

Penurunan berat badan dan peningkatan latihan fisik umumnya

direkomendasikan sebagai terapi lini pertama pada anak perempuan yang

kelebihan berat badan atau obesitas. Dua uji coba terkontrol acak kecil

(RCT) dan satu studi klinis terkontrol dengan baik pada anak perempuan

PCOS yang kelebihan berat badan telah menunjukkan bahwa kombinasi

penurunan berat badan dan olahraga intensif menurunkan kadar testosteron

dan indeks androgen bebas, meningkatkan konsentrasi SHBG, dan

menormalkan keteraturan menstruasi sebanding dengan obat. terapi, dan

tanpa efek samping. Kombinasi intervensi gaya hidup dengan obat-obatan

menormalkan lebih banyak kadar androgen dan menstruasi dalam salah satu

penelitian ini. Namun, data jangka panjang yang melaporkan manfaat

berkelanjutan pada keteraturan siklus atau hasil kehamilan setelah

penurunan berat badan pada remaja perempuan masih kurang.

 Faktor risiko kardiovaskular seperti hipertensi, dislipidemia, dan

gangguan toleransi glukosa, serta penanda awal aterosklerosis seperti

ketebalan media intima karotis juga membaik setelah intervensi gaya hidup.

Penurunan berat badan, tetapi bukan partisipasi dalam intervensi gaya hidup

itu sendiri, memprediksi perbaikan komponen PCOS. Remaja yang sangat

gemuk sering merespons intervensi gaya hidup dengan buruk. Penurunan

BMI SDS 0,25 atau lebih dan/atau 30 menit per hari aktivitas fisik sedang

hingga berat menghasilkan peningkatan faktor risiko kardiovaskular pada

remaja dengan PCOS.

Intervensi gaya hidup harus didasarkan pada kombinasi diet kalori

terbatas (tanpa bukti bahwa satu jenis diet lebih baik untuk remaja),

perawatan perilaku, dan olahraga . Sepanjang garis ini, analisis meta telah

menunjukkan manfaat dari modifikasi diet pada wanita muda dengan PCOS.

Meningkatkan aktivitas fisik dari sedang hingga berat efektif dalam

mengurangi perkembangan sindrom metabolik pada anak perempuan

dengan berat badan kurang.

Mengurangi perilaku menetap setidaknya sama pentingnya dengan

meningkatkan aktivitas fisik. Selanjutnya, perawatan keluarga merupakan

komponen penting dalam intervensi gaya hidup karena kesiapan orang tua

untuk mengubah kebiasaan mempengaruhi hasilnya.

2. Terapi lokal / Kosmetik

Metode penghilangan rambut kosmetik untuk hirsutisme termasuk

pemutihan, pencukuran bulu kimia, pencabutan, waxing, pencukuran,

 elektrolisis, dan laser hair removal. Meskipun hanya yang terakhir yang

menghasilkan penghilangan rambut permanen – meskipun sebagian –,

kemanjuran dan keamanan elektrolisis tidak didukung oleh RCT mana pun.

Studi yang membandingkan perangkat laser dan IPL sedikit dan

berkualitas rendah; semua telah dilakukan pada orang dewasa dengan

bentuk campuran hirsutisme, hiperandrogenisme, atau pertumbuhan rambut

yang tidak diinginkan. Hanya 2 RCT yang mengevaluasi efek fotoepilasi

pada pasien PCOS tertentu yang berusia 16 tahun atau lebih, menunjukkan

manfaat terapi laser pada hirsutisme wajah dan keunggulan laser alexandrite

dibandingkan IPL.

3. Farmasi Adiktif

a. Metformin

1) Metformin memiliki efek menguntungkan pada kelebihan berat badan

atau remaja obesitas dengan PCOS, tetapi hanya jangka pendek data

tersedia (Level A).

2) Pada remaja non-obesitas dengan PCOS dan hiperinsu lineemia,

metformin meningkatkan ovulasi dan satu tingkat testosteron (Level

B)

b. Anti Androgen

1) Anti-androgen mengurangi kelebihan androgen lebih banyak daripada

metformin dalam monoterapi (Level B). Spirono lakton adalah yang

paling umum digunakan Level C).

 2) Anti-androgen hanya boleh digunakan jika tindakan kontrasepsi

dijamin.

c. Pil Kontrasepsi Hormonal Kombinasi

Dalam penelitian dari Stephanie S, et al tahun 2017 menyatakan

Kontrasepsi hormonal kombinasi (CHC), yang mengandung baik estrogen

(etinil estradiol) dan progestin, secara tradisional dapat digunakan untuk

terapi lini untuk remaja yang didiagnosis dengan PCOS. Kontrasepsi oral

kombinasi (COC) adalah paling sering diresepkan. Ada juga data terbatas

untuk merekomendasikan durasi penggunaan CHC pada remaja. Sangat

penting untuk menyaring kontraindikasi sebelummenggunakan CHC sebagai

strategi pengobatan untuk PCOS. Misalnya, komorbiditas tertentu seperti

riwayat tromboemboli vena dalam/emboli paru atau sakit kepala, migrain

sebelumnya akan membuat terapi yang mengandung estrogen

dikontraindikasikan.

Pada pasien yang dipilih dengan tepat, CHC memberikan banyak manfaat

bagi remaja dengan PCOS. CHC memiliki efek anti-androgenik. Komponen

estrogen bertindak untuk meningkatkan SHBG, yang mengurangi

testosteron bioavailable dengan mengikat steroid bebas, akhirnya

menurunkan gejala kelebihan androgen. Progestin menekan kadar LH,

mengarah ke downstream penurunan produksi androgen ovarium. Progestin

juga menghambat 5α aktivitas reduktase, menghasilkan lebih sedikit

konversi perifer testosteron menjadi dihidrotestosteron (DHT), androgen

paling bertanggung jawab atas hirsutisme. Dalam sebuah penelitian yang

membandingkan olahraga dengan CHC di pasien dengan PCOS, hirsutisme,

 testosteron bebas serum, dan FAI menurun secara signifikan dalam

kelompok CHC (p<0,05). Sementara beberapa progestin, seperti

drosperinone, memiliki efek intrinsic sifat antiandrogenik, konsentrasi

progestin di CHCs rendah. Secara acak penelitian, manfaat klinis progestin

anti-androgenik belum signifikan bila dibandingkan ke bentuk lain dari

progestin. CHC juga menghasilkan regulasi menstruasi dan perlindungan

endometrium. Remaja dengan PCOS sering mengalami siklus menstruasi

yang tidak teratur dan berat, yang dapat mengganggu kehidupan sehari-hari

mereka. Menempatkan mereka pada CHC dapat untuk mengatur siklus

mereka, yang mengarah ke lebih dapat diprediksi dan periode yang lebih

ringan. PCOS sering menjadi penyebab amenore primer, dan untuk anak

perempuan dengan bukti hiperandrogenisme yang menunjukkan stadium

lanjut perkembangan pubertas (misalnya Tanner Stage IV breast

development) tetapi belum mulai menstruasi, rekomendasinya adalah: mulai

CHC. Remaja yang aktif secara seksual memiliki manfaat sekunder dari

metode kontrasepsi. Namun, jika disampaikan secara lisan, itu

membutuhkan tanggung jawab dari pihak pasien untuk patuh dengan pil

harian. CHC juga dapat meningkatkan profil lipid pasien. Meskipun tidak

ada data yang tersedia untuk efek jangka panjang.

d. Perawatan Kombinasi

1) Bila tersedia, kombinasi tiga kali lipat dosis rendah dalam sensitisasi

sulin dan obat generik anti-androgenik atau mengurangi risiko

kardiovaskular dan komposisi tubuh lebih dari kombinasi hanya

metformin dan anti-androgen menghasilkan pola pasca pengobatan

 yang lebih menguntungkan dari androgen yang bersirkulasi dan

tingkat ovulasi daripada asupan OCP (Level A).

4. Aspek Reproduksi

a. Ovulasi

b. Kontrasepsi

5. Transisi

Terapi PCOS pada masa remaja harus bertujuan untuk mengurangi

adipositas hepato-viseral, meningkatkan kehilangan lemak sentral, dan

dengan demikian, melemahkan oligo-anovulasi pregestasional, dan

mengurangi komplikasi kehamilan seperti diabetes mellitus, preeklamsia,

dan kelahiran prematur (Tingkat B).

 BAB III

PENUTUP

3.1. Kesimpulan
Sindrom ovarium polikistik (PCOS) merupakan gangguan familial
heterogen yang kompleks dan dialami dalam jangka panjang yang mana gejalanya
biasa berkembang selama masa remaja. Identifikasi seseorang dengan PCOS
dilakukan pada saat pasien datang untuk mendapatkan klinis, termasuk
hiperandrogenisme dan anovulasi kronis, perhatian medis, gangguan multisistem
ini sering kali menjadi kekacauan yang berlangsung terus-menerus di mana
identifikasi faktor pemicu menjadi sulit. Patofisiologis utama PCOS pada remaja
adalah konsentrasi androgen yang meningkat (hirsutisme dan hiperandrogenisme
adalah manifestasi dari produksi androgen yang berlebihan), menekan kadar
konsentrasi sex hormone-binding globulin (SHBG) berkontribusi terhadap
konsentrasi testosteron bebas yang lebih tinggi. Perubahan pada steroidogenesis,
folikulogenesis ovarium, fungsi neuroendokrin, metabolisme, sekresi insulin,
sensitivitas insulin, fungsi sel adiposa, faktor inflamasi, dan fungsi saraf simpatis
berkontribusi pada patogenesis gangguan ini. Faktor lingkungan seperti pilihan
makanan, olahraga, dan pengganggu endokrin mempengaruhi perkembangan.
Diagnosa PCOS pada remaja dapat ditegakkan dengan tanda-tanda
hiperandrogenisme klinis atau biokimia (HA), disfungsi ovulasi kronis (OD), dan
morfologi ovarium polikistik (PCOM). Pemeriksaan PCOS dapat dilakukan dengan
USG dan MRI (Resonansi Magnetik). Dan pengobatan yang dilakukan yakni dengan
perawatan dasar meliputi (Intervensi Gaya Hidup, Terapi lokal / Kosmetik,
Farmasi Adiktif, Aspek Reproduksi, dan Transisi)

3.2. Saran

Demikian analisi yang kami buat, kami berharap apa yang kami telah
paparkan bisa menjadi tambahan pengetahuan bagi kita semua terutama seorang
bidan untuk dapat mengidentifikasi Sindrom ovarium polikistik (PCOS) pada
remaja. Kami menyadari bahwa apa yang kami paparkan dalam tulisan ini belum
sesuai dengan yang diharapkan, dengan ini kami berharap masukan yang lebih
banyak lagi dari dosen pembimbing dan teman-teman semua. Semoga dalam
penulisan makalah ini dapat berguna bagi penulis khususnya, dan bagi pembaca
mungkin dalam penyusunan analisis ini, penulis masih banyak kekurangan. Untuk
itu penulis mengharapkan kritik dan saran yang sifatnya membangun demi
perbaikan penulis di masa yang akan datang.
 DAFTAR PUSTAKA

Irene, Angela, et al. "Hubungan Pola Makan dengan Risiko Terjadinya Sindrom
Ovarium Polikistik pada Remaja." Sriwijaya Journal of Medicine 3.1 (2020):
65-72.
Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo JS.
Polycystic ovary syndrome in adolescents. Best Pract Res Clin Obstet
Gynaecol. 2018 Apr;48:103-114. doi: 10.1016/j.bpobgyn.2017.08.008.
Epub 2017 Sep 1. PMID: 28919160.
Rosenfield RL, Ehrmann DA. Patogenesis Sindrom Ovarium Polikistik (PCOS):
hipotesis PCOS sebagai hiperandrogenisme ovarium fungsional ditinjau
kembali. Ulasan Endokrin. 2016.
Hsueh AJ, Kawamura K, Cheng Y, Fauser BC:Kontrol intraovarium dari
folikulogenesis awal.Endocr Rev 2015;36:1–24.
Ibáñez, L., Oberfield, S. E., Witchel, S., Auchus, R. J., Chang, R. J., Codner, E., ...
& Lee, P. A. (2017). An international consortium update: pathophysiology,
diagnosis, and treatment of polycystic ovarian syndrome in
adolescence. Hormone research in paediatrics, 88, 371-395.
LAMPIRAN
Accepted Manuscript

Polycystic Ovary Syndrome in Adolescents

Stephanie S. Rothenberg, MD, Rachel Beverley, MD, Emily Barnard, DO, Massoud
Baradaran-Shoraka, BS, Joseph S. Sanfilippo, MD, MBA

PII: S1521-6934(17)30126-8
DOI: 10.1016/j.bpobgyn.2017.08.008
Reference: YBEOG 1741

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 31 July 2017

Accepted Date: 24 August 2017

Please cite this article as: Rothenberg SS, Beverley R, Barnard E, Baradaran-Shoraka M, Sanfilippo
JS, Polycystic Ovary Syndrome in Adolescents, Best Practice & Research Clinical Obstetrics &
Gynaecology (2017), doi: 10.1016/j.bpobgyn.2017.08.008.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

TITLE:

Polycystic Ovary Syndrome in Adolescents

AUTHORS:

PT
Stephanie S. Rothenberg, MDa

Rachel Beverley, MDa

RI
Emily Barnard, DOa

SC
Massoud Baradaran-Shoraka, BSa

Joseph S. Sanfilippo, MD, MBAa

U
AN
AUTHOR AFFILIATIONS:
a
Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of UPMC,
300 Halket St, Pittsburgh, PA 15213, USA
M

AUTHOR EMAIL ADDRESSES:

D

Stephanie S. Rothenberg, MD – rothenbergss@upmc.edu

TE

Rachel Beverley, MD – beverleyrm@upmc.edu

Emily Barnard, DO – barnardep@mail.magee.edu

EP

Massoud Baradaran-Shoraka, BS – baradaran-shoraka.massoud@medstudent.pitt.edu

Joseph S. Sanfilippo, MD, MBA – sanfjs@mail.magee.edu

C
AC

CORRESPONDING AUTHOR:

Name: Joseph S. Sanfilippo, MD, MBA

Email: sanfjs@mail.magee.edu

Address: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital,

University of Pittsburgh, 300 Halket St, Pittsburgh, PA 15213, USA
 ACCEPTED MANUSCRIPT

ABSTRACT

Polycystic ovary syndrome (PCOS) typically manifests with a combination of menstrual dysfunction and

evidence of hyperandrogenism in the adolescent population. No single cause has been identified;

however, evidence suggests a complex interplay between genetic and environmental factors. Polycystic

PT
ovary syndrome presents a particular diagnostic challenge in adolescents as normal pubertal changes

can present with a similar phenotype. Management of PCOS in the adolescent population should focus

RI
on a multi-modal approach with lifestyle modification and pharmacologic treatment to address

SC
bothersome symptoms. This chapter outlines the pathogenesis of PCOS, including the effects of obesity,

insulin resistance, genetic, and environmental factors. The evolution of the diagnostic criteria of PCOS as

U
well as specific challenges of diagnosis in the adolescent population are reviewed. Finally, evidence for
AN
lifestyle modification and pharmacologic treatments are discussed.
M
D

KEY WORDS
TE

Polycystic ovary syndrome, adolescent, insulin resistance, hyperandrogenism

C EP
AC
 ACCEPTED MANUSCRIPT

Pathogenesis

Polycystic ovary syndrome (PCOS) is considered a disorder of ovarian function. Prior to

understanding the pathogenesis of the syndrome, it is prudent to review the process of normal

PT
androgen synthesis in the ovaries and adrenal glands. In the ovaries, luteinizing hormone (LH)

stimulates theca cells to initiate the conversion of cholesterol to androstenedione, the major

RI
precursor to testosterone and estrogen synthesis. Androstenedione is then converted to

SC
testosterone in the theca cells via 17β-hydroxysteroid dehydrogenase (17β-HSD).

Androstenedione also diffuses from theca cells to granulosa cells and undergoes conversion to

U
estrone via aromatase, a process catalyzed by follicle stimulating hormone (FSH). Testosterone
AN
produced by theca cells is converted to dihydrotestosterone (DHT) in the granulosa cells via 5α-

reductase. Estrone is subsequently converted in the granulosa cells to estradiol by 17β-HSD.

M
D

Concurrently in the adrenal cortex, the steroid biosynthetic pathway is stimulated by

TE

adrenocorticotropic hormone (ACTH). Adrenal androgen production primarily occurs in the

zona reticularis. The pathway begins with conversion of cholesterol to pregnenolone in the
EP

zona glomerulosa. Pregnenolone is converted to progesterone via 3β-hydroxysteroid

dehydrogenase (3β-HSD). In the zona fasiculata, 17α-hydroxylase catalyzes the formation of 17-
C

hydroxypregnenolone and 17-hydroxyprogesterone (17-OHP) from pregnenolone and

AC

progesterone, respectively. These intermediates are acted on by 17,20 lyase in the zona

reticularis to form dehydroepiandrosterone (DHEA) and androstenedione. DHEA is primarily

converted to dehydroepiandrosterone sulfate (DHEA-S) via steroid sulfotransferase (SUL2A1).

To a lesser extent, 3β-HSD acts on DHEA to form androstenedione. Androstenedione is then

 ACCEPTED MANUSCRIPT

converted to testosterone and estrone via 17β-HSD and aromatase, respectively. Additionally,

androgens are produced peripherally in the liver, adipose and skin.[1]

PT
No single cause for PCOS has been elicited. Rather, it is felt to be a syndrome related to the

interplay of genetic and environmental factors.[1] In vitro studies of theca cells from patients

RI
with PCOS have demonstrated overexpression of LH receptors and steroidogenic enzymes

SC
including cytochrome P450c17, 3β-HSD, and 17β-HSD. As a result, production of steroids such

as 17-OHP and testosterone are elevated compared to controls without PCOS.[2] During

U
puberty, there is maturation of the hypothalamic–pituitary–ovarian axis and subsequent
AN
increase in circulating levels of LH. This increase is exaggerated in girls with a predisposition to

PCOS, further amplifying androgen production [3]. Specifically, adolescents with PCOS exhibit
M

increased GnRH and LH pulse frequency and amplitude, as well as an increased LH to FSH
D

ratio.[4]
TE

Insulin also plays an important role in human androgen regulation. There is a physiologic
EP

increase in insulin resistance, along with an increase in serum concentrations of fasting insulin

during normal puberty and adolescence. As insulin levels rise, there is a reciprocal fall in sex
C

hormone binding globulin (SHBG) by suppressing production in the liver, ultimately increasing
AC

the circulating free concentration of sex steroids.[3] Multiple studies have demonstrated that

insulin resistance and hyperinsulinemia are key findings in patients with PCOS, whether or not

they are obese.[5–9] In vitro studies have demonstrated elevation of LH and GnRH secretion in
 ACCEPTED MANUSCRIPT

response to insulin infusion.[10] Additionally, insulin amplifies steroidogenesis in both ovarian

theca and granulosa cells in response to LH stimulation.

PT
Interestingly, despite the systemic state of insulin resistance in PCOS, the ovary remains

sensitive to insulin.[10] As previously discussed, insulin amplifies the effect of LH on granulosa

RI
cell steroidogenesis. Additionally, insulin resistance and hyperinsulinemia are also implicated in

SC
the underlying mechanism of anovulation by leading to arrest of follicular maturation.[3]

U
Obesity is thought to contribute to the pathophysiology of PCOS, leading to a more severe
AN
PCOS phenotype. Increasing adiposity has been associated with menstrual dysfunction and

increasing androgen concentrations.[4] Obesity promotes insulin resistance and aggravates the
M

hyperandrogenism seen in PCOS.[1] Increased androgen concentration is partially related to a

D

decrease in sex hormone binding globulin seen in obesity. Additionally, excessive adiposity may
TE

contribute to androgen excess as adipose tissue contains several steroidogenic enzymes that

convert androstenedione into testosterone, and testosterone into dihydrotestosterone (DHT), a

EP

more potent androgen. In multiple studies of obese adolescent girls, as body mass index (BMI)

increases, there is a proportional rise in free testosterone concentration.[4,11–13] In normal

C

weight patients with PCOS, insulin resistance may be present, however, insulin resistance is
AC

exaggerated when obesity is present. [10] Additionally, obese adolescent girls with PCOS

demonstrate more significant insulin resistance and hyperinsulinemia compared to patients

who are obese but do not carry a diagnosis of PCOS.[4]

Genetics
 ACCEPTED MANUSCRIPT

To date, greater than 100 candidate genes have been implicated in the pathophysiology of

PCOS, with particular focus on genes affecting the biosynthesis and function of reproductive

hormones, cellular metabolism and chronic inflammation. Several key genes related to

PT
steroidogenesis are implicated, including CYP17A1, CYP19, CYP21, HSD17B5 and HSD17B6. Sex

hormones and their receptors are also involved. PCOS is also a metabolic disorder, with a

RI
strong association with type 2 diabetes, hyperlipidemia, obesity, and the metabolic syndrome.

SC
Associated metabolic candidate genes include genes related to insulin biosynthesis and

function (INS (insulin gene), INSR (insulin receptor), IRS1 (insulin receptor substrate 1), IRS2,

U
IGF, PPAR-g and CAPN10) as well as obesity-related genes (FTO (fat and obesity-associated
AN
gene)).[14,15] Finally, given the relationship of PCOS with a proinflammatory state, genes

related to chronic inflammation are also involved, particularly inflammatory cytokines such as
M

tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1A, IL-1B and plasminogen activator
D

inhibitor (PAI). [14,15]

TE

Environmental Exposures
EP

Adding to the complexity of the pathophysiology of PCOS is the potential contribution of

environmental exposures and lifestyle factors. Endocrine disrupting chemicals (EDCs) are
C

defined as “substances in our environment, food, and consumer products that interfere with
AC

hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic

control or reproduction”.[16] EDCs are a broad class of molecules that include plasticizers such

as phthlates and bisphenol A (BPA), as well as advanced glycation end products (AGEs).[17] The

majority of human exposure is through food packaging, however, these molecules are also used
 ACCEPTED MANUSCRIPT

in the production of medical devices. EDCs have been implicated in many disorders involving

disordered male and female reproduction, abnormal breast development and cancer, prostate

cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular

PT
endocrinology.[16]

RI
Timing of exposure is of utmost importance, with evidence that fetuses and young children are

SC
the most susceptible to the adverse effects of EDCs.[16,18,19] Animal studies have shown that

prenatal exposures to high levels of androgens during key points in gestation result in fetal

U
AN
programming of PCOS traits.[20,21] Parallels have been drawn, therefore, that exposure to

androgen-like EDCs could result in metabolic dysfunction in adulthood, such as PCOS.[16] Adult
M

exposures to EDCs may also be contributing to endocrine disruption in women with PCOS.

Women with PCOS have been found to have higher levels of EDCs compared to ovulatory
D

women.[22,23]
TE

Diagnosis
EP

Evolution of Diagnostic Criteria

PCOS presents a unique diagnostic challenge in the field of gynecology, which is further
C

complicated in the adolescent population. By its nature as a syndrome, PCOS is a collection of

AC

findings, both clinical and diagnostic, as well as a diagnosis of exclusion among other androgen

excess disorders. The characterization of a patient with PCOS is made difficult by a history of

variable and contradictory diagnostic criteria. Increasingly, a system of phenotypic description

of the spectrum of PCOS has been proposed to standardize and aid in diagnosis.
 ACCEPTED MANUSCRIPT

In 1990, the first guidelines for PCOS diagnosis were proposed at a conference sponsored by

the National Institute of Child Health and Human Disease of the US National Institutes of Health

PT
(NIH). A panel of experts concluded that two criteria were essential for the diagnosis of PCOS:

(1) hyperandrogenism and (2) oligoovulation. This remained the sole diagnostic criteria until the

RI
proposal of the “Rotterdam Criteria” in 2003.[24] This updated guideline concluded that for

SC
diagnosis, two of three criteria must be met: (1) signs of clinical or biochemical

hyperandrogenism (2) oligo/anovulation and/or (3) polycystic ovaries. (Table 1) With the

U
addition of the radiologic findings, a new cohort of patients was included in the diagnosis of
AN
PCOS: women with oligo/anovulation and polycystic ovaries, but with no evidence of

hyperandrogenism. The establishment of this criteria significantly increased the prevalence of

M

PCOS, as well as the variability of phenotype in the patient population.

D
TE

In 2006, the Androgen Excess Society released their own guideline proposing that
EP

hyperandrogenism is a requisite component for the diagnosis of PCOS, with the addition of

either ovulatory dysfunction or polycystic ovaries.[25,26] They proposed that patients without
C

hyperandrogenism who met the Rotterdam criteria did not truly represent the same
AC

pathophysiology and should therefore be excluded. The resulting discord temporarily stalled

academic investigation and created clinical confusion regarding the diagnosis of PCOS.
 ACCEPTED MANUSCRIPT

In an attempt to reconcile the proposed criteria, the NIH sponsored an Evidence-Based

Methodology PCOS Workshop in 2012.[27] The resulting recommendations reinforced the use

of the 2003 Rotterdam criteria, but with the addition of a phenotypic classification system to

PT
aid in clinical classification and epidemiologic research. This reinforced the core diagnostic

criteria of PCOS to include (1) clinical/biochemical hyperandrogenism (HA) (2) chronic ovulatory

RI
dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). (Table 2) The broadened term

SC
of ovulatory dysfunction contained the previously recognized oligoovulation, but also included

polymenorrhea and abnormal uterine bleeding. As a result of the introduction and broad usage

U
of the phenotypic system, strides in epidemiologic research have been made to further
AN
characterize the risks and long term health effects of PCOS, including reproductive

abnormalities, endometrial hyperplasia and malignancy, insulin resistance and type 2 diabetes
M

mellitus, coronary heart disease, dyslipidemia and cerebrovascular morbidity, and

D

anxiety/depression.
TE
EP

In 2016, Lizneva et al further refined the phenotypic approach.[28] They proposed three PCOS

phenotypes based on the 2012 modified Rotterdam criteria: “Classic” PCOS (phenotypes A/B),
C

“Ovulatory PCOS” (phenotype C), and “Nonhyperandrogenic PCOS” (phenotype D). (Table 2)
AC

“Classic PCOS” accounted for more than 2/3 of women diagnosed with PCOS in their study.

Compared to the other phenotypes, women with “Classic PCOS” appeared to have more severe

symptoms, as well as an increased risk of significant long term health effects such as

pronounced menstrual dysfunction, higher rates of insulin resistance, higher prevalence of

 ACCEPTED MANUSCRIPT

obesity and more severe dyslipidemia.[28] Women with “Ovulatory PCOS” had an intermediate

severity of symptoms and long term health risks, while women with “Nonhyperandrogenic

PCOS” had the mildest symptoms and smallest long term health risks, though still present. This

PT
system more accurately represents PCOS as a true spectrum of findings with variable severity

and long term health effects. As research continues, more accurate and patient-specific

RI
counseling regarding these factors will be possible.

SC
Diagnosis of PCOS in Adolescents

As noted above, the diagnosis of PCOS is established by the presence of two out of three of the

U
following criteria: (1) signs of clinical or biochemical hyperandrogenism (HA) (2) chronic
AN
ovulatory dysfunction (OD) and (3) polycystic ovarian morphology (PCOM). However, the

adolescent population requires special consideration, as these criteria were developed for
M

diagnosis in adults; during adolescence, PCOS can present differently.

D
TE

Laboratory Evaluation

The most prevalent characteristic seen in adolescents is hyperandrogenism.[29] Contrary to the

EP

adult population, the sole presence of acne and/or hirsutism should not be considered clinical
C

evidence of hyperandrogenism in adolescent girls. However, more severe cases of such clinical
AC

findings could be an indication of hyperandrogenism. For example, comedal acne and mild

hirsutism is common in all adolescent females. Moderate-severe inflammatory acne (defined as

more than 11 inflammatory lesions) unresponsive to topical medications and moderate-severe

hirsutism (based on Ferriman-Gallwey scoring system) would be an indication to initiate testing

for hyperandrogenism.[30]
 ACCEPTED MANUSCRIPT

Biochemical assessment of hyperandrogenism requires reliable assays with well-defined cut

offs. Measurements of serum testosterone levels are recommended as the initial step in

PT
evaluating hyperandrogenism.[29] Free testosterone is the bioactive portion of serum total

testosterone, making it the most sensitive indicator for elevated androgen levels. The

RI
circulating level of free testosterone is governed by sex hormone binding globulin (SHBG) which

SC
is affected by several physiological conditions. Other serum androgens such as

androstenedione and DHEA-S are widely measured, but the cost effectiveness of routinely

U
measuring an extensive array of androgens has not been well substantiated.[30] Shortly after
AN
menarche, serum testosterone reaches adult levels, making use of adult reference ranges

appropriate.[30] There are several factors that make the interpretation of these lab results
M

challenging, however. This includes lack of testosterone assay standardization among hospitals
D

and laboratories as well as lack of sensitivity, specificity, and accuracy of the assays used.
TE

Clinical Symptoms

Irregular menses and anovulatory cycles can be seen in the early stages of normal maturation
EP

of the hypothalamic-pituitary-ovarian axis. In the first year after menarche, approximately 85%

of menstrual cycles are anovulatory, dropping to 25% six years after menarche.[29]
C

Nevertheless, approximately two-thirds of adolescents with PCOS will present with menstrual
AC

symptoms. While difficult to differentiate oligomenorrhea due to PCOS from that of normal

physiology, cycles outside 19 to 90 days, lack of menses by 16 years or 2-3 years after thelarche,

and persistent oligomenorrhea 2 years beyond menarche require further evaluation.[30]

 ACCEPTED MANUSCRIPT

It is critical to keep in mind that PCOS is a diagnosis of exclusion. Evaluation of women with

suspected PCOS should exclude alternative disorders that can lead to androgen excess such as

androgen-secreting tumors, either in the adnexa or adrenal glands, or congenital adrenal

PT
hyperplasia. There is agreement that screening for non-classic congenital adrenal hyperplasia

(NCCAH) is prudent in women presenting with symptoms of PCOS. NCCAH accounts for 1-4% of

RI
patients with hyperandrogenic anovulation in reproductive age women.[30] Follicular phase 17-

SC
OHP levels should be the initial screening tool in these patients. Levels higher than 200 ng/dL

are concerning for NCCAH, with a 92-98% sensitivity.[30] Such a finding should be confirmed

U
with an ACTH stimulation test. For patients with rapid progression of central obesity, hirsutism,
AN
or hypertension, Cushing syndrome should be considered. Late-night salivary cortisol, 24-hour

urinary free cortisol excretion, or an overnight 1 mg dexamethasone suppression test are

M

appropriate screening tests for Cushing syndrome. Screening for hypothyroidism and
D

hyperprolactinemia are also recommended as they can present with menstrual irregularity.[30]
TE

The extent of evaluation and screening should be individualized based on patient presentation

and associated symptomatology.

EP

Imaging
C

In the adult population, the role of imaging in diagnosing PCOS has been well established.
AC

Histopathologically, polycystic ovarian morphology (PCOM) is due to an excess number of small

follicles that arrest before the preovulatory stage of development. PCOM is defined as an antral

follicle count (follicles measuring 2-9mm) ≥12 in at least one ovary or an ovarian volume of

>10.0 cm3.[24] However, ovaries with multiple follicles are normal and commonly seen around

the time of menarche; approximately 50% of normal adolescents would meet the criteria of
 ACCEPTED MANUSCRIPT

polycystic ovarian morphology.[31] Furthermore, anovulatory cycles due to inconsistent

recruitment of a dominant follicle in the early years post menarche can contribute to the

multifollicular appearance of the ovaries characteristically seen during puberty.[32]

PT
In the adolescent population, the diagnosis of PCOS should not be based solely upon the

RI
symptoms of anovulation and polycystic-appearing ovaries on ultrasound, particularly within

SC
two years of menarche.[29] The Endocrine Society guidelines caution against the use of PCOM

as diagnostic criteria for adolescents.[29] However, imaging can be used as a confirmatory test

U
for adolescents in whom the diagnosis of PCOS remains uncertain after clinical and laboratory
AN
evaluation.
M

Ultrasound. Transvaginal ultrasound (TVUS) is the modality of choice for evaluation of pelvic
D

anatomy in the adult female population. (Figure 1) While optimal for evaluating pelvic anatomy,
TE

careful consideration should be taken prior to attempting a transvaginal ultrasound in an

adolescent, particularly if she is virginal. Alternatively, performing a transabdominal ultrasound

EP

(TAUS) in an obese adolescent is technically challenging and often does not provide reliable

imaging of the ovaries.[33] As a result, an antral follicle count it difficult to define by this
C

modality.[32]
AC

Magnetic Resonance Imaging (MRI). Compared to ultrasound, MRI in the adolescent

population provides the most accurate view of the ovaries. (Figure 2) This modality has the

advantage of being accessible for all ages given its noninvasive nature. In a study comparing
 ACCEPTED MANUSCRIPT

obese adolescents with PCOS to obese adolescents without PCOS, it was demonstrated that

MRI findings using Rotterdam criteria had a specificity of 77-82%.[34] In patients with uncertain

clinical and laboratory findings, MRI can be considered as an accurate diagnostic imaging

PT
modality. However, MRI is significantly more expensive than ultrasound making routine

ordering impractical. Additionally, normal values and cutoffs for its use in this instance are not

RI
well established.

SC
MANAGEMENT

U
Management of PCOS in adolescents is multimodal, requiring consideration of lifestyle
AN
modification as well as pharmacotherapy.
M

Lifestyle modification
D

Approximately 50% of patients with PCOS are overweight or obese, which is an important
TE

association as obesity itself is linked to an increased risk for type 2 diabetes, hypertension,

cardiovascular disease, and menstrual dysfunction.[4,35,36] Lifestyle modification comprised

EP

primarily of a calorie-restricted diet and/or physical activity has proven effective in altering the

disease course in PCOS.[29] Studies comparing exercise as an intervention to treat PCOS

C

typically recommend 30 to 45 minutes of vigorous exercise 3 times per week.[37,38]

AC

A meta-analysis of 583 PCOS patients demonstrated improvement in fasting glucose and insulin

levels in patients undergoing lifestyle modification, which was comparable to patients who

were treated with metformin.[35] Likewise, in a randomized trial comprised of 150 women with
 ACCEPTED MANUSCRIPT

PCOS, improved insulin sensitivity indices were demonstrated in women who participated in a

6-month structured exercise training program. Compared to baseline, these women

demonstrated improvement in intima media thickness (a cardiovascular marker predisposing to

PT
atherosclerosis), lipid profile, cardiopulmonary function, and frequency of menses.[37]

RI
In 2013, guidelines set forth by an Endocrine Society-appointed Task Force of experts

SC
recommended lifestyle modification, with an objective of weight loss, as a first-line treatment

for adolescent PCOS patients in the presence of overweight/obesity.[29] In normal weight

U
women with PCOS, it is still unclear as to whether lifestyle modification will improve some
AN
aspects of the PCOS phenotype.[35] Consensus guidelines caution that for these women,

weight loss therapy alone is likely insufficient.[29]

M
D

While there are few studies that have examined the effects of lifestyle modification in
TE

adolescents with PCOS, the results appear promising. A randomized, placebo-controlled trial

was performed to evaluate the impact of multiple treatment modalities on PCOS in obese
EP

adolescent girls ages 12-18. One arm of this trial randomized 43 patients to a single

intervention including metformin, placebo, a lifestyle modification program, or combined oral

C

contraceptives (COC). With lifestyle modification alone, there was a 59% reduction in free
AC

androgen index (FAI) and 122% increase in SHBG.[38] Another prospective study sought to

analyze the impact of a 1 year lifestyle intervention on menstrual irregularity,

hyperandrogenism, cardiovascular risk factors and intima-media thickness in obese adolescent

girls with PCOS aged 12-18 years. Of the 59 patients who completed the intervention at 1 year,
 ACCEPTED MANUSCRIPT

26 patients had weight loss (reduction in BMI by mean 3.9 kg/m2), while 33 patients did not

have weight loss. Researchers found that in the cohort with weight loss, the prevalence of

amenorrhea and oligomenorrhea decreased by 42% and 19%, respectively. Additionally, this

PT
cohort also had significantly decreased testosterone concentrations and increased SHBG

concentrations compared to patients without weight loss.[39]

RI
SC
It should be acknowledged that the adolescent population presents a challenge in regard to

compliance with a diet and exercise regimen. Previous studies have utilized cohorts of

U
adolescents and one support person, typically a parent, who attended classes instructing them
AN
in diet, exercise, and behavioral changes.[38] Greater success was seen when adolescents were

encouraged to correspond outside of the instructional settings.[38] Social media can be utilized
M

to connect adolescents and encourage continued lifestyle changes after the intervention time
D

period has ended.

TE

Medical Therapy
EP

Combined hormonal contraceptives (CHCs). Combined hormonal contraceptives (CHCs), which

contain both an estrogen (ethinyl estradiol) and a progestin, have traditionally been the first-
C

line therapy for adolescents diagnosed with PCOS. Combined oral contraceptives (COCs) are
AC

most commonly prescribed; however, other routes of delivery are available, including the patch

or vaginal ring. There is no evidence to suggest one delivery method is superior to the other,

making patient preference an appropriate guide. There is also limited data to recommend the

duration of CHC use in adolescents.[40] It is imperative to screen for contraindications prior to

 ACCEPTED MANUSCRIPT

employing CHCs as a treatment strategy for PCOS. For example, certain comorbidities such as

prior history of deep venous thromboembolism/pulmonary embolism or migraine headaches

with aura would make estrogen-containing therapies contraindicated.[41]

PT
In appropriately selected patients, CHCs convey multiple benefits for an adolescent with PCOS.

RI
CHCs have an anti-androgenic effect. The estrogen component acts to increase SHBG, which

SC
reduces the bioavailable testosterone by binding the free steroid, ultimately decreasing

symptoms of androgen excess. The progestin suppresses LH levels, leading to a downstream

U
decrease in ovarian androgen production. Progestins additionally inhibit 5α-reductase activity,
AN
resulting in less peripheral conversion of testosterone to dihydrotestosterone (DHT), the

androgen most responsible for hirsutism.[42] In a study that compared exercise to CHCs in
M

patients with PCOS, hirsutism, serum free testosterone, and FAI were significantly decreased in
D

the CHC group (p<0.05).[37] While some progestins, such as drosperinone, have intrinsic
TE

antiandrogenic properties, the concentration of progestin in CHCs is low. In randomized

studies, clinical benefit of anti-androgenic progestins have not been significant when compared
EP

to other forms of progestin.[43]

C

CHCs also result in menstrual regulation and endometrial protection. Adolescents with PCOS
AC

frequently have irregular and heavy menstrual cycles, which can be disruptive to their daily life.

Placing them on a form of CHC can act to regulate their cycles, leading to more predictable and

lighter periods. PCOS is often a cause of primary amenorrhea, and for girls with evidence of

hyperandrogenism who demonstrate advanced stages of pubertal development (e.g. Tanner

 ACCEPTED MANUSCRIPT

Stage IV breast development) but have not yet begun to menstruate, the recommendation is to

start CHCs.[29] Adolescents who are sexually active have the secondary benefit of a

contraceptive method. If delivered orally, however, it requires responsibility on the part of the

PT
patient to be compliant with a daily pill.

RI
CHCs can also improve a patient’s lipid profile. While no data are available for long-term effects,

SC
in the short term, an increase in HDL cholesterol is a favorable aspect of the estrogen

component of CHCs. Total cholesterol and LDL-cholesterol are decreased for users of CHCs.[37]

U
AN
Metformin. Metformin is another commonly prescribed medication for adolescents with PCOS.

Metformin is a biguanide commonly used to treat Type 2 Diabetes Mellitus, which acts to
M

decrease glucose production in the liver and increase the sensitivity of peripheral tissue to
D

insulin.[44,45] Studies are limited for long-term use in adolescents. Metformin’s largest impact
TE

is improvement in glucose tolerance and other components of the metabolic syndrome that

can be seen in both obese and non-obese adolescents with PCOS. Approximately 18-24% of
EP

adolescents with PCOS have abnormal glucose metabolism.[46]

C

The role of metformin in the management of PCOS was evaluated in a small, randomized
AC

placebo-controlled trial. Seventy-nine obese adolescents were randomized to a single

treatment trial of various interventions on clinical and laboratory characteristics seen in PCOS

patients. Interventions included Metformin, COCs, lifestyle modification and placebo alone.
 ACCEPTED MANUSCRIPT

With metformin, there was a significant difference from baseline in improving triglycerides and

fasting blood glucose, though notably, COCs were more effective.

PT
Menstrual regularity is also improved with metformin therapy in adolescents. In individuals

who have a contraindication to CHCs, metformin is an excellent second line option for

RI
improvement in irregular cycles, though it does not exert any anti-androgen effects and will not

SC
significantly improve hirsutism or acne.[29]

U
Spironolactone. Spironolactone is another adjunctive medication used to treat those with PCOS
AN
and hirsutism. This drug is an aldosterone-antagonist diuretic. Its mechanism of action includes

inhibiting ovarian and adrenal biosynthesis of androgens, directly competing for the androgen
M

receptor in the hair follicle and inhibiting 5α-reductase activity.[47] Effects are dose-dependent
D

and occur over about six months of treatment. Side effects are common, and low doses (25
TE

mg/day) are recommended to minimize hypotension, tachycardia and vaginal spotting.[48] This

medication should not be used in adolescents with hyperkalemia or with other drugs that
EP

increase the level of potassium, but monitoring is not required in those with normal renal

function. An effective form of contraception is essential given the risk for fetal virilization with
C

spironolactone if pregnancy were to occur. To date, no studies have evaluated this medication
AC

in the adolescent population; however, studies in adults have shown significant beneficial

effects in reducing DHEAS level and hirsutism score with the addition of low-dose

spironolactone to patients with PCOS already taking metformin.[48]

 ACCEPTED MANUSCRIPT

The authors’ recommendation for treatment would be to take a shared decision-making

approach with the adolescent and their guardian as appropriate. Discussion should focus on

which symptoms are most bothersome to the patient in order to determine the optimal

PT
treatment approach. Clinicians must also recognize that PCOS is a metabolic process and

comprehensive treatment will target underlying glucose intolerance and weight loss. Exercise

RI
and dietary modifications should always be encouraged as a primary treatment with adjunctive

SC
pharmacologic modalities as appropriate.

U
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

SUMMARY

Polycystic ovary syndrome (PCOS) is a heterogenous condition that typically manifests with a

combination of menstrual dysfunction and hyperandrogenism in the adolescent population.

PT
The etiology is unclear but evidence suggests a combination of genetic, metabolic and

environmental factors. Ovarian androgen production is disordered, leading to increased

RI
synthesis of testosterone in proportion to estrogen. Insulin resistance can affect the hormonal

SC
milieu and contribute to arrest of follicular maturation, which is accentuated in obese

adolescents. Diagnosis of PCOS is challenging in adolescents as the immaturity of the

U
hypothalamic-pituitary access and other normal pubertal changes present similarly to an
AN
adolescent with PCOS.
M

Optimal treatment utilizes a multi-modal approach, incorporating lifestyle changes and exercise
D

in both the obese and non-obese adolescent. Pharmacologic therapies can address bothersome
TE

symptoms associated with PCOS. CHCs are utilized for menstrual regulation and also benefit the

adolescent by decreasing testosterone levels through a rise in sex hormone binding globulin.
EP

Metabolic dysfunction can be mitigated with metformin, which demonstrates weight loss and

improved glucose tolerance in its users in randomized trials. Spironolactone can aid in the
C

treatment of hirsutism and acne.

AC
 ACCEPTED MANUSCRIPT

ACKNOWLEDGEMENTS:

Ultrasound images: Kathleen Gustafson, Supervisor, Imaging Services, Magee-Womens Hospital of

UPMC

MRI images: Christiane Hakim, MD, Department of Radiology, Magee-Womens Hospital of UPMC

PT
CONFLICT OF INTEREST STATEMENT:

RI
Stephanie Rothenberg, MD – Conflicts of interest: None

Emily Barnard, DO – Conflicts of interest: None

SC
Rachel Beverley, MD – Conflicts of interest: None

Massoud Baradaran-Shoraka, BS – Conflicts of interest: None

U
Joseph Sanfilippo, MD, MBA – Conflicts of interest: None
AN
M

PRACTICE POINTS:

• Anovulation and polycystic ovarian morphology can be normal in young women.

D

• Diagnosis of PCOS in adolescents should be made with persistent oligomenorrhea and evidence
TE

of hyperandrogenism
• Other disorders that lead to androgen excess should be considered and excluded prior to
diagnosing PCOS
• In the adolescent population, the diagnosis of PCOS should not be based solely upon polycystic-
EP

appearing ovaries on ultrasound, particularly within two years of menarche. Imaging can be
used as a confirmatory test but should not be the first step of evaluation.
• Exercise and dietary modifications should always be encouraged as primary and adjunctive
C

treatment to pharmacologic therapies.

•
AC

First line medical therapy includes combined hormonal contraceptives. In select populations,
spironolactone and metformin can be considered
 ACCEPTED MANUSCRIPT

RESEARCH AGENDA:

-Relationship between obesity and development of PCOS

-Relationship between endocrine disrupting chemicals and PCOS

-Long term risk factors for PCOS based on phenotype

PT
-Long term cardiovascular and metabolic outcomes in women diagnosed with PCOS as adolescents

-Normal values and cutoffs for MRI evaluation of the ovaries

RI
-The benefit of lifestyle modification in normal weight adolescents with PCOS

SC
-Effects of long term use of metformin in adolescents with PCOS

-Efficacy and safety profile of spironolactone in adolescents with PCOS

U
AN
M

REFERENCES:

1. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The
hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews. 2016.
D

2. Nelson VL, Legro RS, Strauss JF, McAllister JM. Augmented androgen production is a stable
TE

steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol.
1999;13(6):946–57.

3. Franks S. PEDIATRIC REVIEW Polycystic ovary syndrome in adolescents. Int J Obes.

EP

2008;32(10):1035–104161.

4. Anderson AD, Solorzano CMB, McCartney CR. Childhood obesity and its impact on the
development of adolescent PCOS. Semin Reprod Med. 2014;
C

5. BURGHEN GA, GIVENS JR, KITABCHI AE. Correlation of Hyperandrogenism with Hyperinsulinism in
AC

Polycystic Ovarian Disease*. J Clin Endocrinol Metab. 1980;50(1):113–6.

6. Chang RJ, Nakamura RM, Judd HL, Kaplan S a. Insulin resistance in nonobese patients with
polycystic ovarian disease. J Clin Endocrinol Metab. 1983;57(2):356–9.

7. Dunaif A, Segal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action
in polycystic ovary syndrome. Diabetes. 1992;41(10):1257–66.

8. Ehrmann DA, Sturis J, Byrne MM, et al. Insulin secretory defects in polycystic ovary syndrome.
Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J
Clin Invest. 1995;96(1):520–7.
 ACCEPTED MANUSCRIPT

9. Nestler JE. Insulin regulation of human ovarian androgens. Hum Reprod [Internet]. 1997;12 Suppl
1:53–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9403321

*10. Rojas J, Chávez M, Olivar L, et al. Polycystic Ovary Syndrome, Insulin Resistance, and Obesity:
Navigating the Pathophysiologic Labyrinth. Int J Reprod Med. 2014;

11. McCartney CR, Blank SK, Prendergast KA, et al. Obesity and sex steroid changes across puberty:
Evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol

PT
Metab. 2007;92(2):430–6.

12. McCartney CR, Prendergast KA, Chhabra S, et al. The association of obesity and

RI
hyperandrogenemia during the pubertal transition in girls: Obesity as a potential factor in the
genesis of postpubertal hyperandrogenism. J Clin Endocrinol Metab. 2006;91(5):1714–22.

13. Reinehr T, de Sousa G, Roth CL, Andler W. Androgens before and after weight loss in obese

SC
children. J Clin Endocrinol Metab. 2005;90(10):5588–95.

14. Zhao H, Lv Y, Li L, Chen Z-J. Genetic Studies on Polycystic Ovary Syndrome. Best Pract Res Clin
Obstet Gynaecol. 2016;37:56–65.

15.
U
Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Prim [Internet].
AN
2016;2:16057. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27510637

16. Diamanti-Kandarakis E, Bourguignon J-P, Giudice LC, et al. Endocrine-Disrupting Chemicals: An

Endocrine Society Scientific Statement. Endocr Rev [Internet]. 2009;30(4):293–342. Available
M

from: http://press.endocrine.org/doi/abs/10.1210/er.2009-0002

*17. Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syndrome and environmental toxins. Vol.
D

106, Fertility and Sterility. 2016. p. 948–58.

18. Beckman U, Binderup M, Bolognesi C, et al. Scientific Opinion on the risks to public health related
TE

to the presence of bisphenol A (BPA) in foodstuffs. EFSA J [Internet]. 2015;13(1):3978. Available

from: http://doi.wiley.com/10.2903/j.efsa.2015.3978

19. Testai E, Hartemann P, Rastogi SC, et al. The safety of medical devices containing DEHP
EP

plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update).
Vol. 76, Regulatory Toxicology and Pharmacology. 2016. p. 209–10.

20. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental
C

origins. Rev Endocr Metab Disord [Internet]. 2007;8(2):127–41. Available from:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2935197&tool=pmcentrez&rendert
AC

ype=abstract

21. Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female
reproduction: A developmental aetiology for polycystic ovary syndrome? Vol. 11, Human
Reproduction Update. 2005. p. 357–74.

22. Takeuchi T, Tsutsumi O, Ikezuki Y, et al. Positive relationship between androgen and the
endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction.
Endocr J. 2004;51(2):165–9.
 ACCEPTED MANUSCRIPT

23. Diamanti-Kandarakis E, Katsikis I, Piperi C, et al. Increased serum advanced glycation end-
products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin
Endocrinol (Oxf). 2008;69(4):634–41.

*24. Fauser BCJM. Revised 2003 consensus on diagnostic criteria and long-term health risks related to
polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.

25. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the

PT
polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456–88.

26. Azziz R, Carmina E, Dewailly D, et al. Position statement: Criteria for defining polycystic ovary

RI
syndrome as a predominantly hyperandrogenic syndrome: An androgen excess society guideline.
Vol. 91, Journal of Clinical Endocrinology and Metabolism. 2006. p. 4237–45.

*27. Timothy R.B. Johnson, M.D., FACOG, Lorrie Kline Kaplan, CAE, Pamela Ouyang, M.B.B.S., Robert

SC
A. Rizza MD. National Institues of Health, Evidence-based Methodology Workshop on Polycystic
Ovary Syndrome December 3-5, 2012. Executive Summary [Internet]. Centers for Medicare &.
2012. Available from: http://nefmc.org/herring/meetsum/herring_may12_ap.pdf

U
*28. Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic ovary
syndrome. Vol. 106, Fertility and Sterility. 2016. p. 6–15.
AN
29. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and Treatment of Polycystic Ovary
Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2013;
M

30. Rosenfield RL. The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics [Internet].
2015;136(6):1154–65. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/26598450%5Cnhttp://pediatrics.aappublications.org/cgi/
D

doi/10.1542/peds.2015-1430

31. Bridges NA, Cooke A, Healy MJ, et al. Standards for ovarian volume in childhood and puberty.
TE

Fertil Steril. 1993;60(3):456–60.

32. Youngster M, Ward VL, Blood EA, et al. Utility of ultrasound in the diagnosis of polycystic ovary
syndrome in adolescents. Fertil Steril. 2014;102(5):1432–8.
EP

33. Shayya R, Chang RJ. Reproductive endocrinology of adolescent polycystic ovary syndrome. Vol.
117, BJOG: An International Journal of Obstetrics and Gynaecology. 2010. p. 150–5.
C

*34. Kenigsberg LE, Agarwal C, Sin S, et al. Clinical utility of magnetic resonance imaging and
ultrasonography for diagnosis of polycystic ovary syndrome in adolescent girls. Fertil Steril.
AC

2015;104(5):1302–1309.e4.

*35. Domecq JP, Prutsky G, Mullan RJ, et al. Lifestyle Modification Programs in Polycystic Ovary
Syndrome: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2013;

36. Cattrall FR, Healy DL. Long-term metabolic, cardiovascular and neoplastic risks with polycystic
ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;

37. Orio F, Muscogiuri G, Giallauria F, et al. Oral contraceptives versus physical exercise on
cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a
 ACCEPTED MANUSCRIPT

randomized controlled trial. Clin Endocrinol (Oxf). 2016;

*38. Hoeger K, Davidson K, Kochman L, et al. The Impact of Metformin, Oral Contraceptives, and
Lifestyle Modification on Polycystic Ovary Syndrome in Obese Adolescent Women in Two
Randomized, Placebo-Controlled Clinical Trials. J Clin Endocrinol Metab. 2008;

*39. Lass N, Kleber M, Winkel K, et al. Effect of lifestyle intervention on features of polycystic ovarian
syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin

PT
Endocrinol Metab. 2011;96(11):3533–40.

40. Pfeifer SM, Kives S. Polycystic Ovary Syndrome in the Adolescent. Vol. 36, Obstetrics and

RI
Gynecology Clinics of North America. 2009. p. 129–52.

*41. Powers BJ, Brown G, Williams RW, Speers W. Medical eligibility criteria for contraceptive use.
World Heal Organ. 2015;87(5):276.

SC
42. Cassidenti DL, Paulson RJ, Serafini P, et al. Effects of sex steroids on skin 5 alpha-reductase
activity in vitro. Obstet Gynecol [Internet]. 1991;78(1):103–7. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/1828548

43.
U
van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral
AN
Contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea.
Cutis. 2002;69(4 Suppl):2–15.

44. Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic

M

glucose production and stimulation of glucose uptake in type 2 diabetes: A systematic review.
Vol. 49, Diabetologia. 2006. p. 434–41.
D

45. Foretz M, Guigas B, Bertrand L, et al. Metformin: From mechanisms of action to therapies. Vol.
20, Cell Metabolism. 2014. p. 953–66.
TE

46. Gooding HC, Milliren C, St. Paul M, et al. Diagnosing dysglycemia in adolescents with polycystic
ovary syndrome. J Adolesc Heal. 2014;55(1):79–84.

47. Fritz M, Speroff L. Clinical Gynecologic Endocrinology and Infertility, 8th Edition. Philadelphia:
EP

Lippincott Williams & Wilkins; 2011. 560 p.

48. Mazza A, Fruci B, Guzzi P, et al. In PCOS patients the addition of low-dose spironolactone induces
a more marked reduction of clinical and biochemical hyperandrogenism than metformin alone.
C

Nutr Metab Cardiovasc Dis. 2014;24(2):132–9.

AC
 ACCEPTED MANUSCRIPT

ESRE/ASRM 2003 Diagnostic Criteria for PCOS [24]

PT
“Rotterdam Criteria”
Patient must meet 2 out of 3 criteria

RI
(1) Oligo- or anovulation

SC
(2) Clinical and/or biochemical signs of hyperandrogenismi

U
AN
(3) Polycystic ovariesii and exclusion of other etiologiesiii

M
i- Hirsutism, severe acne and/or elevation of total/free testosterone or DHEA-S
ii- Presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume (>10cm3)

D
iii- Including congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome

TE
C EP
AC
 ACCEPTED MANUSCRIPT

The Phenotypic System of PCOS Diagnosis

PT
NIH 2012 extension of ESHRE/ASRM Lizneva 2016 [28]

RI
2003 [27]

SC
Phenotype A: HA + OD + PCOM
“Classic” PCOS

U
Phenotype B: HA + OD

AN
Phenotype C: HA + PCOM “Ovulatory” PCOS

M
Phenotype D: OD +PCOM “Nonhyperandrogenic” PCOS

D
TE
HA: clinical and/or biochemical hyperandrogenism
OD: ovulatory dysfunction
PCOM: polycystic ovarian morphology
C EP
AC
 ACCEPTED MANUSCRIPT

Ultrasound appearance of polycystic ovaries

PT
RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

MRI appearance of polycystic ovaries

PT
RI
U SC
AN
M
D
TE
EP
C
AC

Images courtesy of
 ACCEPTED MANUSCRIPT

• PCOS is a metabolic disorder

• The pathophysiology of PCOS is multifactorial
• Diagnosis in adolescents requires persistent oligomenorrhea and hyperandrogenism
• Exercise and dietary modifications are considered first line therapy in obese PCOS patients
• Medical therapy includes combined hormonal contraceptives, spironolactone and metformin

PT
RI
U SC
AN
M
D
TE
C EP
AC
 Clinical Practice
HOR MONE Horm Res Paediatr Received: May 22, 2017
RESEARCH I N DOI: 10.1159/000479371 Accepted: July 10, 2017
Published online: November 13, 2017
PÆDIATRIC S

An International Consortium Update:

Pathophysiology, Diagnosis, and Treatment of
Polycystic Ovarian Syndrome in Adolescence
Lourdes Ibáñez a, b Sharon E. Oberfield c Selma F. Witchel d Richard J. Auchus e R. Jeffrey Chang f
         

Ethel Codner g Preeti Dabadghao h Feyza Darendeliler i Nancy Samir Elbarbary j

       

Alessandra Gambineri k Cecilia Garcia Rudaz l Kathleen M. Hoeger m Abel López-Bermejo n

       

Ken Ong o Alexia S. Peña p Thomas Reinehr q Nicola Santoro r Manuel Tena-Sempere s

         

Rachel Tao t Bulent O. Yildiz u Haya Alkhayyat v Asma Deeb w Dipesalema Joel x

         

Reiko Horikawa y Francis de Zegher z Peter A. Lee A

     

a Endocrinology,
Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain; and bCIBERDEM, ISCIII, Madrid, Spain; c Division of  

Pediatric Endocrinology, CUMC, New York-Presbyterian Morgan Stanley Children’s Hospital, New York, NY, USA;
d Division of Pediatric Endocrinology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA; eUniversity of
 

Michigan, MSRBII, Ann Arbor, MI, USA; f Department of Reproductive Medicine, UCSD School of Medicine, La Jolla, CA,
 

USA; g Institute of Maternal and Child Research, University of Chile, School of Medicine, Santiago, Chile; h Department of
   

Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; i Istanbul Tıp Fakültesi, Çocuk  

Kliniği, Istanbul, Turkey; j Ain Shams University, Cairo, Faculty of Medicine, Cairo, Egypt; k Department of Medical and
   

Surgical Sciences, University of Bologna, Bologna, Italy; l Division of Women, Youth and Children, Australian National
 

University, Canberra, ACT, Australia; m Department of OBGYN, University of Rochester Medical Center, Rochester, NY,
 

USA; n Pediatric Endocrinology, Hospital de Girona Dr. Josep Trueta, Girona, Spain; o MRC Epidemiology Unit, University
   

of Cambridge, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK; p Women’s and Children’s  

Hospital, North Adelaide, SA, Australia; q University of Witten/Herdecke, Vestische Kinder- und Jugendklinik, Pediatric
 

Endocrinology, Diabetes, and Nutrition Medicine, Datteln, Germany; r Pediatrics, Yale School of Medicine, New Haven, CT,
 

USA; s University of Córdoba, Edificio IMIBIC, Córdoba, Spain; t Division of Pediatric Endocrinology, CUMC,
   

New York-Presbyterian Morgan Stanley Children’s Hospital, New York, NY, USA; u Department of Internal Medicine,  

Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey; v Medical University  

of Bahrain, BDF Hospital, Riffa, Kingdom of Bahrain; w Mafraq Hospital, Abu Dhabi, UAE; x Department of Paediatrics and
   

Adolescent Health, University of Botswana Teaching Hospital, Gaborone, Botswana; y Endocrinology and Metabolism,  

National Center for Child Health and Development, Tokyo, Japan; z Department Pediatrics, University Hospital
 

Gasthuisberg, Leuven, Belgium; A Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
 

Keywords Abstract
Polycystic ovary syndrome · Polycystic ovarian morphology · This paper represents an international collaboration of pae-
Hyperinsulinism · Hirsutism · Menstrual irregularities · diatric endocrine and other societies (listed in the Appendix)
Obesity · Insulin sensitizers · Anti-androgen under the International Consortium of Paediatric Endocrinol-
ogy (ICPE) aiming to improve worldwide care of adolescent
girls with polycystic ovary syndrome (PCOS)1. The manu-
L.I., S.E.O., and S.F.W. contributed equally and should be considered script examines pathophysiology and guidelines for the di-
to be first authors. agnosis and management of PCOS during adolescence. The

© 2017 S. Karger AG, Basel Peter A. Lee, MD, PhD

Department of Pediatrics, Penn State College of Medicine
500 University Drive
E-Mail karger@karger.com
Hershey, PA 17033 (USA)
www.karger.com/hrp E-Mail plee @ psu.edu
complex pathophysiology of PCOS involves the interaction
of genetic and epigenetic changes, primary ovarian abnor- 1,200
malities, neuroendocrine alterations, and endocrine and 1,100
metabolic modifiers such as anti-Müllerian hormone, hyper- 1,000
900

Number of citations
insulinemia, insulin resistance, adiposity, and adiponectin
levels. Appropriate diagnosis of adolescent PCOS should in- 800
clude adequate and careful evaluation of symptoms, such as 700
600
hirsutism, severe acne, and menstrual irregularities 2 years
500
beyond menarche, and elevated androgen levels. Polycystic
400
ovarian morphology on ultrasound without hyperandrogen-
300
ism or menstrual irregularities should not be used to diag- 200
nose adolescent PCOS. Hyperinsulinemia, insulin resistance, 100
and obesity may be present in adolescents with PCOS, but

1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
are not considered to be diagnostic criteria. Treatment of ad- a
olescent PCOS should include lifestyle intervention, local
therapies, and medications. Insulin sensitizers like metformin
60
and oral contraceptive pills provide short-term benefits on
55
PCOS symptoms. There are limited data on anti-androgens
50
and combined therapies showing additive/synergistic ac-

Number of publications
45
tions for adolescents. Reproductive aspects and transition
40
should be taken into account when managing adolescents.
35
© 2017 S. Karger AG, Basel
30
25
20
Introduction
15
10
Polycystic ovary syndrome (PCOS) is a long-term rec- 5
ognized, complex heterogeneous familial disorder [1, 2].
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
Yet, despite decades of research, the etiology of PCOS re- b
mains elusive [3]. This collaborative effort, initiated by
Pediatric Endocrine Societies, was undertaken because of
Fig. 1. a Annual number of citations for “adolescent PCOS” over
persistent questions in three areas: pathophysiology, di- the past 2 decades. b Annual number of publications for “adoles-
agnosis, and treatment1. This is attested to increased fo- cent PCOS” over the past 2 decades. Web of Science, Thomson
cus and number of publications related to PCOS, both in Reuters, 2017.
general and in the adolescent female (Fig. 1a, b).
The clinical symptoms, including hyperandrogenism
and chronic anovulation, typically develop during ado-
lescence. Further, the early onset of adrenarche may rep- Since this is a review of published manuscripts and ex-
resent the initial clinical feature of PCOS for some girls isting diagnostic and clinical practices and meets ethical
[4]. By the time patients present for medical attention, guidelines, it is exempt from Human Rights Review Com-
this multisystem disorder often has become a self-perpet- mittees and none have indicated any conflict of interest.
uating derangement in which identification of initiating
factors are difficult. Recent insights from genetic epide-
miology support long-standing clinical investigations in- A. Pathophysiology
dicating a broad etiopathology of PCOS.
Androgen excess, observed in approximately 60–80%
of patients with PCOS, is a key feature of the disorder.
1 Note that each of the societies designated one or more experts regarding
Hirsutism and hyperandrogenism are manifestations of
aspects of PCOS to participate in this endeavor. This is intended to be an up-
date of the current status of knowledge for the perspective that etiologic fac- the excessive androgen production. Indeed, hyperan-
tors, diagnostic criteria and treatment guidelines continue to be elucidated. drogenism, commonly demonstrated by elevated free

2 Horm Res Paediatr Ibáñez et al.

DOI: 10.1159/000479371
Fig. 2. Potential factors involved in pathophysiology of PCOS. Al-
terations in steroidogenesis, ovarian folliculogenesis, neuroendo-
crine function, metabolism, insulin secretion, insulin sensitivity,
adipose cell function, inflammatory factors, and sympathetic
nerve function contribute to the pathogenesis of this disorder. Not
all factors play roles in individual patients. Environment factors
(unbound) testosterone in circulation, is the most com-
mon abnormality observed in the syndrome and plays a
major role in perpetuating the aberrant hormone con-
tributors to the pathophysiology of PCOS. Excessive
ovarian androgen production is present in the majority of
cases, but excessive adrenal androgen production can oc-
cur among some. The elevated androgen concentrations
suppress sex hormone-binding globulin (SHBG) con­
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
such as food choice, exercise, and endocrine disruptors influence
the development of clinical features. Genome-wide association
studies have identified loci of interest in close proximity to genes
involved in gonadotropin secretion, gonadotropin action, ovarian
follicular development, and insulin sensitivity.
centrations contributing to higher free testosterone con-
centrations [5]. Herein, we deconstruct this complex
disorder into its major pathophysiologic components.
Although we discuss specific elements, PCOS represents
an example of systems biology with multiple intercon-
nected signaling networks, which in individual instances
may not involve all networks (Fig. 2).
Horm Res Paediatr 3
DOI: 10.1159/000479371
 1.1 Primary Ovarian Pathophysiology
In humans, the factors influencing follicular growth
are coordinated such that typically there is only a single
follicle selected for terminal maturation and ovulation in
a sequential fashion. The maximum number of ovarian
follicles, approximately 6–7 million, exist during mid-
gestation and decrease to roughly 2–3 million primordial
follicles at birth. Subsequently, primordial follicles are
continuously recruited from this pool, with mechanisms
to control the rate of entry of primordial follicles into the
growing pool being essential to maintain the ovarian re-
serve to preserve fertility [6]. These poorly understood
initial phases of follicular growth are gonadotropin-inde-
pendent and influenced by autocrine, paracrine, and local
endocrine factors.
There is a dynamic balance between growing and dor-
mant follicles. In PCOS, the balance between androgens,
anti-Müllerian hormone (AMH), and FSH is disrupted
leading to follicular arrest [7]. Abundant LH drives the
theca cells to produce androgens, but FSH concentrations
and conversion of androgens to estradiol are insufficient,
resulting in failure to select a dominant follicle, thus
chronic anovulation [8]. AMH, secreted by granulosa
cells, plays a major role in governing this balance because
it inhibits transition from primordial to primary follicles.
Hence, PCOS is characterized by increased growth of
small follicles but subsequent growth arrest leading to the
typical polycystic morphology. It has been suggested that
the follicles in a PCOS ovary inherently differ from folli-
cles in a normal ovary [9].
Theca cells obtained from women with PCOS retain
their phenotype with increased androgen secretion from
increased CYP17A1 expression or P450c17 activity [10].
Immunohistochemical studies have indicated that pro-
teins involved in the alternate “backdoor pathway” of ste-
roidogenesis are more highly expressed in PCOS theca
cells [11]. Genome-wide association studies (GWAS) di-
rected investigation to a specific locus, DENND1A, alter-
native splicing of the DENND1A transcript generates sev-
eral variants. Expression of one variant, DENND1A.V2,
is greater in PCOS theca cells. Curiously, knockdown of
this variant recapitulates a normal theca cell phenotype in
PCOS ovaries, whereas overexpression in theca cells from
normal women recapitulates PCOS phenotype [12]. The
mechanism governing the regulation of the alternative
splicing appears to reside outside of the DENND1A gene
[13].
Many steroidogenic enzymes are expressed in both the
adrenal cortex, especially the zona reticularis, and the the-
ca cell. Hormones secreted by the zona reticularis include
4 Horm Res Paediatr
DOI: 10.1159/000479371
dehydroepiandrosterone (DHEA), DHEA sulfate, and
androstenedione. It is becoming apparent that the ste-
roidogenic repertoire of the adrenal and, perhaps, the
theca cell include 11-hydroxyandrostenedione, which is
ultimately converted to the potent androgen 11-ketotes-
tosterone [14]. Women with PCOS showed higher serum
concentrations of the 11-oxygenated androgens 11β-hy-
droxyandrostenedione, 11-ketoandrostenedione, 11β-hy-
droxytestosterone, and 11-ketotestosterone concentra-
tions than control women [15].
2. Insulin Resistance/Hyperinsulinemia
Insulin resistance (IR) and hyperinsulinemia are com-
mon findings in women with PCOS independent of their
degree of adiposity, body fat topography, and androgen
levels [16]. Women with PCOS have a high risk of devel-
oping impaired glucose tolerance and type 2 diabetes
mellitus [17, 18] The pathogenesis of IR in PCOS reflects
the interaction of genetic influences, non-heritable intra-
and extrauterine environmental factors, and alternative
adaptations to energy excess. However in the context of
PCOS, puberty per se might play an important role in the
molecular origins of IR and hyperinsulinemia. During
puberty, adolescents experience a temporary decline in
insulin sensitivity with a nadir in mid-puberty [19–21].
This was first described in an effort to understand the de-
terioration of glycemic control in type 1 diabetes during
adolescence [20]. This transient IR and hyperinsulinemia
have been attributed to the increases in growth hormone
and IGF-1 concentrations in this period of growth to pro-
vide more amino acids [20]. Pubertal IR appears to be
selective for glucose metabolism, whereas protein metab-
olism seems to respond normally to insulin action [22].
Importantly, IR in PCOS women is tissue-selective.
Resistance to the metabolic actions of insulin has been
reported primarily in skeletal muscle, adipose tissue, and
liver; while sensitivity to insulin actions on steroidogen-
esis persists in the adrenal gland and ovary. Hence the
paradox: whereas some tissues manifest IR in women
with PCOS, steroid-producing tissues remain insulin
sensitive [23].
While early studies attributed the IR in PCOS to obe-
sity, subsequent studies including euglycemic-hyperinsu-
linemic clamp studies demonstrated the existence of IR
in lean PCOS women [16, 24]. However, Stepto et al. [24]
included patients diagnosed using the Rotterdam criteria
in their study (2 of the 3 criteria: oligo/anovulation, hy-
perandrogenism, and polycystic ovaries on ultrasound
were used). Nevertheless, another large study found that
only 53 out of 201 (26.3%) lean PCOS women (body mass
Ibáñez et al.
index [BMI] less than 25) had IR, suggesting that ethnic
background and dietary composition might play a role in
the metabolic factors among these women [25].
Both in vivo and in vitro studies suggest that insulin as
well as IGF-1 can synergize with LH to increase theca cell
androgen production [26]. Insulin can also decrease the
hepatic synthesis of SHBG increasing circulating free an-
drogens [27]. Additionally, insulin may directly stimulate
the activity of ovarian P450c17 and P450scc enzymes to
promote ovarian androgen steroidogenesis [28]. In addi-
tion, pancreatic beta cell secretory dysfunction has been
described in a subset of women with PCOS; this subset
probably has the highest risk of developing carbohydrate
intolerance and type 2 diabetes [29].
Other potential mechanisms, including pubertal in-
crease in androgen production are hypothesized to con-
tribute to IR and hyperinsulinemia. The association be-
tween IR and androgen excess in women has long been
recognized because of the association of hyperandrogen-
ic features with the rare syndromes of extreme IR due to
mutations of the insulin receptor or autoantibodies tar-
geting the insulin receptor [30–32]. Insulin may also po-
tentiate the steroidogenic response to gonadotropins in-
directly, by acting at the pituitary to increase gonadotrope
sensitivity to GnRH [33]. Furthermore, increased andro-
gen levels have been associated with decreased adiponec-
tin secretion by adipocytes in PCOS women, thereby fur-
ther reducing insulin sensitivity and consequently in-
creasing compensatory insulin levels [34]. In addition,
insulin may also drive adipose androgen generation by
increasing aldo-keto reductase 1C3 (AKR1C3) activity in
female subcutaneous adipose tissue [35].
Obesity alone is associated with IR and compensatory
hyperinsulinemia. Although the prevalence rates of obe-
sity vary widely across different geographic regions and
ethnicities, a large proportion of PCOS patients are over-
weight or obese [36, 37]. Among obese adolescents, obe-
sity-associated IR may exacerbate the IR associated with
puberty during this period of life, predisposing this group
of individuals to develop prediabetes and type 2 diabetes
[38].
Several studies have reported associations for visceral
obesity, proinflammatory markers, elevated fasting and
glucose-stimulated insulin levels, and greater IR among
women with PCOS [39–42]. Endothelial dysfunction has
been described and may promote chronic inflammation
[43]. Although the mechanisms responsible for obesity-
related IR are not completely clear, ectopic accumulation
of fatty acids in organs and tissue that are not meant to
store large amounts of fat appears to play a role [44]. Ec-
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
topic fat accumulation can also occur in the absence of
obesity, i.e., when there has been reduced prenatal growth
and thus a reduction in subcutaneous fat storage capacity
that is followed by rapid postnatal catch-up and a relative
excess of fat, which is stored in the same ectopic depots
[45].
Molecular mechanisms responsible for IR in PCOS
include defective post-receptor insulin activity, in-
creased free fatty acids, increased cytokine secretion,
and increased androgens [46–50]. Intra-abdominal adi-
pocytes show increased release of free fatty acids and
increased cytokine secretion, e.g., TNF-α, IL-6, leptin,
and resistin [51, 52]. The increased free fatty acids drain
via the portal vein to the liver and subsequently affect
the secretion, metabolism, and peripheral actions of in-
sulin. Hence, the distribution of fat, rather than the mere
presence of obesity or increased BMI, may be highly rel-
evant in PCOS [53, 54]. Some studies have also suggest-
ed that IR in subjects with PCOS might be driven by
alternative mechanisms differing from those occurring
in obesity. In fact, women with PCOS are reported to
have a higher degree of serine phosphorylation of the
insulin receptor and insulin receptor substrate-1 result-
ing in impaired insulin signal transduction and intrinsic
IR independent of total or fat-free body mass [55]. In
addition, a proinflammatory milieu amplified by PCOS
and obesity has been described in ovarian granulosa
cells and stroma [56, 57].
Accumulation of lipids, i.e., diacylglycerol (DAG) and
ceramides, in muscle and liver interferes with insulin sig-
naling [58]. Intra-cellular ceramides can also impair in-
sulin signaling by blocking the translocation of Akt, an
important mediator of insulin sensitivity, to the plasma
membrane [59, 60]. Interestingly, animal data have shown
that disrupted insulin signaling in the central nervous
system is associated with the development of obesity and
impaired ovarian follicular maturation [61], suggesting
another link between IR, hyperinsulinemia, obesity, and
PCOS.
3. Neuroendocrine Alterations
3.1. Changes in GnRH and Gonadotropin Secretion
in PCOS
Although not mandatory for diagnosis, a hallmark of
PCOS is the presence of deregulated secretion of the go-
nadotropins, LH and FSH, which control ovarian ste-
roidogenesis, follicular dynamics, and ovulation [3, 62–
64]. Hence, it is reasonable to hypothesize that altered
gonadotropin secretory profiles could impact the cardi-
nal features of PCOS, including hyperandrogenism and
Horm Res Paediatr 5
DOI: 10.1159/000479371
ovulatory dysfunction [3, 4]. In fact, increased circulating
LH levels, increased LH:FSH ratios, elevated LH pulse
frequency and/or amplitude, as well as relatively de-
creased FSH levels have been typically described in wom-
en with PCOS [3, 65]. Yet, a fraction of PCOS patients
with hyperandrogenism, especially when associated with
obesity, display non-elevated basal or stimulated LH lev-
els, which further attests the heterogeneity of presenta-
tions (and pathophysiology) of the syndrome. Although
LH is considered to be the biomarker of GnRH pulses,
dissociation between GnRH and LH has been reported in
several models which may contribute to the lower LH se-
cretion in some obese women with PCOS [66].
The alterations in gonadotropin secretory profiles are
compatible with changes in the profiles of GnRH pulsatil-
ity, presumably reflecting an increase in the activity of the
GnRH pulse generator. Indeed, classical neuroendocrine
studies established that a pattern of GnRH secretion de-
fined by increased number of pulses favors LH over FSH
secretion by the pituitary [67]. While it is possible that
primary (e.g., genetically determined) alterations at the
GnRH pulse generator network might drive such changes
in some patients, data from different clinical and experi-
mental studies have pointed out contributing roles of per-
turbations of key modulators of GnRH neurosecretion,
including insulin and androgens, whose levels are report-
edly altered in PCOS [68].
Considering that hyperandrogenism is a hallmark of
PCOS, considerable attention has been devoted to the in-
vestigation of potential mechanisms through which de-
regulated androgen secretion contributes to the neuroen-
docrine alterations of the syndrome [3]. Indeed, compel-
ling evidence suggests that elevated androgens disrupt the
capacity of sex steroids to regulate GnRH/LH secretion
via classical feedback loops. This would result in dimin-
ished negative feedback actions of ovarian steroids (estro-
gens and progesterone) that would contribute to and per-
petuate the LH hypersecretion characteristic of PCOS
[67]. In fact, clinical data point out that diminished pro-
gesterone- and estrogen-negative feedback, linked to an-
drogen excess, has a role in the reported elevation of LH
pulsatility in patients with PCOS [69]. Furthermore, re-
duced sensitivity to progesterone-negative feedback, due
to early-onset hyperandrogenism, has been mechanisti-
cally linked to elevated LH secretion in women with
PCOS, although only half of the patients seem to display
overtly impaired negative feedback of progesterone [69].
From a mechanistic standpoint, it is notable that GnRH
neurons appear to be devoid of the major sex steroid re-
ceptors responsible for negative feedback [70], while the
6 Horm Res Paediatr
DOI: 10.1159/000479371
estrogen receptor-β (ERβ), whose role in feedback con-
trol of GnRH neurons remains unclear, is present. Ac-
cordingly, it is tenable that the primary impact of andro-
gen excess on the feedback regulatory loops during differ-
ent developmental windows occurs at neuronal sites
other than (and likely upstream of) GnRH cells.
3.2. Altered Kisspeptin Signaling in PCOS
Among the various afferent neurons to GnRH neu-
rons, Kiss1 neurons, which produce kisspeptins (encoded
by the KISS1 gene), have emerged in the last decade as
master regulators of GnRH neurosecretion and ovula-
tion. Kisspeptins are among the most potent activators of
GnRH neurons identified to date [70]. Various KISS1/
Kiss1 neuronal populations have been identified in differ-
ent mammalian species, including humans, rodents, and
non-human primates. A prominent and highly conserved
population of KISS1 neurons has been reported at the ar-
cuate nucleus (ARC) of the mediobasal hypothalamus, or
its equivalent infundibular region in humans [71]. In ro-
dents, this ARC Kiss1 neuronal population has been pro-
posed to operate as a major hub for mediating the nega-
tive feedback effects of sex steroids, as sex steroids consis-
tently suppress Kiss1 expression at this site. In contrast, a
second more rostral hypothalamic population of Kiss1
neurons may participate in positive feedback, as estrogen
enhances Kiss1 expression at this site [70].
One interesting feature of the population of Kiss1 neu-
rons in the ARC is that at least a fraction of them co-ex-
press other neurotransmitters that also play major roles
in the control of GnRH/gonadotropin secretion [72].
These other neurotransmitters include neurokinin B
(NKB) and dynorphin. The NKB receptor NK3R is also
expressed in Kiss1 neurons. This population of neurons
which co-express kisspeptins, NKB, and dynorphin has
been called KNDy neurons [73]. Based on the reported
actions of NKB and dynorphin, which predominantly
stimulate and inhibit LH secretion, respectively, and the
dense interconnection of KNDy neurons within the ARC,
it has been proposed that NKB and dynorphin participate
in a Ying-Yang fashion in the (auto)regulation of kiss-
peptin output to GnRH neurons, and hence in the gen-
eration of GnRH pulses. As KNDy neurons are sensitive
to sex steroids and modulate GnRH pulse generation, it
is reasonable to speculate that deregulated function of this
neuronal population might contribute to the neuroendo-
crine alterations of PCOS.
However, limited experimental evidence is available to
support or refute this possibility. Despite the meager data
for human and non-human primates, review of preclini-
Ibáñez et al.
cal rodent models can provide insights into the neuroen-
docrinology of PCOS. To date, some studies have report-
ed alterations in Kiss1 expression and/or the number of
Kiss1 neurons in the hypothalamus of various preclinical
animal models of PCOS, generated by excessive androgen
exposure at different developmental windows. Studies in
rodent models of PCOS due to postnatal exposure to an-
drogens have reported persistent suppression of hypotha-
lamic Kiss1 expression [74]; a finding that is consistent
with the proven inhibitory action of sex steroids on Kiss1
expression in the ARC and compatible with similar ob-
servations in models of neonatal estrogenization of fe-
male rats [75]. However, different models of androgen-
ization have been reported to cause variable deregulation
of Kiss1/kisspeptin expression in the hypothalamus.
Thus, it is likely that the actual change (up- or downregu-
lation) of the Kiss1 system depends on the developmental
window and regimen of exposure to androgens.
Although supportive evidence is sparse, the other
KNDy neuropeptides might also be involved in the patho-
physiology of neuroendocrine alterations of PCOS [70,
72]. NKB has been suggested to operate as stimulatory
drive for kisspeptin neurosecretion onto GnRH neurons.
Hence, alterations of central NKB levels might impact
GnRH and LH secretory profiles. This corresponds with
recent evidence showing that oral administration of the
antagonist of NKB receptor, ESN364, to intact female
monkeys lowered LH concentrations and blocked the LH
surge [76]. Another NK3R antagonist (AZD4901) was
administered to 67 women with PCOS for 28 days; treat-
ment with the highest dose was associated with decreased
LH pulse frequency and decreased testosterone concen-
trations [77]. Interestingly, pharmacological studies in
humans have also shown that while administration of
NKB alone did not alter circulating gonadotropin levels,
NKB partially suppressed gonadotropin responses to
kisspeptin [78]. Thus, multidimensional interactions
likely modulate the actions of the KNDy peptides in the
control of gonadotropin secretion. This complexity has
also been documented in equivalent preclinical studies
[79, 80]. Whether such interactions are appreciably per-
turbed in PCOS remains to be clarified.
3.3. Altered GABA Signaling and PCOS
In addition to perturbed kisspeptin/KNDy signaling,
evidence for deregulation of other key central neuroen-
docrine pathways governing GnRH neuron function has
been presented in preclinical models of PCOS. Among
those, elegant studies conducted by Campbell and co-
workers have convincingly demonstrated a multi-factori-
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
al alteration of gamma-aminobutyric acid (GABA) sig-
naling following early androgenization in a mouse model
of PCOS, which might explain part of the neuroendocrine
alterations of the syndrome [81].
While GABA is generally regarded as inhibitory trans-
mitter, different studies have documented that under cer-
tain conditions, acting via GABA-A receptors, GABA can
evoke depolarization (activation) responses directly in
GnRH neurons [82]. Moreover, a GABA neuronal path-
way originating from the ARC is likely to play a role in
transmitting the feedback actions of sex steroids. In this
context, studies in a mouse PCOS model of prenatal ex-
posure to dihydrotestosterone (DHT) has documented
an increase in the GABAergic drive to GnRH neurons, as
evidenced by functional (increased postsynaptic cur-
rents) and morphological (increased number of apposi-
tions of GABA fibers) data. This state of enhanced GABA
input would derive from suppressed progesterone recep-
tor expression in ARC GABA neurons projecting to
GnRH neurons, thus resulting in diminished restraint of
GABA signaling to GnRH neurons with consequent ele-
vated GnRH neurosecretion. In addition, androgenic me-
tabolites generated following inappropriate exposures to
DHT, such as 3α- and 3β-androstanediols, may also con-
tribute to activation of GABA-A receptors and suppres-
sion of the negative feedback machinery in GnRH neu-
rons [81]. Admittedly, the experimental data supporting
such a pathogenic GABA pathway derive from a single
mouse PCOS model, which does not mimic the obese
phenotype that is commonly seen in at least half of PCOS
patients. Hence, it remains unclear whether GABAergic
deregulation is commonplace in the wide spectrum of
clinical cases of PCOS.
3.4. Other Endocrine and Metabolic Modifiers
of GnRH Secretion in PCOS: AMH, Insulin, and
Adiponectin
Recent data has revealed a previously unknown role of
AMH in the stimulatory control of GnRH neurons [83].
Central injection of AMH has been shown to increase the
pulsatile secretion of LH in female mice in a dose-depen-
dent manner. This GnRH-dependent effect was associ-
ated to an increase in the firing of GnRH neurons, which
express the AMH receptor AMHR2 [83]. In this context,
it has been proposed that deregulated AMH levels in
PCOS might contribute to the state of LH hypersecretion.
However, it is important to note that the stimulatory ac-
tions of AMH on GnRH neurosecretion have been ob-
served in control mice, not in PCOS models or patients;
hence, although very appealing, the potential central role
Horm Res Paediatr 7
DOI: 10.1159/000479371
of AMH in the neuroendocrine dysfunction associated
with PCOS remains to be verified.
Although hyperandrogenism and possibly other ovar-
ian factors are major factors contributing to the increased
GnRH/LH secretion, the elevated insulin levels and IR are
also putatively involved in such neuroendocrine altera-
tions. In fact, central insulin actions are indispensable for
proper functioning of the gonadotropic axis in mice; lack
of brain insulin signaling decreases LH levels and disturbs
follicular maturation [60]. In good agreement, insulin in-
fusion in control women increased LH pulse frequency,
reminiscent of secretory profiles of women with PCOS
[84]. In fact, lean patients with PCOS have been shown to
display increased basal LH levels and LH:FSH ratios. Yet,
another study involving women with PCOS reported that
insulin administration failed to alter LH pulsatility [85].
The mechanisms responsible for the effects of high in-
sulin levels on the GnRH pulse generator need further
elucidation. Insulin receptors in GnRH neurons appear
dispensable for proper pubertal maturation and fertility,
therefore pointing to a primary action of insulin at other
brain targets, likely occurring upstream of the GnRH
neurons [86]. Studies in sheep and rodents suggest that
insulin signaling may modulate Kiss1 neuron function,
thereby regulating GnRH neurosecretion [87, 88]. In fact,
analyses in a sheep model of PCOS generated by gesta-
tional androgenization revealed a decrease in IR expres-
sion in ARC KNDy neurons [87]. However, the function-
al relevance of such direct actions of insulin in Kiss1 neu-
rons, in terms of control of gonadotropin secretion and
fertility appear to be modest, if any, according to rodent
studies [89]. This would suggest that insulin operates at
other elements of the GnRH pulse generator to modulate
GnRH secretion. Alternatively, related factors, such a
IGF-I, known to act directly at GnRH neurons to control
the reproductive axis might contribute to deregulated go-
nadotropin secretory profiles in women with PCOS.
Another metabolic regulator with putative pathophys-
iological roles in PCOS is adiponectin, an adipokine neg-
atively correlated with IR and adiposity. Although con-
flicting results have been reported on changes in circulat-
ing adiponectin in women with PCOS, systematic analyses
of published data suggest that women with PCOS display
lower adiponectin levels, which correlate with IR [90].
While the pathogenic relevance of such alterations re-
mains to be established in humans, an experimental rat
model of PCOS associated with DHEA administration re-
vealed that adiponectin administration was largely suffi-
cient to reverse the PCOS-like phenotypes of DHEA-
treated rats [91]. Moreover, transplantation of brown ad-
8 Horm Res Paediatr
DOI: 10.1159/000479371
ipose tissue (BAT) in this model, which caused an increase
in circulating adiponectin, equally corrected the metabol-
ic and ovarian abnormalities of this preclinical model of
PCOS [91]. It must be stressed, however, that the thera-
peutic benefits of adiponectin administration and/or
BAT transplantation in women with PCOS are yet to be
demonstrated.
4. Genetics
Studies of monozygotic and dizygotic twins have indi-
cated a moderate heritability of PCOS. Other epidemio-
logical studies have indicated the likely importance of
considering risk factors and biological processes acting
throughout the life-course: low birth weight and fetal ex-
posure to androgens; postnatal rapid weight gain; preco-
cious adrenarche and early age at pubertal development;
adult weight status and lifestyle.
Until recently, candidate gene studies have been un-
derpowered leading to poorly reproducible results. The
advent of large-scale GWAS with their stringent statisti-
cal thresholds has brought robust new insights, although
as yet these have been limited to adult PCOS cases and
their direct relevance to adolescent PCOS is yet to be es-
tablished. The first GWAS for PCOS were performed in
Han Chinese populations [92, 93]; while the identified
genomic loci were replicable in that population, their ef-
fects estimates are consistently smaller in Caucasian
PCOS cases, possibly due to population differences in
genetic architecture or even PCOS sub-phenotypes [94,
95].
Several of the individual genomic signals for PCOS
have provided new insights into its pathophysiology. As
noted above, the role of DENND1A splice transcripts in
ovarian theca cell steroidogenesis is being investigated.
The PCOS susceptibility allele in the FSHB gene is also
associated robustly with lower circulating FSH levels [94,
95], and with other phenotypes indicative of diminished
ovarian follicle stimulation: later onset of puberty, and
lower risk for dizygotic twinning [96]. Together, these
genetic findings indicate a co-primary neuroendocrine
pathogenesis of PCOS, alongside its likely ovarian etiol-
ogy. These genetic studies and the pharmacologic studies
involving NK3R antagonists encourage further investiga-
tion into the neuroendocrine features of PCOS. GWAS
findings also suggest the importance of future studies of
the possible role of epidermal growth factor receptors on
ovarian follicle development/steroidogenesis [94].
Another powerful use of the genomic data is to test
combinations of signals that indicate the potential causal
influences of biological pathways. Such Mendelian ran-
Ibáñez et al.
domization analyses have indicated causal roles in PCOS
etiology for higher BMI, higher IR, and lower serum
SHBG concentrations, which could act by increasing the
bioactivity of androgens or other sex steroids [94]. Final-
ly, a highly robust yet unexplained association between
genetic variants that confer a later age at menopause and
higher susceptibility to PCOS is intriguing [94]. It sug-
gests that perhaps the evolutionary incongruity of this
common heritable disorder impacting fertility might be
explained by its co-susceptibility to preserved fecundity
at older age.
5. Epigenetics
A number of GWAS as well as replication studies in
Chinese and Caucasian subjects have identified the LH/
choriogonadotropin receptor (LHCGR) (locus 2p16.3) as
a susceptibility gene for PCOS [97]. Increased LH activity
is a common feature in PCOS and may contribute to the
defective folliculogenesis and hyperandrogenism com-
monly seen in these patients. Hypomethylation of the
LHCGR was first described in a mouse model of PCOS
and has been recently confirmed in human peripheral
blood cells and granulosa cells from PCOS subjects [98,
99]. Decreased LHCGR methylation is known to increase
gene expression [100]. Hypomethylation of LHCGR, by
causing hypersensitivity to LH pulses, may thus be a plau-
sible mechanism underlying susceptibility to PCOS.
Aromatase, encoded by CYP19A1, is another candi-
date gene in PCOS. As estrogens are required for follicle
selection and growth, decreased aromatase may contrib-
ute to the defective folliculogenesis observed in PCOS pa-
tients. In Chinese women with PCOS, CYP19A1 was hy-
permethylated in ovarian tissue, which correlated with
decreased mRNA and protein levels [101]. In another
study, EPHX1, which encodes for epoxide hydrolase 1, an
enzyme necessary for the degradation of aromatic com-
pounds, was hypomethylated in peripheral blood cells
from women with PCOS. In human granulosa-like tumor
cells, it was also demonstrated that EPHX1 regulated es-
tradiol concentrations, indicating a role for EPHX1 hypo-
methylation in ovarian steroidogenesis [102]. Alterations
in the methylation pattern and expression of peroxisome
proliferator-activated receptor gamma 1 (PPARG1),
which is involved in the regulation of ovarian function,
and of its co-repressors has also been described in granu-
losa cells from women with PCOS and in animal models
of PCOS [103].
Besides gene-targeted studies, genome-wide methyla-
tion studies in ovaries of women with PCOS have re-
vealed alterations in DNA methylation and gene expres-
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
sion in pathways such as the type 1 diabetes mellitus path-
way, p53 signaling pathway and NOD-like receptor
signaling pathway (involved in immune responses), as
well as in metabolic pathways involved in ovarian func-
tion (IGFBP2, INSR, SLC2A8, NRIP1) and in ovarian ste-
roidogenesis (CYP19A1, AMH and its receptor AMHR2)
[104, 105].
In peripheral blood cells, differential methylation was
observed in pathways related to the immune response
and to cancer pathways (cellular survival, proliferation,
pluripotency, invasion, metastasis, and angiogenesis)
[106]. Interestingly, the association with immune path-
ways was also described in another report relating PCOS
with epigenetic changes in pathways involved in autoim-
mune and allergic diseases, such as type 1 diabetes mel-
litus, thyroid disease, and asthma [107], and was consis-
tent with the abovementioned results in ovarian tissue
[104].
In addition to the ovary and peripheral blood cells, ge-
nome-wide methylation studies have been performed in
adipose tissue from women with PCOS and in a primate
model of PCOS. In women, differential methylation
was observed in genes involved in steroid metabolism
(CYP1B1), liver function (GPT), in a candidate gene for
PCOS (RAB5B, which participates in intracellular vesicle
transport), in two genes related to type 2 diabetes mellitus
(PPARG, SVEP1) and in one gene involved in DNA meth-
ylation (DMAP1) [108]. In prenatally androgenized fe-
male rhesus monkeys, differential methylation in adipose
tissue was observed for two anti-proliferative gene signal-
ing pathways: TOB (involved in T-cell signaling) and
transforming growth factor-β (TGFB) [109]. The avail-
able genome-wide methylation studies in women with
PCOS are summarized in a recent review by Li et al. [110].
The authors highlight the significant association of PCOS
phenotype with immune responses both in ovaries and in
peripheral blood cells.
Regulation of gene expression by microRNAs (mi­
RNAs) is considered to be an additional layer of epige­
netic regulation. A genome-wide circulating miRNA ex-
pression profile identified a number of miRNAs dysregu-
lated in women with PCOS. These miRNA species are
involved in glycometabolism and ovarian follicle devel-
opment pathways [111, 112]. Interestingly, miRNA-592
has been shown to be downregulated and to be inversely
related to LHCGR levels in PCOS patients [113].
6. Altered Sympathetic Nerve Activity
An alteration in sympathetic nerve activity has been
proposed to contribute to the etiology of PCOS. Indeed,
Horm Res Paediatr 9
DOI: 10.1159/000479371
Table 1. Suggested criteria for the diagnosis of PCOS in adolescence
Required Optionala
1. Irregular menses/ 1. PCOM
oligomenorrhea 2. Severe cystic acne
2. Evidence of hyperandrogenism:
a. Biochemical
b. Clinical (e.g., progressive
hirsutism)
PCOS; polycystic ovary syndrome; PCOM, polycystic ovarian morphology; AMH, anti-Müllerian hormone; T/DHT, testosterone to
dihydrotestosterone; NC-CAH, non-classical congenital adrenal hyperplasia. a These criteria are often used in concert with the required
criteria, but should not be used independently as diagnostic features. b  These criteria have been associated with PCOS but are not
diagnostic.
many of the common clinical symptoms of PCOS, includ-
ing central obesity, hyperinsulinemia, and hyperandro-
genemia, are associated with chronic increased activity of
the sympathetic nervous system [114, 115]. Direct assess-
ment of sympathetic activity in PCOS women revealed an
association between high muscle sympathetic nerve ac-
tivity and PCOS independently of BMI [116]. Additional
indirect markers of autonomic activity including heart
rate variability and heart rate recovery after exercise have
demonstrated that young PCOS women exhibit increased
sympathetic and decreased parasympathetic responses to
these challenges [117–119].
Increased ovarian sympathetic tone in PCOS is sup-
ported by the finding of a greater density of catechol-
aminergic nerve fibers in polycystic ovaries [120] and ad-
ditional studies in a rat PCOS model that demonstrated
increased sympathetic outflow previous to the appear-
ance of ovarian cysts [121]. Additional studies in this rat
model showed an association between the development
of follicular cysts and chronic increased production of
nerve growth factor in the ovary [122], a hallmark of sym-
pathetic hyperactivity. The association between the neu-
rotrophins and PCOS was strengthened by the finding
that ovarian nerve growth factor production is increased
in PCOS women [123].
B. Diagnosis
As previously reviewed [124], diagnostic criteria for
PCOS in adolescence remain controversial, primarily be-
cause the diagnostic pathological features used in adult
women may be normal pubertal physiological events.
These features include irregular menses, cystic acne, and
polycystic ovarian morphology (PCOM) [125, 126]. In-
10 Horm Res Paediatr
DOI: 10.1159/000479371
Not recommendedb Comments
1. Obesity 1. Must generally be 2 years
2. Insulin resistance post-menarche
3. Hyperinsulinemia 2. Must rule out other disorders
4. Biomarkers (e.g., AMH, of hyperandrogenism (e.g.,
T/DHT ratio) NC-CAH, Cushing syndrome)
5. Acanthosis nigricans
deed, it is possible that adolescent hyperandrogenemia is
a consequence of the lack of full maturation of the hypo-
thalamic-pituitary-ovarian axis during this time of life.
Similarly, prolonged anovulatory cycles are simply typi-
cal of pubertal development rather than an early manifes-
tation of PCOS. Most importantly, it remains unclear
when persistence of adolescent oligomenorrhea becomes
a significant clinical finding (Table 1).
As noted above, IR and hyperinsulinemia are often
noted in women with PCOS and may influence the devel-
opment of PCOS in some patients. However, current def-
initions of PCOS do not include obesity, IR, or hyperin-
sulinemia as diagnostic criteria [127–135]. Nevertheless,
we will discuss as to whether adolescents with these find-
ings should be considered as being at risk for PCOS, since
they may carry an additional risk for manifestation of
metabolic disease in adult life.
1. Clinical Features
As in adults, signs of hyperandrogenism in adolescents
can be clinical or biochemical. Hirsutism is defined as ex-
cessive, coarse, terminal hairs distributed in a male fash-
ion, and PCOS is the most common cause of hirsutism in
adolescence [136]. The severity of hirsutism may not cor-
relate with serum androgen levels; moreover, there are
ethnic/genetic differences that may affect the degree of
hirsutism [137–139]. Hirsutism must be distinguished
from hypertrichosis defined as excessive vellus hair dis-
tributed in a non-sexual pattern. Mild hirsutism may not
be a sign of hyperandrogenemia [140], but the likelihood
of androgen excess is increased when associated with oth-
er findings such as menstrual irregularities [141, 142].
Moderate or severe hirsutism may be a sign of androgen
excess in early postmenarcheal years. In adults, the eval­
uation and grading of hirsutism can be done using the
Ibáñez et al.
Ferriman-Gallwey scoring system, which may not be suit-
able for adolescents (modified Ferriman-Gallwey) [132].
Adult terminal hair distribution is usually achieved by 2
years after menarche. The original report of Ferriman and
Gallwey included females starting from the age of 15 years
[143]. Ethnic and racial variation in the extent of hair
growth influences this semi-subjective cutaneous sign of
androgen excess [131].
Although acne is a common problem in adolescence,
it is usually transient and may not be indicative of hyper-
androgenism [144, 145]. Moderate or severe inflamma-
tory acne, especially if unresponsive to topical therapy,
however, may require investigation of androgen excess
[124, 146]. In a 5-year longitudinal analysis, development
of moderate to severe inflammatory acne has been report-
ed to be associated with androgen excess [147]. Alopecia
is rare and not well studied in adolescents [148]. Isolated
acne and alopecia should not be considered to be diag-
nostic criteria of PCOS in adolescence.
Premature adrenarche (PA), defined in girls as the ap-
pearance of pubic hair before 8 years of age with Tanner
II–III levels of adrenal androgens, may herald PCOS in
childhood [149]. However, PA does not precede PCOS in
all girls [148] and not all girls with PA will develop PCOS
[4, 150]. Persistent hyperandrogenemia in girls with PA
may lead to PCOS, especially if accompanied by obesity
[151]. Continued prospective monitoring of girls with PA
should be performed. The diagnosis of non-classic con-
genital adrenal hyperplasia should be excluded based on
history, examination, and hormone levels including
ACTH stimulation tests if warranted [152]. Similarly, pa-
tients should be screened for Cushing syndrome, if clini-
cal features are suggestive.
Irregular menses should also not be used as the only
criterion for PCOS in adolescence because menstrual ir-
regularities are typical for at least 2 years after menarche
[124]. In adolescence, irregular menses that persist 2 years
after menarche may be a sign of PCOS, although irregular
menses may continue up to the 5th year after menarche
without development of PCOS [153, 154]. About 85% of
cycles are anovulatory during the 1st year after menarche,
59% during the 3rd year, and 25% in the 6th year [154].
Moreover, irregular cycles may not necessarily be associ-
ated with clinical or biochemical hyperandrogenism
[155]. The Endocrine Society Guidelines required persis-
tent oligomenorrhea (menstrual cycles longer than 45
days) for the diagnosis of PCOS in adolescents [134].
Based on the expected variation of menstrual cycles in
normal girls [156, 157], the persistence of oligomenor-
rhea, secondary amenorrhea (absence of cycles for more
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
than 3 months), or primary amenorrhea in girls with com-
pleted puberty may suggest androgen excess [158, 159].
Ovulatory dysfunction may also present as dysfunctional
uterine bleeding (cycles shorter than 21 days or lasting
more than 7 days) [160–162]. These menstrual distur-
bances may all be reflective of androgen excess [154]. One
should keep in mind that age at menarche may differ in
girls with PCOS due to variable presentation, including
early puberty and primary amenorrhea. Age at menarche
may be inversely correlated to obesity [163, 164].
Confirmation of biochemical hyperandrogenism is
important in symptomatic adolescents before a defini-
tive diagnosis of PCOS can be considered. As described
in prior publications on PCOS in adolescents, measure-
ments of total and/or free testosterone have been the
most recommended hormone determinations to docu-
ment hyperandrogenemia [165]. Methodological prob-
lems regarding testosterone determinations include the
following: (1) inadequate assay sensitivity to measure
low testosterone concentrations in girls and women; (2)
assay interference due to simultaneous presence of other
steroid molecules with similar structure; (3) lack of well-
defined normative values; (4) binding of testosterone to
SHBG and other proteins in the peripheral circulation,
and (5) technical aspects of testosterone assays [166–
168].
Most recommendations advocate utilization of high-
quality liquid chromatography/tandem mass spectrom-
etry (LC-MS/MS) to measure testosterone. However, un-
til this technology is universally available, high-quality
RIA with extraction and chromotography should be em-
ployed. Available guidelines have suggested total testos-
terone concentrations >55 ng/dL (1.91 nmol/L) are likely
consistent with hyperandrogenism. Further, Gambineri
et al. [169] defined hyperandrogenism during the follicu-
lar phase as total testosterone concentrations >42 ng/dL
(1.45 nmol/L) using a LC-MS/MS assay. Because of the
variability in the results of testosterone assays and the
limited data on the normal development fluctuations in
testosterone levels during adolescence, no clear cutoff tes-
tosterone concentrations can be given.
2. Polycystic Ovary on Ultrasound: PCOM
The presence of enlarged ovaries with increased stro-
ma and multiple small peripheral cysts is known as
PCOM. PCOM is associated with hyperandrogenism but
is not always included as a diagnostic element of PCOS.
PCOM is an inconsistent finding in healthy girls [170]
and adults [171], but a higher persistence of PCOM over
time is observed in hyperandrogenic adolescents [172].
Horm Res Paediatr 11
DOI: 10.1159/000479371
Furthermore, the criteria to define the ultrasonographic
pattern of PCOS continue to be modified [173].
The anatomic appearance of the ovary changes with
age [174]. Ovarian volume increases during puberty and
reaches the adult volume in the years following men-
arche. It remains stable in young adulthood and decreas-
es after the middle of the fourth decade of life. [175]. Fol-
licle size also changes with age, and the greatest number
of small follicles is observed during adolescence and
young adulthood, with a significant decrease in follicle
count with age [176].
The ultrasonographic diagnosis of PCOM has been
standardized for adults using the transvaginal route. In
adolescents, however, most exams are performed by the
transabdominal route, where the high physiologic follicle
number may render the follicle count an unreliable crite-
rion for the diagnosis of PCOM. The importance of using
appropriate diagnostic criteria of PCOM in adolescents is
emphasized because application of the adult criteria can
lead to a falsely elevated prevalence of PCOM (30–40%
range) [177, 178]. Therefore, ovarian volume is better
suited than follicle count to determine the presence of
PCOM in adolescence [179]. The Androgen Excess and
PCOS Society suggested that an ovarian volume of 10 mL
be recommended for the diagnosis of PCOM in adoles-
cents [132]. Later, based on an ovarian volume larger than
2 SD above the mean in the healthy adolescent population
[180], an enlarged ovarian volume of 12 mL was recom-
mended by an international consensus [179].
Available data suggest that among non-obese, non-
hirsute girls with regular menstrual cycles, PCOM is not
associated with hyperandrogenism or IR. Similar levels of
androgens and indexes of insulin sensitivity were ob-
served in healthy girls with and without PCOM [181].
Nevertheless, persistence of enlarged ovaries and men-
strual irregularities may foretell the future development
of PCOS [176, 182, 183].
3. Biomarkers for PCOS
Limited data are available regarding newer biomark-
ers, except for AMH, nor has their utility to aid in the es-
tablishment of the diagnosis of PCOS in adolescence been
completely verified. AMH is a glycoprotein secreted by
the granulosa cells of small, growing follicles. As noted
above, animal studies have inferred a possible role for
AMH in the ontogeny of PCOS. AMH serum levels cor-
relate with the number of small antral follicles (2–5 mm)
identified by transvaginal ultrasound in adult women
[184, 185]. Elevated AMH levels have been a consistent
hormone finding in women with PCOS [186, 187]. How-
12 Horm Res Paediatr
DOI: 10.1159/000479371
ever, in adolescents, AMH should not be used as a crite-
rion of PCOS since there is a weaker association of AMH
levels with the disorder [188, 189]. This divergence may
be due to the presence of higher AMH serum levels in
healthy adolescents compared to adult women, with a
wide normal range [178, 180, 190, 191].
Besides AMH, several biomarkers may be associated
with PCOS. A high ratio of total testosterone to dihy-
drotestosterone (T/DHT) is associated with an adverse
metabolic phenotype in PCOS patients [192]. Munzker et
al. [192] found that T/DHT was significantly higher in
PCOS patients than in non-PCOS patients, and T/DHT
was even higher in obese PCOS patients than in non-
obese PCOS patients. This phenomenon may be linked to
conversion of testosterone to DHT by the 5α-reductase
enzymes, and may ultimately be useful to assess for the
diagnosis of PCOS.
Proteomic profiling studies have indicated specific
proteins to be used as biomarkers for PCOS. Sarray and
Almawi [193] detected significantly elevated sCD40L in
women with PCOS. They posited that sCD40L, a trans-
membrane glycoprotein that regulates several cell types
in the inflammatory network, can be used as a predictor
for PCOS in a Bahraini Arab population [193]. Though
this result cannot be generalized across ethnic groups, it
is an important finding for future replication and valida-
tion. HSP90B1, a stress-inducible chaperone protein as-
sociated with the growth of cancerous cells, has also been
identified as a potential biomarker for PCOS [194].
HSP90B1 may have a role in promoting granulosa cellu-
lar activity in the ovary, leading to PCOS. Further study
is necessary to confirm this action [194].
Alongside proteomics and hormone discoveries,
promising preliminary work in the use of microRNA for
PCOS diagnosis is underway [195]. Circulating or ovari-
an miRNAs could potentially modulate steroidogenesis
and ovarian function in women with PCOS [195]. Bio-
markers are useful tools in general, and progress contin-
ues in the discovery of newer biomarkers to assist in mak-
ing the diagnosis of PCOS.
4. IR in the Context of PCOS
IR and compensatory hyperinsulinemia are not con-
sidered to be diagnostic criteria for PCOS. Yet, IR and
hyperinsulinemia have been documented in women with
PCOS since the late 1980s, when some studies showed
that obese women with PCOS had significantly increased
glucose levels during an oral glucose tolerance test com-
pared to age- and weight-matched ovulatory women with
elevated plasma androgen levels and control women.
Ibáñez et al.
Moreover, the presence of some degree of IR in subjects
with PCOS is corroborated by the high prevalence of glu-
cose intolerance in obese PCOS adolescents. Estimated at
∼40% [37], glucose intolerance in obese PCOS adoles-
cents is much higher than in the general US population
of obese adolescents in which the prevalence of impaired
glucose tolerance is about 15–20% [196].
The diagnosis of IR in PCOS is unfortunately con-
founded by the variety of definitions used in different
studies [16, 18, 37, 197]. IR may be measured directly us-
ing a euglycemic insulin clamp (requiring an intravenous
line), but is usually measured indirectly, through the oral
glucose tolerance test, or most commonly through fasting
levels of glucose and insulin [197]. Though the derived
indices obtained from indirect measures may be some-
what less accurate than direct, whole-body measurement,
their utility as non-invasive measures of IR is vital. Indi-
rect measurements of IR may be calculated in a variety
of ways. These include fasting glucose to insulin ratio,
early insulin response, homeostatic model assessment
(HOMA), the Matsuda Index, and oral Sg index [197–
201]. These methods are particularly useful in individual
or population studies.
B. Diagnosis: Conclusions with Level of Evidence
1. Clinical Features of PCOS
• Moderate to severe hirsutism constitutes clinical evi-
dence of androgen excess (Level B).
• Mild hirsutism may be a sign of androgen excess when
associated with menstrual irregularities (Level C).
• Moderate or severe inflammatory acne unresponsive
to topical therapy may require investigation of andro-
gen excess (Level C).
• Isolated acne and/or alopecia should not be consid-
ered diagnostic criteria for PCOS in adolescence (Lev-
el C).
• Persistent menstrual disturbances (oligomenorrhea
and secondary amenorrhea) beyond 2 years after men-
arche or primary amenorrhea in girls with completed
puberty may suggest androgen excess (Level B).
• Biochemical hyperandrogenism should be defined
based on the methodology used, as no clear cutoff for
testosterone concentrations exists for adolescents
(Level A).
• Biochemical evidence of hyperandrogenism based on
elevations of total and/or free testosterone measured
in a reliable reference laboratory documents hyperan-
drogenemia in a symptomatic adolescent (Level B).
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
2. Polycystic Ovarian Morphology
• The presence of PCOM in an adolescent who does not
have hyperandrogenism/oligo-anovulation does not
indicate a diagnosis of PCOS (Level A).
• The measurement of ovarian volume, follicle number
and size, and uterine dimensions may be useful in the
evaluation of amenorrhea, but is not needed for PCOS
diagnosis in adolescents (Level A).
3. Biomarkers of PCOS
• The use of AMH, T/DHT ratios, and specific proteins
or microRNA as biomarkers of PCOS has not been
validated in adolescents (Level C.).
4. Insulin Resistance
• IR, compensatory hyperinsulinemia, or obesity should
not be considered as diagnostic criteria for PCOS in
adolescents (Level A).
C. Treatment of PCOS
No pharmacological treatment has been approved so
far by FDA/EMA for use in adolescents with PCOS; how-
ever, some pharmacological interventions have been used
to manage PCOS symptoms. In the following sections,
the baseline and additive pharmacological treatments
and their potential benefits, as well as reproductive as-
pects in PCOS adolescents are discussed. Doses and se-
quences of intervention combinations need to be indi-
vidualized.
1. Baseline Treatment
1.1. Lifestyle Intervention
Weight loss and increased physical exercise are gener-
ally recommended as the first-line therapy in overweight
or obese girls [134]. Two small randomized controlled
trials (RCTs) [202, 203] and one well-controlled clinical
study [204] in overweight PCOS girls have shown that the
combination of weight loss and intensified exercise de-
creases testosterone levels and the free androgen index,
increases SHBG concentrations, and normalizes men-
strual regularity comparably to drug therapy, and is de-
void of side effects. The combination of lifestyle interven-
tion with medications normalized more androgen levels
and menses in one of these studies [204]. However, long-
term data reporting sustained benefits on cycle regularity
or on pregnancy outcomes after weight loss in adolescent
girls are lacking.
Horm Res Paediatr 13
DOI: 10.1159/000479371
 Cardiovascular risk factors such as hypertension, dys-
lipidemia, and impaired glucose tolerance, as well as ear-
ly markers of atherosclerosis such as carotid intima-me-
dia thickness also improved after lifestyle intervention
[134]. Weight loss, but not participation in lifestyle inter-
vention itself, predicted the amelioration of components
of PCOS [134]. Extremely obese adolescents often re-
spond poorly to lifestyle intervention [205]. A reduction
of BMI SDS of 0.25 or greater [206] and/or 30 min per day
of moderate to vigorous physical activity resulted in an
improvement of cardiovascular risk factors in adoles-
cents with PCOS [207].
Lifestyle intervention should be based on the combi-
nation of calorie-restricted diets (with no evidence that
one type of diet is superior for adolescents), behavioral
treatment, and exercise [208]. Along these lines, a meta-
analysis has demonstrated the benefits of dietary modifi-
cation in young women with PCOS [209]. Increasing
physical activity from moderate to vigorous is effective in
reducing the development of metabolic syndrome in nor-
mal-weight girls [209]. However, no large RCTs support
the benefits of exclusive weight loss in normal-weight
PCOS adolescents.
Decreasing sedentary behavior is at least as important
as increasing physical activity [210]. Furthermore, family
treatment is an essential component in lifestyle interven-
tion since parents’ readiness to change habits affects the
outcome [208, 210].
1.2 Local Therapies/Cosmetics
Cosmetic hair-removal methods for hirsutism include
bleaching, chemical epilation, plucking, waxing, shaving,
electrolysis, and laser hair removal. Although only the lat-
ter result in permanent – albeit partial – hair removal, ef-
ficacy and safety of electrolysis is not supported by any
RCT.
Evidence based on 11 RCTs [211] and 21 controlled
trials [212] supports the efficacy for up to 6 months of
partial hair removal with laser or intense pulsed light
(IPL), despite a great variability following photoepilation
[212]. Partial long-term hair removal efficacy (beyond 6
months) has been observed for all laser therapies after re-
petitive treatments, although the data are limited [212].
The data comparing different laser methods are few and
contradictory; however, the available studies show that
diode and alexandrite offer the higher success rate, where-
as Nd:Yag provides the lowest [213]. The studies compar-
ing laser and IPL devices are few and of low quality; all
have been performed in adults with mixed forms of hir-
sutism, hyperandrogenism, or unwanted hair growth.
14 Horm Res Paediatr
DOI: 10.1159/000479371
Only 2 RCTs have evaluated the effect of photoepilation
in selected PCOS patients aged 16 years or older, showing
the benefits of laser therapy on facial hirsutism [214] and
the superiority of alexandrite laser over IPL [215].
Two RCTs performed in hirsute patients aged 16 years
or older reported the benefits of topical eflornithine HCl
13.9% cream applied twice daily in reducing facial hirsut-
ism [216]. The safety profile was good and percutaneous
absorption was minimal. Drawbacks included non-re-
sponse in 30% of users and regrowth to pretreatment lev-
els within 8 weeks of discontinuation. Three other RCTs
performed in hirsute women showed the ability of topical
eflornithine when added to photoepilation to promote
faster and more complete laser removal of facial hirsut-
ism and to reduce hair regrowth between laser sessions
and after cessation of IPL use [216, 217]. Laser epilation
is most effective when used to treat areas of full, dark hair
on light-skinned people. The studies reporting the effects
of topical finasteride on idiopathic hirsutism are limited
and contradictory.
We suggest photoepilation as first-line management of
localized hirsutism in PCOS; diode and alexandrite lasers
are preferred. Topical eflornithine is recommended as an
adjuvant to photoepilation in cases with laser-resistant
facial hirsutism or as monotherapy in patients with facial
hirsutism where photoepilation is not indicated. The use
of topical finasteride is not recommended based on the
existing data.
2. Additive Pharmaceuticals
Pharmacological interventions that have been used in
adolescent PCOS are included in Table 2.
2.1. Metformin
Metformin is the only insulin sensitizer that has been
evaluated in double-blind RCTs as single medication for
adolescent PCOS; metformin use has increased over the
last 10 years despite not being licensed for PCOS [218].
A meta-analysis of metformin use with and without
lifestyle changes in PCOS up to August 2014 showed ben-
eficial effects on BMI and menstrual cycles [219]. Of the
12 RCTs included, 2 were performed in adolescents [202,
220]. The meta-analysis also highlighted the many limita-
tions of the RCTs such as small sample size, short dura-
tion (most trials had a duration of 6 months), and a mod-
erate risk for bias.
Observational studies and 6 randomized trials [202,
220–224] (Table 2) have demonstrated short-term ben-
eficial effects of metformin in PCOS adolescents who
were mostly overweight or obese. There are only 2 small
Ibáñez et al.
Table 2. Medications used in the treatment of polycystic ovary syndrome in adolescent girls

Medication Mechanism(s) of action Dosage Side effects Contraindications

Estroprogestagen Inhibition of ovarian androgen secretion
OCP and increase in hepatic SHBG production,
resulting in less circulating free androgens
Metformin Upregulation of the energy sensors
STK11 and AMPK
Improvement of insulin sensitivity in
muscle and adipose tissue
Downregulation of hepatic gluconeogenesis
(improves fasting blood glucose)
Increase of GLP-1 secretion and GLP-1
receptor expression (improves postprandial
blood glucose)
Decrease of ovarian and adrenal androgen
production
Pioglitazone Peroxisome proliferator-activated
receptor-γ activator
At low dose, inhibition of CDK5-
mediated phosphorylation of peroxisome
proliferator-activated receptor-γ
Flutamide Androgen receptor blockade
Spironolactone Aldosterone antagonism
Androgen receptor blockade
21 out of 28 Breast tenderness, headache,
days/month increased risk of venous
thromboembolism, tend to increase
insulin resistance
850 mg/day Gastrointestinal discomfort1,
up to 1 g lactic acidosis2
b.i.d.
7.5 mg/day Weight gain (higher doses),
up to 30 mg/ bladder cancer risk inconclusive
day results; studies include only male
diabetic patients >40 years, risk
with cumulative doses >28,000 mg
62.5 mg/day Dose-dependent hepatotoxicity
up to 250 Absent at doses of 1 mg/kg/day
mg/day Feminization of male fetuses
50–200 mg/ Mostly dose-dependent: irregular
day menstrual bleeding, headache,
hypotension, nausea, decreased
libido, feminization of male fetuses
Pregnancy, uncontrolled
hypertension, liver dysfunction,
complicated valvular heart
disease, migraines with aura or
focal neurologic symptoms,
thromboembolism, diabetes
complications, organ
transplantation
Renal and liver dysfunction,
surgery, use of contrast agents,
heart failure, alcoholism,
metabolic acidosis, dehydration,
hypoxemia
Pregnancy, liver dysfunction,
bladder cancer
Pregnancy, renal and liver
dysfunction
Pregnancy, renal failure,
hyperkalemia

Cyproterone Competition with dihydrotestosterone at 50–100 mg/ Liver toxicity, irregular menstrual Pregnancy, renal and liver
acetate receptor level day bleeding, nausea, decreased libido, dysfunction
Inhibition of 5α-reductase, prevents Combined feminization of male fetuses
conversion of testosterone to with OCP
dihydrotestosterone 2 mg/day
Finasteride Inhibition of 5α-reductase, prevents 1–5 mg/day Feminization of male fetuses, liver Pregnancy
conversion of testosterone to dysfunction (rare)
dihydrotestosterone
OCP, oral contraceptive pill; SHBG, sex hormone-binding globulin; STK11, serine/threonine protein kinase; AMPK, adenosine monophosphate-
activated protein kinase; b.i.d., bis in die. 1 Gradually increasing doses minimizes the appearance of gastrointestinal symptoms. 2 Older patients with type
2 diabetes and renal failure.

observational studies in non-obese PCOS adolescents
with hyperinsulinemia showing improvement in ovula-
tion and testosterone levels with doses as low as 850 mg/
day [225, 226]. Most studies failed to accurately report
side effects and adherence to interventions. Overall,
metformin was associated with gastrointestinal dis-
comfort, but no serious adverse effects have been re-
ported.
A recent meta-analysis of metformin versus oral con-
traceptive pills (OCP) including 4 RCTs [202, 221, 224]
and a total of 170 adolescents showed that metformin and
OCP had similar benefits on hirsutism, triglycerides, and
HDL cholesterol. Metformin was accompanied by a
greater improvement of BMI, while the use of OCP was
associated with improvement in menstrual regularity
(modest) and acne (mild). The conclusion was that these

Update: PCOS Pathophysiology, Horm Res Paediatr 15

Diagnosis, and Treatment DOI: 10.1159/000479371
estimates were derived from low-quality evidence involv-
ing small studies and that further research is required
[227].
2.2 Anti-Androgens
Two types of anti-androgens are used in the manage-
ment of PCOS: androgen receptor blockers like spirono-
lactone, flutamide, and the third generation progestin,
cyproterone acetate, and inhibitors of 5-alpha reductase
such as finasteride, which prevents the conversion of tes-
tosterone to DHT. In adolescents with PCOS, direct com-
parisons of the various anti-androgens or RCTs are not
available [228, 229]. Spironolactone is the most common-
ly used because of its availability and safety profile, with
an initial dose of 25 mg/day gradually increasing up to
200 mg/day. At initiation, spironolactone may be associ-
ated with transient menstrual irregularity or spotting,
breast tenderness, and occasionally fatigue or orthostasis
from volume depletion. Flutamide is not available in
some countries and is used sparingly because of concerns
regarding its potential hepatotoxicity at high doses (>250
mg/day). Evidence indicates that 1 mg/kg/day is effective
and not hepatotoxic, even with extended use [230]. Data
on efficacy of spironolactone compared to flutamide are
limited, and the methodological quality of the studies is
low [231]. Anti-androgens significantly reduce hirsutism
compared with placebo [232] and normalize menstrual
cyclicity and endocrine-metabolic variables better than
monotherapy with metformin [231]. The efficacy is en-
hanced when combined with OCP, metformin, or other
anti-androgens [231–234]. In sexually active adolescents,
anti-androgens should only be used when adequate con-
traceptive measures are ensured, to avoid incomplete vir-
ilization of male fetuses.
2.3. Oral Contraceptive Pills
Combination OCP containing an estrogen component
(typically ethinylestradiol) and a progestin component
address multiple concerns in adolescents with PCOS. An
increase in SHBG and decreased LH release due to the
estrogen component leads to a decreased free androgen
index, and the progestin component allows for suppres-
sion of endometrial proliferation and regular withdrawal
bleeding. As such, there is improvement in acne and hir-
sutism and reduction in menstrual irregularity with OCP.
Unfortunately, there are few RCTs comparing the relative
efficacy or metabolic impact of the different formulations
of hormonal contraceptives in adolescents. An RCT com-
paring the progestins desogestrel and cyproterone acetate
in combination with ethinylestradiol found equal im-
16 Horm Res Paediatr
DOI: 10.1159/000479371
provements in hirsutism, but total and LDL cholesterol
were increased by both formulations [235]. Additionally,
there was evidence for worsening of HOMA-IR and fast-
ing glycemia with both preparations [236]. Metabolic
changes overall, however, did not result in significant
concentrations outside the normal ranges. In young
women with PCOS (aged 20–25 years) treated with an
OCP containing drospirenone versus a combined contra-
ceptive vaginal ring, an RCT suggested that both methods
worsened the lipid profile, but OCP significantly wors-
ened triglycerides while remaining within the normal
range [237]. In adult women, an RCT involving OCP with
3 different progestins (desogestrel, drospirenone, and cy-
proterone acetate) showed identical metabolic impact
[238]. Overall, high-quality RCTs of specific OCP formu-
lations for adolescents with PCOS are lacking to fully in-
form decision-making in this population; no specific for-
mulation can be recommended over another.
2.4. Combination Treatments
Combination treatments under development for
PCOS in adolescent girls aim at improving the function
of multiple pathways and at obtaining additive/synergis-
tic actions that lead collectively to a profile with high ben-
efit and low risk. Lifestyle improvement is the baseline
treatment for most adolescent girls with PCOS, particu-
larly if overweight or obese (see Lifestyle Intervention
section C.1.1.). In most adolescents with PCOS, the addi-
tion of an OCP will be followed by a reduction of PCOS
symptoms via normalization of circulating free andro-
gens (primarily due to increased circulating SHBG con-
centrations) and via pseudo-normalization of the men-
strual pattern within a state of anovulatory infertility (see
Oral Contraceptive Pills section C.2.3.).
Slower reductions of PCOS symptoms can be obtained
with combinations of insulin-sensitizing and anti-andro-
genic generics, the most promising low-dose combina-
tion nowadays perhaps being that of metformin (850 mg/
day), spironolactone (50 mg/day), and pioglitazone (7.5
mg/day) [239]. This triple combination appears to nor-
malize cardiovascular risk and body composition more
than combinations of only metformin and an anti-andro-
gen [54, 234] and to result in a more favorable post-treat-
ment pattern of circulating androgens and ovulation rates
than oral contraceptive intake [239].
3. Reproductive Aspects
3.1. Ovulation
Ovulation may occur in about 10% of adult women
with PCOS. The frequency of ovulation in adolescent
Ibáñez et al.
PCOS is unknown. In normal puberty, menarche is fol-
lowed by an interval of anovulatory bleeding of variable
length. During this interval, synchronization of hypotha-
lamic-pituitary-ovarian activity takes place that leads to
ovulation and regular menstrual cycles. In adolescent
PCOS, there is persisting anovulation in most but not all
individuals. Notably, girls with premature pubarche (PP)
that are at risk for PCOS may exhibit ovulatory frequency
(25%) during early postmenarche (1–3 years), which is
indistinguishable from non-PP individuals [240]. Beyond
3 years after menarche, the ovulatory rate in PP was re-
duced. It was also noted that some early postmenarchal
adolescents (<3 years) with irregular menstruation and
elevated androgen levels followed for 3 years developed
regular ovulatory cycles [182]. These findings suggest
that in some adolescents with or at risk for PCOS, normal
ovulatory function may exist or emerge with time and
present as ovulatory adolescent PCOS.
3.2 Contraception
There is no evidence to suggest a decreased pregnancy
risk in adolescents with PCOS compared to that of adult
women with PCOS. Given that ovulation may occur
spontaneously despite a pattern of chronic menstrual ir-
regularity, contraceptive decision-making is important
in sexually active adolescents with this disorder. Men-
strual irregularity and menorrhagia in adolescents with
PCOS can be difficult to manage without hormonal in-
tervention. Accordingly, OCP are recommended as a
first-line therapy for adolescents with PCOS consistent
with published guidelines [134]. The anti-androgenic
properties of OCP and the benefit of menstrual control
make them an excellent contraceptive choice in young
women with PCOS. Medical contraindications for the
use of OCP are outlined in the 2010 Center for Disease
Control guidelines [241]. The potential metabolic impact
of OCP in PCOS is outlined in the above section (see Oral
Contraceptives section C.2.3.). The use of progestin-only
contraception, such as depot medroxyprogesterone ace-
tate, is associated with weight gain in adolescents and
possibly bone loss, although this is recoverable [242,
243]. Progestin-only therapy does not raise SHBG as do
OCP containing ethinylestradiol. The progestin-only in-
trauterine device may be an alternative first-line therapy
given the low systemic impact and overall high contra-
ceptive effectiveness [244]. Overall, there is a lack of
high-quality RCTs of contraceptive treatment options
for adolescents with PCOS to fully inform decision-mak-
ing in this population.
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
4. Transition
Management of girls with PCOS should focus on ap-
propriate diagnosis, reduction of symptoms in adoles-
cence, and improvement of post-treatment health in
adulthood. Specific therapeutic goals include attenua-
tion of pregestational oligo-anovulation (thus the need
for assisted reproduction) and reduction of gestational
complications such as diabetes mellitus, preeclampsia,
and preterm delivery [245]. Given the apparent role of
hepato-visceral fat excess in the pathogenesis of anovula-
tory androgen excess [246, 247], PCOS therapy in ado-
lescence should also aim at reducing hepato-visceral ad-
iposity via lifestyle measures leading to weight loss in
obese girls (see Lifestyle Intervention section C.1.1.) and
via pharmacological measures. These approaches would
enhance the preferential loss of central fat in non-obese
girls with a low subcutaneous fat storage capacity, such
as girls with a lipodystrophy, girls with ethnic back-
grounds associated with a high risk of developing diabe-
tes, and girls with a history of prenatal growth restraint
[54]. The more low-risk and/or low-cost interventions
for PCOS during adolescence, the fewer high-risk and/or
high-cost treatments will be needed during adulthood,
and the better the outlook will be for the offspring of
PCOS mothers.
C. Treatment: Conclusions with Level of Evidence
1. Baseline Treatments
1.1. Lifestyle Intervention
• Lifestyle intervention should be based on the combi-
nation of calorie-restricted diets, behavioral treat-
ment, and exercise (Level A).
• Combined weight loss and physical exercise are the
first-line therapy in overweight and obese girls (Level
C). They decrease androgen levels, normalize men-
strual cycles (Level A), and improve markers of cardio-
metabolic health (Level B).
• Extremely obese adolescents respond poorly to life-
style intervention (Level B).
• In normal-weight girls, increasing physical activity is
effective in reducing the development of metabolic
syndrome (Level C). However, the benefits of exclu-
sive weight loss in these adolescents are not supported
by RCTs (Level C).
1.2 Local Therapies/Cosmetic
• Photoepilation is the first-line management of localized
hirsutism in PCOS (Level B). Diode and alexandrite la-
Horm Res Paediatr 17
DOI: 10.1159/000479371
 sers are preferred (Level C). The alexandrite laser is su-
perior to IPL methods in facial hirsutism (Level B).
• Topical eflornithine is recommended as an adjuvant
to photoepilation in girls with laser-resistant facial
hirsutism aged 16 years or older, or as monotherapy
in those where photoepilation is not indicated (Level
A).
• The use of topical finasteride is not recommended
based on existing data (Level C).
2. Additive Pharmaceuticals
2.1 Metformin
• Metformin has beneficial effects in overweight or
obese adolescents with PCOS, but only short-term
data are available (Level A).
• In non-obese adolescents with PCOS and hyperinsu-
linemia, metformin improves ovulation and testoster-
one levels (Level B).
2.2. Anti-Androgens
• Anti-androgens reduce androgen excess features more
than metformin in monotherapy (Level B). Spirono-
lactone is the most commonly used albeit data on ef-
ficacy compared to flutamide are limited (Level C).
• Anti-androgens should only be used when contracep-
tive measures are guaranteed.
2.3. Oral Contraceptive Pills
• There are no high-quality RCTs of specific OCP for-
mulations for adolescents with PCOS to help decision-
making in this population, and no specific formulation
can be recommended over another (Level B).
2.4. Combination Treatments
• Where available, triple low-dose combinations of in-
sulin-sensitizing and anti-androgenic generics nor-
malize cardiovascular risk and body composition
more than combinations of only metformin and an
anti-androgen and result in a more favorable post-
treatment pattern of circulating androgens and ovula-
tion rates than OCP intake (Level A).
3. Reproductive Aspects
• In some adolescents with or at risk for PCOS, normal
ovulatory function may exist or emerge with time and
present as ovulatory adolescent PCOS (Level A).
4. Transition
• PCOS therapy in adolescence should aim at decreasing
hepato-visceral adiposity, enhancing central fat loss,
18 Horm Res Paediatr
DOI: 10.1159/000479371
and thus, attenuating pregestational oligo-anovula-
tion, and reducing gestational complications such as
diabetes mellitus, preeclampsia, and preterm delivery
(Level B).
Conclusion
This first global update on the pathophysiology, diag-
nosis, and treatment of adolescent PCOS is the outcome
of an international collaborative effort initiated by Pedi-
atric Endocrine Societies.
One aim of this update was to offer a more develop-
mental perspective than previous reports on adolescent
PCOS. The authors have attempted to merge many opin-
ions on much evidence, and they realize that there may be
apparent inconsistencies between consecutive sections.
Hence, this report discloses the many uncertainties and
knowledge gaps persisting at the time of writing.
A second aim of this initiative was to document the
main directions of past, present, and future investigations
into adolescent PCOS. In the past, the keywords for
pathogenesis, diagnosis, and treatment may have been,
respectively, ovarian and adrenal steroidogenesis, IR and
LH hypersecretion; hirsutism and menstrual pattern; cos-
metics and oral contraceptives. Current focuses have
shifted to include (epi)genetics and body adiposity; an-
drogens (by LC-MS/MS) and ovulatory function; lifestyle
measures, insulin sensitization and anti-androgens. In
the near future, the keywords are expected to include ec-
topic lipids and microbiome; miRNAs, metabolomics,
and adipo-, hepato-, myo-, and osteo-kines. Treatment
will aim at a slow but steady return to an overall healthy
state with combination therapies that may vary over time
and allow for spontaneous ovulations, uncomplicated
pregnancies, and healthy offspring.
Finally and most importantly, this global update
should contribute to improvement of the care worldwide
for adolescent girls with PCOS.
Appendix
S.E.O., S.F.W., and P.A.L. are members of the Pediatric Endo-
crine Society (PES); L.I., S.F.W., F.D., A.G., A.L.-B., K.O., T.R., N.S.,
F.Z., and P.A.L. are members of the European Society for Paediatric
Endocrinology (ESPE); C.G.R. and A.S.P. are members of the Aus-
tralasian Paediatric Endocrine Group (APEG); P.D. is a member of
the Asia Pacific Paediatric Endocrine Society (APPES); D.J. is a mem-
ber of the African Society for Paediatric and Adolescent Endocrinol-
ogy (ASPAE); Xiao-Ping Luo is a member of the Chinese Society of
Pediatric Endocrinology and Metabolism (CSPEM); R.H. is a mem-
Ibáñez et al.
ber of the Japanese Society for Pediatric Endocrinology (JSPE); E.C. Acknowledgement
is a member of the Sociedad Latinoamericana de Endocrinología
Pediátrica (SLEP); N.S.E., H.A., and A.D. are members of the Arab We would like to acknowledge Dr. Xiao-Ping Luo for represent-
Society of Paediatric Endocrinology and Diabetes (ASPED); P.D. is ing the Chinese Society of Pediatric Endocrinology and Metabolism
a member of the Indian Society for Pediatric and Adolescent Endo- (CSPEM).
crinology (ISPAE); S.F.W., S.E.O., R.J.C., and K.M.H. are members
of The Androgen Excess and PCOS Society (AE-PCOS); and R.J.A.,
and M.T.-S. are members of the Endocrine Society (ES).

References
  1 Azziz R, Dumesic DA, Goodarzi MO: Poly-
cystic ovary syndrome: an ancient disorder?
Fertil Steril 2011;95:1544–1548.
  2 Unluturk U, Sezgin E, Yildiz BO: Evolution-
ary determinants of polycystic ovary syn-
drome: part 1. Fertil Steril 2016;106:33–41.
  3 Azziz R, Carmina E, Chen Z, Dunaif A, Laven
JS, Legro RS, Lizneva D, Natterson-Horowtiz
B, Teede HJ, Yildiz BO: Polycystic ovary syn-
drome. Nat Rev Dis Primers 2016;2:16057.
 4 Oberfield SE, Sopher AB, Gerken AT: Ap-
proach to the girl with early onset of pubic
hair. J Clin Endocrinol Metab 2011;96:1610–
1622.
  5 Chang AY, Abdullah SM, Jain T, Stanek HG,
Das SR, McGuire DK, Auchus RJ, de Lemos
JA: Associations among androgens, estro-
gens, and natriuretic peptides in young wom-
en: observations from the Dallas Heart Study.
J Am Coll Cardiol 2007;49:109–116.
  6 Hsueh AJ, Kawamura K, Cheng Y, Fauser BC:
Intraovarian control of early folliculogenesis.
Endocr Rev 2015;36:1–24.
  7 Franks S, Stark J, Hardy K: Follicle dynamics
and anovulation in polycystic ovary syn-
drome. Hum Reprod Update 2008; 14: 367–
378.
  8 Lebbe M, Woodruff TK: Involvement of an-
drogens in ovarian health and disease. Mol
Hum Reprod 2013:19:828–837.
  9 Webber LJ, Stubbs S, Stark J, Trew GH, Mar-
gara R, Hardy K, Franks S: Formation and
early development of follicles in the polycystic
ovary. Lancet 2003;362:1017–1021.
10 Nelson VL, Legro RS, Strauss JF 3rd, McAl-
lister JM: Augmented androgen production is
a stable steroidogenic phenotype of propagat-
ed theca cells from polycystic ovaries. Mol En-
docrinol 1999;13:946–957.
11 Marti N, Galván JA, Pandey AV, Trippel M,
Tapia C, Müller M, Perren A, Flück CE: Genes
and proteins of the alternative steroid back-
door pathway for dihydrotestosterone synthe-
sis are expressed in the human ovary and seem
enhanced in the polycystic ovary syndrome.
Mol Cell Endocrinol 2017;441:116–123.
12 McAllister JM, Modi B, Miller BA, Biegler J,
Bruggeman R, Legro RS, Strauss JF 3rd: Over-
expression of a DENND1A isoform produces
a polycystic ovary syndrome theca pheno-
type. Proc Natl Acad Sci USA 2014; 111:
E1519–E1527.
13 Tee MK, Speek M, Legeza B, Modi B, Teves
ME, McAllister JM, Strauss JF 3rd, Miller WL:
Alternative splicing of DENND1A, a PCOS
candidate gene, generates variant 2. Mol Cell
Endocrinol 2016;434:25–35.
14 Turcu A, Smith JM, Auchus R, Rainey WE: Ad-
renal androgens and androgen precursors-def-
inition, synthesis, regulation and physiologic
actions. Compr Physiol 2014;4:1369–1381.
15 O’Reilly MW, Kempegowda P, Jenkinson C,
Taylor AE, Quanson JL, Storbeck KH, Arlt W:
11-oxygenated C19 steroids are the predomi-
nant androgens in polycystic ovary syn-
drome. J Clin Endocrinol Metab 2017; 102:
840–848.
16 Dunaif A, Segal KR, Shelley DR, Green G, Do-
brjansky A, Licholai T: Evidence for distinc-
tive and intrinsic defects in insulin action in
polycystic ovary syndrome. Diabetes 1992;41:
1257–1266.
17 Dunaif A, Graf M, Mandeli J, Laumas V, Do-
brjansky A: Characterization of groups of hy-
perandrogenic women with acanthosis nigri-
cans, impaired glucose tolerance, and/or hy-
perinsulinemia. J Clin Endocrinol Metab
1987;65:499–507.
18 Diamanti-Kandarakis E, Dunaif A: Insulin re-
sistance and the polycystic ovary syndrome
revisited: an update on mechanisms and im-
plications. Endocr Rev 2012;33:981–1030.
19 Moran A, Jacobs DR Jr, Steinberger J, Hong
CP, Prineas R, Luepker R, Sinaiko AR: Insulin
resistance during puberty: results from clamp
studies in 357 children. Diabetes 1999; 48:
2039–2044.
20 Amiel SA, Sherwin RS, Simonson DC, Lauri-
tano AA, Tamborlane WV: Impaired insulin
action in puberty. A contributing factor to
poor glycemic control in adolescents with di-
abetes. N Engl J Med 1986;315:215–219.
21 Ball GD, Huang TT, Gower BA, Cruz ML,
Shaibi GQ, Weigensberg MJ, Goran MI: Lon-
gitudinal changes in insulin sensitivity, insu-
lin secretion, and beta-cell function during
puberty. J Pediatr 2006;148:16–22.
22 Saenger P: Metabolic consequences of growth
hormone treatment in paediatric practice.
Horm Res 2000;53(suppl 1):60–69.
23 Geffner ME, Golde DW: Selective insulin ac-
tion on skin, ovary, and heart in insulin-resis-
tant states. Diabetes Care 1988;11:500–505.
24 Stepto NK, Cassar S, Joham AE, Hutchison
SK, Harrison CL, Goldstein RF, Teede HJ:
Women with polycystic ovary syndrome have
intrinsic insulin resistance on euglycaemic-
hyperinsulaemic clamp. Hum Reprod 2013;
28:777–784.
25 Morciano, A. Romani F, Sagnella F, Scarinci
E, Palla C, Moro F, Tropea A, Policola C, Del-
la Casa S, Guido M, Lanzone A, Apa R: As-
sessment of insulin resistance in lean women
with polycystic ovary syndrome. Fertil Steril
2014;102:250–256.
26 Willis D, Franks S: Insulin action in human
granulosa cells from normal and polycystic ova-
ries is mediated by the insulin receptor and not
the type-I insulin-like growth factor receptor. J
Clin Endocrinol Metab 1995;80:3788–3790.
27 Nestler JE, Powers LP, Matt DW, Steingold
KA, Plymate SR, Rittmaster RS, Clore JN,
Blackard WG: A direct effect of hyperinsu-
linemia on serum sex hormone-binding glob-
ulin levels in obese women with the polycystic
ovary syndrome. J Clin Endocrinol Metab
1991;72:83–89.
28 Adashi EY, Hsueh AJW, Yen SSC: Insulin en-
hancement of luteinizing hormone and follicle-
stimulating hormone release by cultured pitu-
itary cells. Endocrinology 1981;108:1441–1449.
29 Torchen LC, Fogel NR, Brickman WJ, Papa-
rodis R, Dunaif A: Persistent apparent pan-
creatic β-cell defects in premenarchal PCOS
relatives. J Clin Endocrinol Metab 2014; 99:
3855–3862.
30 Taylor SI, Cama A, Accili D, Barbetti F, Quon
MJ, de la Luz Sierra M, Suzuki Y, Koller E,
Levy-Toledano R, Wertheimer E, Moncadaj
VY, Kadowaki H, Kadowaki T: Mutations in
the insulin receptor gene. Endocr Rev 1992;
13:566–595.
31 Moller DE, Flier JS: Insulin resistance – mech-
anisms, syndromes, and implications. N Engl
J Med 1991;325:938–948.
32 Corbould A: Effects of androgens on insulin
action in women: is androgen excess a com-
ponent of female metabolic syndrome? Dia-
betes Metab Res Rev 2008;24:520–532.
33 Soldani, R, Cagnacci A, Yen SSC: Insulin in-
sulin-like growth factor I (IGF-I) and IGF-II
enhance basal and gonadotrophin-releasing
hormone-stimulated luteinizing hormone re-
lease from rat anterior pituitary cells in vitro.
Eur J Endocrinol 1994;131:641–645.

Update: PCOS Pathophysiology, Horm Res Paediatr 19

Diagnosis, and Treatment DOI: 10.1159/000479371
34 O’Connor A, Phelan N, Tun TK, Boran G, Gib-
ney J, Roche HM: High-molecular-weight adi-
ponectin is selectively reduced in women with
polycystic ovary syndrome independent of body
mass index and severity of insulin resistance. J
Clin Endocrinol Metab 2010;95:1378–1385.
35 O’Reilly M, Gathercole L, Capper F, Arlt W,
Tomlinson J: Effect of insulin on AKR1C3 ex-
pression in female adipose tissue: in-vivo and
in-vitro study of adipose androgen generation
in polycystic ovary syndrome. Lancet 2015;
385(suppl 1):S16.
36 Lim SS, Davies MJ, Norman RJ, Moran LJ:
Overweight, obesity and central obesity in
women with polycystic ovary syndrome: a
systematic review and meta-analysis. Hum
Reprod Update 2012;18:618–637.
37 Hoeger KM: Obesity and lifestyle manage-
ment in polycystic ovary syndrome. Clin Ob-
stet Gynecol 2007;50:277–294.
38 Sinha R, Fisch G, Teague B, Tamborlane WV,
Banyas B, Allen K, Savoye M, Rieger V, Tak-
sali S, Barbetta G, Sherwin RS, Caprio S: Prev-
alence of impaired glucose tolerance among
children and adolescents with marked obesi-
ty. N Engl J Med 2002;346:802–810.
39 Hughan KS, Tfayli H, Warren-Ulanch JG, Ba-
rinas-Mitchell E, Arslanian SA: Early bio-
markers of subclinical atherosclerosis in
obese adolescent girls with polycystic ovary
syndrome. J Pediatr 2016;168:104–111.
40 Puder JJ: Central fat excess in polycystic ovary
syndrome: relation to low-grade inflamma-
tion and insulin resistance. J Clin Endocrinol
Metab 2005;90:6014–6021.
41 Pasquali R, Casimirri F, Venturoli S, Antonio
M, Morselli L, Reho S, Pezzoli A, Paradisi R:
Body fat distribution has weight-independent
effects on clinical, hormonal, and metabolic
features of women with polycystic ovary syn-
drome. Metabolism 1994;43:706–713.
42 Ojeda-Ojeda M, Murri M, Insenser M, Esco-
bar-Morreale HF: Mediators of low-grade
chronic inflammation in polycystic ovary
syndrome (PCOS). Curr Pharm Des 2013;19:
5775–5791.
43 Lambert EA, Teede H, Sari CI, Jona E, Shor-
akae S, Woodington K, Hemmes R, Eikelis N,
Straznicky NE, De Courten B, Dixon JB,
Schlaich MP, Lambert GW: Sympathetic acti-
vation and endothelial dysfunction in poly-
cystic ovary syndrome are not explained by
either obesity or insulin resistance. Clin En-
docrinol (Oxf) 2015;83:812–819.
44 de Zegher F, López-Bermejo A, Ibáñez L: Ad-
ipose tissue expandability and the early ori-
gins of PCOS. Trends Endocrinol Metab
2009;20:418–423.
45 de Zegher F, Reinher T, Malpique R, Daren-
deliler F, López-Bermejo A, Ibáñez L: Re-
duced prenatal weight gain and/or augment-
ed postnatal weight gain precede polycystic
ovary syndrome in adolescent girls. Obesity
(Silver Spring) 2017;25:1486–1489. DOI:
10.1002/oby.21935.
20 Horm Res Paediatr
DOI: 10.1159/000479371
46 Escobar-Morreale HF, Luque-Ramírez M,
González F: Circulating inflammatory mark-
ers in polycystic ovary syndrome: a system-
atic review and metaanalysis. Fertil Steril
2011;95:1048–1058.
47 Spranger J, Kroke A, Mohlig M, Hoffmann K,
Bergmann MM, Ristow M, Boeing H, Pfeiffer
AF: Inflammatory cytokines and the risk to de-
velop type 2 diabetes: Results of the prospective
population-based European Prospective Inves-
tigation into Cancer and Nutrition (EPIC)-
Potsdam Study. Diabetes 2003;52:812–817.
48 Ciaraldi TP, Carter L, Nikoulina S, Mudaliar
S, McClain DA, Henry RR: Glucosamine reg-
ulation of glucose metabolism in cultured hu-
man skeletal muscle cells: divergent effects on
glucose transport/phosphorylation and gly-
cogen synthase in non-diabetic and type 2 di-
abetic subjects. Endocrinology 1999; 140:
3971–380.
49 Previs SF, Withers DJ, Ren JM, White MF,
Shulman GI: Contrasting effects of IRS-1 ver-
sus IRS-2 gene disruption on carbohydrate
and lipid metabolism. J Biol Chem 2000;275:
38990–38994.
50 Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q,
Crenshaw EB 3rd, Kaestner KH, Bartolomei
MS, Shulman GI, Birnbaum MJ: Insulin resis-
tance and a diabetes mellitus-like syndrome
in mice lacking the protein kinase Akt2
(PKBb). Science 2001;292:1728–1731.
51 Carpentier AC: Postprandial fatty acid me-
tabolism in the development of lipotoxicity
and type 2 diabetes. Diabetes Metab 2008;34:
97–107.
52 Gambineri A, Pelusi C, Vicennati V, Pagotto
U, Pasquali R: Obesity and the polycystic ova-
ry syndrome. Int J Obes Relat Metab Disord
2002;26:883–96.
53 Lord J, Wilkin T: Polycystic ovary syndrome
and fat distribution: the central issue? Hum
Fertil (Cambr) 2002;5:67–71.
54 Ibáñez L, Ong KK, López-Bermejo A, Dunger
DB, de Zegher F: Hyperinsulinaemic andro-
gen excess in adolescent girls. Nat Rev Endo-
crinol 2014;10:499–508.
55 Dhindsa G, Bhatia R, Dhindsa M, Bhatia V:
Insulin resistance, insulin sensitization and
inflammation in polycystic ovarian syndrome
inflammation in polycystic ovarian syndrome
inflammation in polycystic ovarian syn-
drome. J Postgrad Med 2004;50:140–144.
56 Adams J, Liu Z, Ren YA, Wun WS, Zhou W,
Kenigsberg S, Librach C, Valdes C, Gibbons
W, Richards J: Enhanced inflammatory tran-
scriptome in the granulosa cells of women
with polycystic ovarian syndrome. J Clin En-
docrinol Metab 2016;101:3459–3468.
57 Schmidt J, Weijdegard B, Mikkelsen AL, Lin-
denberg S, Nilsson L, Brannstrom M: Differ-
ential expression of inflammation-related
genes in the ovarian stroma and granulosa
cells of PCOS women. Mol Hum Reprod
2014;20:49–58.
58 Jornayvaz FR, Shulman GI: Diacylglycerol ac-
tivation of protein kinase Cε and hepatic in-
sulin resistance. Cell Metab 2012;15:574–584.
59 Badin PM, Langin D, Moro C: Dynamics of
skeletal muscle lipid pools. Trends Endocri-
nol Metab 2013;24:607–615.
60 Chavez JA, Summers SA: A ceramide-centric
view of insulin resistance. Cell Metab 2012;15:
585–594.
61 Bruning JC, Gautam D, Burks DJ, Gillette J,
Schubert M, Orban PC, Klein R, Krone W,
Muller-Wieland D, Kahn CR: Role of brain
insulin receptor in control of body weight and
reproduction. Science 2000;289:2122–2125.
62 Fauser BC, Tarlatzis BC, Rebar RW, Legro RS,
Balen AH, Lobo R, Carmina E, Chang J, Yildiz
BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne
CN, Norman RJ, Dunaif A, Franks S, Wild RA,
Dumesic D, Barnhart K: Consensus on wom-
en’s health aspects of polycystic ovary syn-
drome (PCOS): the Amsterdam ESHRE/AS-
RM-Sponsored 3rd PCOS Consensus Work-
shop Group. Fertil Steril 2012;97:28–38.e25.
63 Dumesic DA, Oberfield SE, Stener-Victorin
E, Marshall JC, Laven JS, Legro RS: Scientific
statement on the diagnostic criteria, epidemi-
ology, pathophysiology, and molecular genet-
ics of polycystic ovary syndrome. Endocr Rev
2015;36:487–525.
64 Rosenfield RL, Ehrmann DA: The pathogen-
esis of polycystic ovary syndrome (PCOS): the
hypothesis of PCOS as functional ovarian hy-
perandrogenism revisited. Endocr Rev 2016;
37:467–520.
65 Taylor AE, McCourt B, Martin KA, Anderson
EJ, Adams JM, Schoenfeld D, Hall JE: Deter-
minants of abnormal gonadotropin secretion
in clinically defined women with polycystic
ovary syndrome. J Clin Endocrinol Metab
1997;82 2248–56.
66 Moenter SM: Leap of faith: does serum lutein-
izing hormone always accurately reflect cen-
tral reproductive neuroendocrine activity?
Neuroendocrinology 2015;102:256–266.
67 Thompson IR, Kaiser UB: GnRH pulse fre-
quency-dependent differential regulation of
LH and FSH gene expression. Mol Cell Endo-
crinol 2014;385:28–35.
68 Moore AM, Campbell RE: The neuroendo-
crine genesis of polycystic ovary syndrome: a
role for arcuate nucleus GABA neurons. J Ste-
roid Biochem Mol Biol 2016;160:106–117.
69 Eagleson CA, Gingrich MB, Pastor CL,
Arora TK, Burt CM, Evans WS, Marshall JC:
Polycystic ovarian syndrome: evidence that
flutamide restores sensitivity of the gonadotro-
pin-releasing hormone pulse generator to in-
hibition by estradiol and progesterone. J Clin
Endocrinol Metab 2000;85:4047–52.
70 Pinilla L, Aguilar E, Dieguez C, Millar RP, Te-
na-Sempere M: Kisspeptins and reproduc-
tion: physiological roles and regulatory mech-
anisms. Physiol Rev 2012;92:1235–316.
71 Oakley AE, Clifton DK, Steiner RA: Kiss-
peptin signaling in the brain. Endocr Rev
2009;30:713–43.
72 Navarro VM, Tena-Sempere M: Neuroendo-
crine control by kisspeptins: role in metabolic
regulation of fertility. Nat Rev Endocrinol
2012;8:40–53.
Ibáñez et al.
73 Lehman MN, Coolen LM, Goodman RL:
Minireview: kisspeptin/neurokinin B/dynor-
phin (KNDy) cells of the arcuate nucleus: a
central node in the control of gonadotropin-
releasing hormone secretion. Endocrinology
2010;151:3479–3489.
74 Brown RE, Wilkinson DA, Imran SA, Caraty
A, Wilkinson M: Hypothalamic kiss1 mRNA
and kisspeptin immunoreactivity are reduced
in a rat model of polycystic ovary syndrome
(PCOS). Brain Res 2012;1467:1–9.
75 Navarro VM, Sánchez-Garrido MA, Caste­
llano JM, Roa J, García-Galiano D, Pineda R,
Aguilar E, Pinilla L, Tena-Sempere M: Persis-
tent impairment of hypothalamic KiSS-1 sys-
tem after exposures to estrogenic compounds
at critical periods of brain sex differentiation.
Endocrinology 2009;150:2359–2367.
76 Fraser GL, Hoveyda HR, Clarke IJ, Ramaswa-
my S, Plant TM, Rose C, Millar RP: The NK3
receptor antagonist ESN364 interrupts pulsa-
tile LH secretion and moderates levels of
ovarian hormones throughout the menstrual
cycle. Endocrinology 2015;156:4214–4225.
77 George JT, Kakkar R, Marshall J, Scott ML,
Finkelman RD, Ho TW, Veldhuis J, Skorup-
skaite K, Anderson RA, McIntosh S, Webber
L: Neurokinin B receptor antagonism in
women with polycystic ovary syndrome: a
randomized, placebo-controlled trial. J Clin
Endocrinol Metab 2016;101:4313–4321.
78 Narayanaswamy S, Prague JK, Jayasena CN,
Papadopoulou DA, Mizamtsidi M, Shah AJ,
Bassett P, Comninos AN, Abbara A, Bloom
SR, Veldhuis JD, Dhillo WS: Investigating the
KNDy hypothesis in humans by coadminis-
tration of kisspeptin, neurokinin B, and nal-
trexone in men. J Clin Endocrinol Metab
2016;101:3429–3436.
79 Ruiz-Pino F, Garcia-Galiano D, Manfredi-
Lozano M, Leon S, Sánchez-Garrido MA, Roa
J, Pinilla L, Navarro VM, Tena-Sempere M:
Effects and interactions of tachykinins and
dynorphin on FSH and LH secretion in devel-
oping and adult rats. Endocrinology 2015;
156:576–588.
80 García-Galiano D, Pineda R, Roa J, Ruiz-Pino
F, Sánchez-Garrido MA, Castellano JM,
Aguilar E, Navarro VM, Pinilla L, Tena-Sem-
pere M: Differential modulation of gonado-
tropin responses to kisspeptin by aminoaci-
dergic, peptidergic, and nitric oxide neuro-
transmission. Am J Physiol Endocrinol Metab
2012;303:E1252–E1263.
81 Moore AM, Prescott M, Marshall CJ, Yip SH,
Campbell RE: Enhancement of a robust arcu-
ate GABAergic input to gonadotropin-releas-
ing hormone neurons in a model of polycystic
ovarian syndrome. Proc Natl Acad Sci USA
2015;112:596–601.
82 Herbison AE, Moenter SM: Depolarising and
hyperpolarising actions of GABA(A) receptor
activation on gonadotrophin-releasing hor-
mone neurones: towards an emerging con-
sensus. J Neuroendocrinol 2011;23:557–569.
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
83 Cimino I, Casoni F, Liu X, Messina A, Parkash
J, Jamin SP, Catteau-Jonard S, Collier F, Ba­
roncini M, Dewailly D, Pigny P, Prescott M,
Campbell R, Herbison AE, Prevot V, Giaco-
bini P: Novel role for anti-Mullerian hormone
in the regulation of GnRH neuron excitability
and hormone secretion. Nat Commun 2016;
7:10055.
84 Moret M, Stettler R, Rodieux F, Gaillard RC,
Waeber G, Wirthner D, Giusti V, Tappy L,
Pralong FP: Insulin modulation of luteinizing
hormone secretion in normal female volun-
teers and lean polycystic ovary syndrome pa-
tients. Neuroendocrinology 2009;89:131–139.
85 Patel K, Coffler MS, Dahan MH, Yoo RY,
Lawson MA, Malcom PJ, Chang RJ: Increased
luteinizing hormone secretion in women with
polycystic ovary syndrome is unaltered by
prolonged insulin infusion. J Clin Endocrinol
Metab 2003;88:5456–5461.
86 Divall SA, Williams TR, Carver SE, Koch L,
Brüning JC, Kahn CR, Wondisford F, Ra-
dovick S, Wolfe A: Divergent roles of growth
factors in the GnRH regulation of puberty in
mice. J Clin Invest 2010;120:2900–2909.
87 Cernea M, Phillips R, Padmanabhan V, Cool-
en LM, Lehman MN: Prenatal testosterone
exposure decreases colocalization of insulin
receptors in kisspeptin/neurokinin B/dynor-
phin and agouti-related peptide neurons of
the adult ewe. Eur J Neurosci 2016; 44: 2557–
2568.
88 Qiu X, Dao H, Wang M, Heston A, Garcia
KM, Sangal A, Dowling AR, Faulkner LD,
Molitor SC, Elias CF, Hill JW: Insulin and
leptin signaling interact in the mouse Kiss1
neuron during the peripubertal period. PLoS
One 2015;10:e0121974.
89 Evans MC, Rizwan M, Mayer C, Boehm U,
Anderson GM: Evidence that insulin signal-
ling in gonadotrophin-releasing hormone
and kisspeptin neurones does not play an es-
sential role in metabolic regulation of fertil-
ity in mice. J Neuroendocrinol 2014; 26: 468–
479.
90 Toulis KA, Goulis DG, Farmakiotis D, Geor-
gopoulos NA, Katsikis I, Tarlatzis BC, Papa­
dimas I, Panidis D: Adiponectin levels in
women with polycystic ovary syndrome: a
systematic review and a meta-analysis. Hum
Reprod Update 2009;15:297–307.
91 Yuan X, Hu T, Zhao H, Huang Y, Ye R, Lin J,
Zhang C, Zhang H, Wei G, Zhou H, Dong M,
Zhao J, Wang H, Liu Q, Lee HJ, Jin W, Chen
ZJ: Brown adipose tissue transplantation
ameliorates polycystic ovary syndrome. Proc
Natl Acad Sci USA 2016;113:2708–2713.
92 Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y,
Li Z, You L, Zhao J, Liu J, Liang X, Zhao X,
Zhao J, Sun Y, Zhang B, Jiang H, Zhao D, Bian
Y, Gao X, Geng L, Li Y, Zhu D, Sun X, Xu JE,
Hao C, Ren CE, Zhang Y, Chen S, Zhang W,
Yang A, Yan J, Li Y, Ma J, Zhao Y: Genome-
wide association study identifies susceptibili-
ty loci for polycystic ovary syndrome on chro-
mosome 2p16.3, 2p21 and 9q33.3. Nat Genet
2011;43:55–59.
Horm Res Paediatr
DOI: 10.1159/000479371
93 Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z,
Zhang B, Liang X, Li T, Chen J, Shen J, Zhao
J, You L, Gao X, Zhu D, Zhao X, Yan Y, Qin
Y, Li W, Yan J, Wang Q, Zhao J, Geng L, Ma
J, Zhao Y, He G, Zhang A, Zou S, Yang A, Liu
J, Li W, Li B, Wan C, Qin Y, Shi J, Yang J, Jiang
H, Xu JE, Qi X, Sun Y, Zhang Y, Hao C, Ju X,
Zhao D, Ren CE, Li X, Zhang W, Zhang Y,
Zhang J, Wu D, Zhang C, He L, Chen ZJ: Ge-
nome-wide association study identifies eight
new risk loci for polycystic ovary syndrome.
Nat Genet 2012;44:1020–1025.
94 Hayes MG, Urbanek M, Ehrmann DA, Arm-
strong LL, Lee JY, Sisk R, Karaderi T, Barber
TM, McCarthy MI, Franks S, Lindgren CM,
Welt CK, Diamanti-Kandarakis E, Panidis D,
Goodarzi MO, Azziz R, Zhang Y, James RG,
Olivier M, Kissebah AH; Reproductive Medi-
cine Network, Stener-Victorin E, Legro RS,
Dunaif A: Genome-wide association of poly-
cystic ovary syndrome implicates alterations
in gonadotropin secretion in European ances-
try populations. Nat Commun 2015;18:7502.
95 Day FR, Hinds DA, Tung JY, Stolk L, Styrkars-
dottir U, Saxena R, Bjonnes A, Broer L, Dung-
er DB, Halldorsson BV, Lawlor DA, Laval G,
Mathieson I, McCardle WL, Louwers Y,
Meun C, Ring S, Scott RA, Sulem P, Uitterlin-
den AG, Wareham NJ, Thorsteinsdottir U,
Welt C, Stefansson K, Laven JS, Ong KK, Per-
ry JR: Causal mechanisms and balancing se-
lection inferred from genetic associations
with polycystic ovary syndrome. Nat Com-
mun 2015;6:8464.
96 Mbarek H, Steinberg S, Nyholt DR, Gordon
SD, Miller MB, McRae AF, Hottenga JJ, Day
FR, Willemsen G, de Geus EJ, Davies GE,
Martin HC, Penninx BW, Jansen R, McAlo-
ney K, Vink JM, Kaprio J, Plomin R, Spector
TD, Magnusson PK, Reversade B, Harris RA,
Aagaard K, Kristjansson RP, Olafsson I, Ey-
jolfsson GI, Sigurdardottir O, Iacono WG,
Lambalk CB, Montgomery GW, McGue M,
Ong KK, Perry JR, Martin NG, Stefánsson H,
Stefánsson K, Boomsma DI: Identification of
common genetic variants influencing spon-
taneous dizygotic twinning and female fertil-
ity. Am J Hum Genet 2016; 98: 898–908.
97 Mutharasan P, Galdones E, Peñalver Ber­nabé
B, Garcia OA, Jafari N, Shea LD, Woodruff
TK, Legro RS, Dunaif A, Urbanek M: Evi-
dence for chromosome 2p16.3 polycystic ova-
ry syndrome susceptibility locus in affected
women of European ancestry. J Clin Endocri-
nol Metab 2013;98:E185–E190.
98 Zhu JQ, Zhu L, Liang XW, Xing FQ, Schatten
H, Sun QY: Demethylation of LHR in dehy-
droepiandrosterone-induced mouse model of
polycystic ovary syndrome. Mol Hum Reprod
2010;16:260–266.
99 Wang P, Zhao H, Li T, Zhang W, Wu K, Li M,
Bian Y, Liu H, Ning Y, Li G, Chen ZJ: Hypo-
methylation of the LH/choriogonadotropin
receptor promoter region is a potential mech-
anism underlying susceptibility to polycystic
ovary syndrome. Endocrinology 2014; 155:
1445–1452.
21
100 Zhang Y, Fatima N, Dufau ML: Coordinated
changes in DNA methylation and histone
modifications regulate silencing/derepression
of luteinizing hormone receptor gene tran-
scription. Mol Cell Biol 2005;25:7929–7939.
101 Yu YY, Sun CX, Liu YK, Li Y, Wang L,
Zhang W: Promoter methylation of CY-
P19A1 gene in Chinese polycystic ovary syn-
drome patients. Gynecol Obstet Invest 2013;
76:209–213.
102 Sang Q, Li X, Wang H, Wang H, Zhang S, Xu
N, Kwon S, Abbott DH, Geller DH, Dumesic
DA, Azziz R, Guo X, Goodarzi MO: Quanti-
tative methylation level of the EPHX1 pro-
moter in peripheral blood DNA Is associated
with polycystic ovary syndrome. PLoS One
2014;9:e88013.
103 Qu F, Wang FF, Yin R, Ding GL, El-Prince
M, Gao Q, Shi BW, Pan HH, Huang YT, Jin
M, Leung PC, Sheng JZ, Huang HF: A mo-
lecular mechanism underlying ovarian dys-
function of polycystic ovary syndrome: hy-
perandrogenism induces epigenetic altera-
tions in the granulosa cells. J Mol Med 2012;
90:911–923.
104 Wang XX, Wei JZ, Jiao J, Jiang SY, Yu DH,
Li D: Genome-wide DNA methylation and
gene expression patterns provide insight
into polycystic ovary syndrome develop-
ment. Oncotarget 2014;5:6603–6610.
105 Yu YY, Sun CX, Liu YK, Li Y, Wang L, Zhang
W: Genome-wide screen of ovary-specific
DNA methylation in polycystic ovary syn-
drome. Fertil Steril 2015;104:145–153.e6.
106 Shen HR, Qiu LH, Zhang ZQ, Qin YY, Cao
C, Di W: Genome-wide methylated DNA
immunoprecipitation analysis of patients
with polycystic ovary syndrome. PLoS One
2013;8:e64801.
107 Li S, Zhu D, Duan H, Ren A, Glintborg D,
Andersen M, Skov V, Thomassen M, Kruse
T, Tan: Differential DNA methylation pat-
terns of polycystic ovarian syndrome in
whole blood of Chinese women. Oncotarget
2017;8:20656–20666.
108 Kokosar M, Benrick A, Perfilyev A, Fornes
R, Nilsson E, Maliqueo M, Behre CJ, Sazon-
ova, A, Ohlsson C, Ling C, Stener-Victorin
E: Epigenetic and transcriptional alterations
in human adipose tissue of polycystic ovary
syndrome. Sci Rep 2016;6:22883.
109 Xu N, Kwon S, Abbott DH, Geller DH, Du-
mesic DA, Azziz R, Guo X, Goodarzi MO:
Epigenetic mechanism underlying the de-
velopment of polycystic ovary syndrome
(PCOS)-like phenotypes in prenatally an-
drogenized rhesus monkeys. PLoS One
2011;6:e27286.
110 Li S, Zhu D, Duan H, Tan Q: The epigenom-
ics of polycystic ovarian syndrome: from
pathogenesis to clinical manifestations. Gy-
necol Endocrinol 2016;32:942–946.
111 Jiang L, Huang J, Chen Y, Yang Y, Li R, Li Y,
Chen X, Yang D: Identification of several
circulating microRNAs from a genome-
wide circulating microRNA expression pro-
file as potential biomarkers for impaired glu-
22 Horm Res Paediatr
DOI: 10.1159/000479371
cose metabolism in polycystic ovarian syn-
drome. Endocrine 2016;53:280–90.
112 Wu HL, Heneidi S, Chuang TY, Diaond MP,
Layman LC, Azziz R, Chen YH: The expres-
sion of the miR-25/93/106b family of micro-
RNAs in the adipose tissue of women with
polycystic ovary syndrome. J Clin Endocri-
nol Metab 2014;99:E2754–E2761.
113 Song J, Luo S, Li SW: miRNA-592 is down-
regulated and may target LHCGR in poly-
cystic ovary syndrome patients. Reprod Biol
2015;15:229–237.
114 Lansdown A, Rees DA: The sympathetic
nervous system in polycystic ovary syn-
drome: a novel therapeutic target? Clin En-
docrinol (Oxford) 2012;77:791–801.
115 Rahmouni K, Morgan DA, Morgan GM, Liu
X, Sigmund CD, Mark AL, Haynes WG: Hy-
pothalamic PI3K and MAPK differentially
mediate regional sympathetic activation to
insulin. J Clin Invest 2004;114:652–658.
116 Rahmouni K, Morgan DA, Morgan GM, Liu
X, Sigmund CD, Mark AL, Haynes WG: Ab-
normal heart rate recovery after maximal
cardiopulmonary exercise stress testing in
young overweight women with polycystic
ovary syndrome. Clin Endocrinol (Oxford)
2008;68:88–93.
117 Tekin G, Tekin A, Kiliçarslan EB, Hay­
dardedeoğlu B, Katircibaşi T, Koçum T, Erol
T, Cölkesen Y, Sezgin AT, Müderrisoğlu H:
Altered autonomic neural control of the car-
diovascular system in patients with polycystic
ovary syndrome. Int J Cardiol 2008;130:49–55.
118 Yildirir A, Aybar F, Kabakci G, Yarali H, Oto
A: Heart rate variability in young women
with polycystic ovary syndrome. Ann Non-
invasive Electrocardiol 2006;11:306–312.
119 Sverrisdottir YB, Mogren T, Kataoka J, Janson
PO, Stener-Victorin E: Is polycystic ovary
syndrome associated with high sympathetic
nerveactivity and size at birth? Am J Physiol
Endocrinol Metab 2008;294:E576–E581.
120 Heider U, Pedal I, Spanel-Borowski K: In-
crease in nerve fibers and loss of mast cells
in polycystic and postmenopausal ovaries.
Fertil Steril 2001;75:1141–1147.
121 Lara HE, Ferruz JL, Luza S, Bustamante DA,
Borges Y, Ojeda SR: Activation of ovarian
sympathetic nerves in polycystic ovary syn-
drome. Endocrinology 1993;133:2690–2695.
122 Lara HE, Dissen GA, Leyton V, Paredes A,
Fuenzalida H, Fiedler JL, Ojeda SR: An in-
creased intraovarian synthesis of nerve
growth factor and its low affinity receptor is
a principal component of steroid-induced
polycystic ovary in the rat. Endocrinology
2000;141:1059–1072.
123 Dissen GA, Garcia-Rudaz C, Paredes A,
Mayer C, Mayerhofer A, Ojeda SR: Excessive
ovarian production of nerve growth factor
facilitates development of cystic ovarian
morphology in mice and is a feature of poly-
cystic ovarian syndrome in humans. Endo-
crinology 2009;150:2906–2914.
124 Witchel SF, Oberfield S, Rosenfield RL, Cod-
ner E, Bonny A, Ibáñez L, Pena A, Horikawa
R, Gomez-Lobo V, Joel D, Tfayli H, Arsla-
nian S, Dabadghao P, Garcia Rudaz C, Lee
PA: The diagnosis of polycystic ovary syn-
drome during adolescence. Horm Res Pae-
diatr 2015;83:376–389.
125 Carmina E, Oberfield SE, Lobo R: The diag-
nosis of polycystic in adolescents. Am J Ob-
stet Gynecol 2010;203:201.e1–e5.
126 Di Fede G, Mansueto P, Pepe G, Rini B, Car-
mina E: High prevalence of polycystic ovary
syndrome in women with mild hirsutism
and no other significant clinical symptoms.
Fertil Steril 2010;94:194–197.
127 Reinehr T, Bosse C, Lass N, Rothermel J,
Knop C, Roth CL: Effect of weight loss on
puberty onset in overweight children. J Pe-
diatr 2017;184:143–50.
128 Reinehr T, Kulle A, Rothermel J, Knop-
Schmenn C, Lass N, Bosse C, Holtherus PM:
Longitudinal analyses of the steroid metabo-
lome in obese girls with weight loss. Endocr
Connect 2017;6:213–224.
129 Zawadzki J, Dunaif A: Diagnostic criteria for
polycystic ovary syndrome: towards a ratio-
nal approach; in Dunaif A, Givens JR, Hasel-
tine FP, Merriam GR (eds): Polycystic Ovary
Syndrome. Boston, Blackwell Scientific Pub-
lications, 1992, vol 4, pp 377–384.
130 Rotterdam ESHRE/ASRM-Sponsored PCOS
Consensus Workshop Group: Revised 2003
consensus on diagnostic criteria and long-
term health risks related to polycystic ovary
syndrome. Fertil Steril 2004;81:19–25.
131 Yildiz BO, Bolour S, Woods K, Moore A,
Azziz R: Visually scoring hirsutism. Hum
Reprod Update 2010;16:51–64.
132 Azziz R, Carmina E, Dewailly D, Diamanti-
Kandarakis E, Escobar-Morreale HF, Fut-
terweit W, Janssen OE, Legro RS, Norman
RJ, Taylor AE, Witchel SF; Task Force on the
Phenotype of the Polycystic Ovary Syn-
drome of The Androgen Excess and PCOS
Society: The Androgen Excess and PCOS
Society criteria for the polycystic ovary syn-
drome: the complete task force report. Fertil
Steril 2009;91:456–488.
133 Johnson T, Kaplan L, Ouyang P, Rizza R:
National Institutes of Health evidence-based
methodology workshop on polycystic ovary
syndrome (PCOS). NIH EbMW Report.
Bethesda, National Institutes of Health,
2012, vol 1, pp 1–14.
134 Legro RS, Arslanian SA, Ehrmann DA,
Hoeger KM, Murad MH, Pasquali R, Welt
CK; Endocrine Society: Diagnosis and treat-
ment of polycystic ovary syndrome: an En-
docrine Society clinical practice guideline. J
Clin Endocrinol Metab 2013;98:4565–4592.
135 Azziz R, Carmina E, Dewailly D, Diamanti-
Kandarakis E, Escobar-Morreale HF, Fut-
terweit W, Janssen OE, Legro RS, Norman
RJ, Taylor AE, Witchel SF; Androgen Excess
Society: Position statement: criteria for de-
fining polycystic ovary syndrome as a pre-
dominantly hyperandrogenic syndrome: an
Androgen Excess Society guideline. J Clin
Endocrinol Metab 2006;91:4237–4245.
Ibáñez et al.
136 Plouffe L Jr: Disorders of excessive hair
growth in the adolescent. Obstet Gynecol
Clin North Am 2000;27:79–99.
137 Engmann L, Jin S, Sun F, Legro RS, Polotsky
AJ, Hansen KR, Coutifaris C, Diamond MP,
Eisenberg E, Zhang H, Santoro N; Repro-
ductive Medicine Network: Racial and eth-
nic differences in the polycystic ovary syn-
drome (PCOS) metabolic phenotype. Am J
Obstet Gynecol 2017;216:493.e1–e13.
138 Yıldız BO, Bolour S, Woods K, Moore A,
Azziz R: Visually scoring hirsutism. Hum
Reprod Update 2010;16:51–64.
139 Li R, Qiao J, Yang D, Li S, Lu S, Wu X, Wei
Z: Epidemiology of hirsutism among wom-
en of reproductive age in the community: a
simplified scoring system. Eur J Obstet Gy-
necol Reprod Biol 2012;163:165–169.
140 Martin KA, Chang RJ, Ehrmann DA, Ibanez
L, Lobo RA, Rosenfield RL, Shapiro J, Mon-
tori VM, Swiglo BA: Evaluation and treatment
of hirsutism in premenopausal women: an en-
docrine society clinical practice guideline. J
Clin Endocrinol Metab 2008;98:1105–1120.
141 Souter I, Sanchez A, Perez M, Bartolucci A,
Azziz R: The prevalence of androgen excess
among patients with minimal unwanted
hair growth. Am J Obstet Gynecol 2004;191:
1914–1920.
142 Hawryluk EB, English JC 3rd: Female ado-
lescent hair disorders. J Pediatr Adolesc Gy-
necol 2009;22:271–281.
143 Ferriman D, Gallwey JD: Clinical assess-
ment of body hair growth in women. J Clin
Endocrinol Metab. 1961;21:1440–1447.
144 Dilutunmbi Y, Paley K, English JC: Adoles-
cent female acne: etiology and management.
J Pediatr Adolesc Gynecol 2008;21:171–176.
145 Chang RJ, Coffler MS: Polycystic ovary syn-
drome: early detection in the adolescent.
Clin Obstet Gynecol 2007;50:178–187.
146 Chen WC, Zouboulis CC: Hormones and
the pilosebaceous unit. Dermatoendocrinol
2009;1:81–86.
147 Lucky AW, Biro FM, Simbartl LA, Morrison
JA, Sorg NW: Predictors of severity of acne
vulgaris in young adolescent girls: results of
a five-year longitudinal study. J Pediatr
1997;130:30–39.
148 Merino PM, Codner E, Cassorla F: A ratio-
nal approach to the diagnosis of polycystic
ovarian syndrome during adolescence. Arq
Bras Endocrinol Metabol 2011;55:590–598.
149 Ibañez L, Potau N, Virdis R, Zampolli M,
Terzi C, Gussinyé M, Carrascosa A, Vicens-
Calvet E: Postpubertal outcome in girls diag-
nosed of premature pubarche during child-
hood: increased frequency of functional
ovarian hyperandrogenism. J Clin Endocri-
nol Metab 1993;76:1599–1603.
150 Witchel SF: Puberty and polycystic ovary
syndrome. Mol Cell Endocrinol 2006; 254–
255:146–153.
151 McCartney CR, Blank SK, Prendergast KA,
Chhabra S, Eagleson CA, Helm KD, Yoo R,
Chang RJ, Foster CM, Caprio S, Marshall JC:
Obesity and sex steroid changes across pu-
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
berty: evidence for marked hyperandrogen-
emia in pre- and early pubertal obese girls. J
Clin Endocrinol Metab 2007;92:430–436.
152 Carmina E, Dewailly D, Escobar-Morreale
HF, Kelestimur F, Moran C, Oberfield S,
Witchel SF, Azziz R: Non-classic congenital
adrenal hyperplasia due to 21-hydroxylase
deficiency revisited: an update with a special
focus on adolescent and adult women. Hum
Reprod Update 2017;5:1–20.
153 Metcalf MG, Skidmore DS, Lowry GF,
Mackenzie JA: Incidence of ovulation in the
years after the menarche. J Endocrinol 1983;
97:213–219.
154 Apter D: Endocrine and metabolic abnormal-
ities in adolescents with a PCOS-like condi-
tion: consequences for adult reproduction.
Trends Endocrinol Metab 1998;9:58–61.
155 Hickey M, Doherty DA, Atkinson H, Slobo-
da DM, Franks S, Norman RJ, Hart R: Clini-
cal, ultrasound and biochemical features of
polycystic ovary syndrome in adolescents:
implications for diagnosis. Hum Reprod
2011;26:1469–1477.
156 Diaz A, Laufer MR, Breech LL: Menstrua-
tion in girls and adolescents: using the men-
strual cycle as a vital sign. Pediatrics 2006;
118:2245–2250.
157 World Health Organization multicenter
study on menstrual and ovulatory patterns
in adolescent girls. I. A multicenter cross-
sectional study of menarche. World Health
Organization Task Force on Adolescent Re-
productive Health. J Adolesc Health Care
1986;7:229–235.
158 Southam AL, Richart RM: The prognosis for
adolescents with menstrual abnormalities.
Am J Obstet Gynecol 1966;94:637–645.
159 Franks S: Adult polycystic ovary syndrome
begins in childhood. Best Pract Res Clin En-
docrinol Metab 2002;16:263–272.
160 van Hooff MH, Voorhorst FJ, Kaptein MB,
Hirasing RA, Koppenaal C, Schoemaker J:
Predictive value of menstrual cycle pattern,
body mass index, hormone levels and poly-
cystic ovaries at age 15 years for oligo-amen-
errohea at age 18 years. Hum Reprod 2004;
19:383–392.
161 Wiksten-Almströmer M, Hirschberg AL,
Hagenfeldt K: Prospective follow-up of
menstrual disorders in adolescence and
prognostic factors. Acta Obstet Gynecol
Scand 2008;87:1162–1168.
162 Rosenfield RL, Ehrmann DA, Littlejohn EE:
Adolescent polycystic ovary syndrome due
to functional ovarian hyperandrogenism
persists into adulthood. J Clin Endocrinol
Metab 2015;100:1537–1543.
163 Carroll J, Saxena R, Welt CK: Environmental
and genetic factors influence age at menarche
in women with polycystic ovary syndrome. J
Pediatr Endocrinol Metab 2012;25:459–466.
164 Dahlgren E, Johansson S, Lindstedt G,
Knutsson F, Odén A, Janson PO, Mattson
LA, Crona N, Lundberg PA: Women with
polycystic ovary syndrome wedge resected
in 1956 to 1965: a long-term follow-up fo-
Horm Res Paediatr
DOI: 10.1159/000479371
cusing on natural history and circulating
hormones. Fertil Steril 1992;57:505–513.
165 Escobar-Morreale HF, Carmina E, Dewailly
D, Gambineri A, Kelestimur F, Moghetti P,
Pugeat M, Qiao J, Wijeyaratne CN, Witchel
SF, Norman RJ: Epidemiology, diagnosis
and management of hirsutism: a consensus
statement by the Androgen Excess and Poly-
cystic Ovary Syndrome Society. Hum Re-
prod Update 2012;18:146–170.
166 Rosner W, Vesper H: Toward excellence in
testosterone testing: a consensus statement. J
Clin Endocrinol Metab 2010;95:4542–4548.
167 Legro RS, Schlaff WD, Diamond MP, Couti-
faris C, Casson PR, Brzyski RG, Christman
GM, Trussell JC, Krawetz SA, Snyder PJ, Ohl
D, Carson SA, Steinkampf MP, Carr BR,
McGovern PG, Cataldo NA, Gosman GG,
Nestler JE, Myers ER, Santoro N, Eisenberg
E, Zhang M, Zhang H; Reproductive Medi-
cine Network: Total testosterone assays in
women with polycystic ovary syndrome:
precision and correlation with hirsutism. J
Clin Endocrinol Metab 2010;95:5305–5313.
168 Auchus RJ: Steroid assays and endocrinolo-
gy. Best practices for basic scientists. Endo-
crinology 2014;155:2049–2051.
169 Gambineri A, Fanelli F, Prontera O, Repaci A,
Di Dalmazi G, Zanotti L, Pagotto U, Flacco
ME, Guidi J, Fava GA, Manzoli L, Pasquali R:
Prevalence of hyperandrogenic states in late
adolescent and young women: epidemiologi-
cal survey on Italian high-school students. J
Clin Endocrinol Metab 2013;98:1641–1650.
170 Codner E, Villarroel C, Eyzaguirre FC,
López P, Merino PM, Pérez-Bravo F, Iñiguez
G, Cassorla F: Polycystic ovarian morphol-
ogy in postmenarchal adolescents. Fertil
Steril 2011;95:702–6.e1–e2.
171 Murphy MK, Hall JE, Adams JM, Lee H,
Welt CK: Polycystic ovarian morphology in
normal women does not predict the devel-
opment of polycystic ovary syndrome. J Clin
Endocrinol Metab 2006;91:3878–3884.
172 Venturoli S, Porcu E, Fabbri R, Pluchinotta
V, Ruggeri S, Macrelli S, Paradisi R, Flami-
gni C: Longitudinal change of sonographic
ovarian aspects and endocrine parameters in
irregular cycles of adolescence. Pediatr Res
1995;38:974–980.
173 Dewailey D: Diagnostic criteria for PCOS: is
there a need for a rethink? Best Pract Res
Clin Obstet Gynaecol 2016:37:5–11.
174 Holm K, Laursen EM, Brocks V, Muller J:
Pubertal maturation of the internal genita-
lia: an ultrasound evaluation of 166. Ultra-
sound Obstet Gynecol 1995;6:175–181.
175 Kelsey TW, Dodwell SK, Wilkinson AG,
Greve T, Andersen CY, Anderson RA, Wal-
lace WH: Ovarian volume throughout life: a
validated normative model. PLoS One 2013;
8:e71465.
176 Bentzen JG, Forman JL, Johannsen TH, Pin-
borg A, Larsen EC, Andersen AN: Ovarian
antral follicle subclasses and anti-mullerian
hormone during normal reproductive aging.
J Clin Endocrinol Metab 2013;98:1602–1611.
23
177 Mortensen M, Rosenfield RL, Littlejohn E:
Functional significance of polycystic-size
ovaries in healthy adolescents. J Clin Endo-
crinol Metab 2006;91:3786–3790.
178 Villarroel C, Merino PM, López P, Eyza­
guirre FC, Van Velzen A, Iñiguez G, Codner
E: Polycystic ovarian morphology in adoles-
cents with regular menstrual cycles is associ-
ated with elevated anti-Mullerian hormone.
Hum Reprod 2011;26:2861–2868.
179 Dewailly D, Lujan ME, Carmina E, Cedars
MI, Laven J, Norman RJ, Escobar-Morreale
HF: Definition and significance of polycystic
ovarian morphology: a task force report
from the Androgen Excess and Polycystic
Ovary Syndrome Society. Hum Reprod Up-
date 2014;20:334–352.
180 Rosenfield RL: The polycystic ovary mor-
phology-polycystic ovary syndrome spec-
trum. J Pediatr Adolesc Gynecol 2014; 28:
412–419.
181 van Hooff MH, Voorhorst FJ, Kaptein MB,
Hirasing RA, Koppenaal C, Schoemaker J:
Polycystic ovaries in adolescents and the re-
lationship with menstrual cycle patterns, lu-
teinizing hormone, androgens, and insulin.
Fertil Steril 2000;74:49–58.
182 Venturoli S, Porcu E, Fabbri R, Magrini O,
Gammi L, Paradisi R, Flamigni R: Longitu-
dinal evaluation of the different gonadotro-
pin pulsatile patterns in anovulatory cycles
of young girls. J Clin Endocrinol Metab
1992;74:836–841.
183 Mortensen M, Ehrmann DA, Littlejohn E,
Rosenfield RL: Asymptomatic volunteers
with a polycystic ovary are a functionally dis-
tinct but heterogeneous population. J Clin
Endocrinol Metab 2009;94:1579–1586.
184 Pigny P, Merlen E, Robert Y, Cortet-Rudelli
C, Decanter C, Jonard S, Dewailly D: Elevat-
ed serum level of anti-mullerian hormone in
patients with polycystic ovary syndrome: re-
lationship to the ovarian follicle excess and
to the follicular arrest. J Clin Endocrinol
Metab 2003;88:5957–5962.
185 Pigny P, Jonard S, Robert Y, Dewailly D: Se-
rum anti-Mullerian hormone as a surrogate
for antral follicle count for definition of the
polycystic ovary syndrome. J Clin Endocri-
nol Metab 2006;91:941–945.
186 Hart R, Doherty DA, Norman RJ, Franks S,
Dickinson JE, Hickey M, Sloboda DM: Se-
rum antimullerian hormone (AMH) levels
are elevated in adolescent girls with polycys-
tic ovaries and the polycystic ovarian syn-
drome (PCOS). Fertil Steril 2010; 94: 1118–
1121.
187 Rosenfield RL, Wroblewski K, Padmanab-
han V, Littlejohn E, Mortensen M, Ehrmann
DA: Antimullerian hormone levels are in­
dependently related to ovarian hyperan-
drogenism and polycystic ovaries. Fertil
Steril 2012;98:242–249.
188 Villarroel C, Lopez P, Merino PM, Iniguez
G, Sir-Petermann T, Codner E: Hirsutism
and oligomenorrhea are appropriate screen-
ing criteria for polycystic ovary syndrome in
24 Horm Res Paediatr
DOI: 10.1159/000479371
adolescents. Gynecol Endocrinol 2015; 31:
625–629.
189 Lie Fong S, Visser JA, Welt CK, de Rijke YB,
Eijkemans MJ, Broekmans FJ, Roes EM, Pe-
ters WH, Hokken-Koelega AC, Fauser BC,
Themmen AP, de Jong FH, Schipper I,
Laven JS: Serum anti-mullerian hormone
levels in healthy females: a nomogram rang-
ing from infancy to adulthood. J Clin Endo-
crinol Metab 2012;97:4650–4655.
190 Kelsey TW, Wright P, Nelson SM, Anderson
RA, Wallace WH: A validated model of se-
rum anti-mullerian hormone from concep-
tion to menopause. PLoS One 2011;6:e22024.
191 Sopher AB, Grigoriev G, Laura D, Cameo T,
Lerner JP, Chang RJ, McMahon DJ, Ober-
field SE: Anti-Mullerian hormone may be a
useful adjunct in the diagnosis of polycystic
ovary syndrome in nonobese adolescents. J
Pediatr Endocrinol Metab 2014; 27: 1175–
1179.
192 Munzker J, Hofer D, Trummer C, Ulbing M,
Harger A, Pieber T, Owen L, Keevil B, Bra-
bant G, Lerchbaum E, Obermayer-Pietsch B:
Testosterone to dihydrotestosterone ratio as
a new biomarker for an adverse metabolic
phenotype in the polycystic ovary syn-
drome. J Clin Endocrinol Metab 2015; 100:
653–660.
193 Sarray S, Almawi WY: Levels of CD40L and
other inflammatory biomarkers in obese
and non-obese women with polycystic ovary
syndrome. Am J Reprod Immunol 2016; 76:
285–291.
194 Li Li, Zhang J, Deng Q, Li J, Li Z, Xiao Y, Hu
S, Li T, Tan Q, Li X, Luo B, Mo H: Proteomic
profiling for identification of novel bio-
markers differentially expressed in human
ovaries from polycystic ovary syndrome pa-
tients. PLoS One 2016;11:e0164538.
195 Sorensen AE, Udesen PB, Wissing ML, En-
glund AM, Dalgaard LT: MicroRNAs relat-
ed to androgen metabolism and polycystic
ovary syndrome. Chem Biol Interact 2016;
259:8–16.
196 Harris MI, Hadden WC, Knowler WC, Ben-
nett PH: Prevalence of diabetes and im-
paired glucose tolerance and plasma glucose
levels in U.S. population aged 20–74 yr. Dia-
betes 1987;36:523–34.
197 Matsuda M: Measuring and estimating insu-
lin resistance in clinical and research set-
tings. Nutr Metab Cardiovasc Dis 2010; 20:
79–86.
198 Burgert TS, Vuguin PM, DiMartino-Nardi J,
Attie KM, Saenger P: Assessing insulin resis-
tance: application of a fasting glucose to in-
sulin ratio in growth hormone-treated chil-
dren. Horm Res 2002;57:37–42.
199 Jean AM, Hassoun A, Hughes J, Pomeranz
C, Fennoy I, McMahon DJ, Oberfield SE:
Utility of insulin response and proinsulin to
assess insulin resistance. J Pediatr 2009;155:
893–899.
200 Nagasaka S, Kusaka I, Yamashita K, Funase
Y, Yamauchi K, Katakura M, Ishibashi S,
Aizawa T: Index of glucose effectiveness de-
rived from oral glucose tolerance test. Acta
Diabetol 2012;49:S195–S204.
201 Matsuda M, DeFronzo R: Insulin sensitivity
indices obtained from oral glucose tolerance
test: comparison with the euglycemic insulin
clamp. Diabetes Care 1999;22:1462–1470.
202 Hoeger K, Davidson K, Kochman L, Cherry
T, Kopin L, Guzick DS: The impact of met-
formin, oral contraceptives, and lifestyle
modification on polycystic ovary syndrome
in obese adolescent women in two random-
ized, placebo-controlled clinical trials. J Clin
Endocrinol Metab 2008;93:4299–4306.
203 Ornstein RM, Copperman NM, Jacobson MS:
Effect of weight loss on menstrual function in
adolescents with polycystic ovary syndrome. J
Pediatr Adolesc Gynecol 2011;24:161–165.
204 Lass N, Kleber M, Winkel K, Wunsch R,
Reinehr T: Effect of lifestyle intervention on
features of polycystic ovarian syndrome,
metabolic syndrome, and intima-media
thickness in obese adolescent girls. J Clin
Endocrinol Metab 2011;96:3533–3540.
205 Knop C, Singer V, Uysal Y, Schaefer A,
Wolters B, Reinehr T: Extremely obese chil-
dren respond better than extremely obese
adolescents to lifestyle interventions. Pediatr
Obes 2015;10:7–14.
206 Reinehr T, Lass N, Toschke C, Rothermel J,
Lanzinger S, Holl RW: Which amount of
BMI-SDS reduction Is necessary to improve
cardiovascular risk factors in overweight
children? J Clin Endocrinol Metab 2016;101:
3171–3179.
207 Harrison CL, Lombard CB, Moran LJ, Teede
HJ: Exercise therapy in polycystic ovary syn-
drome: a systematic review. Hum Reprod
Update 2011;17:171–183.
208 Oude Luttikhuis H, Baur L, Jansen H,
Shrewsbury VA, O'Malley C, Stolk RP, Sum-
merbell CD: Interventions for treating obe-
sity in children. Cochrane Database Syst Rev
2009;1:CD001872.
209 Moran LJ, Ko H, Misso M, Marsh K, Noakes
M, Talbot M, Frearson M, Thondan M, Stepto
N, Teede HJ: Dietary composition in the treat-
ment of polycystic ovary syndrome: a system-
atic review to inform evidence-based guide-
lines. J Acad Nutr Diet 2013;113:520–545.
210 Reinehr T: Lifestyle intervention in child-
hood obesity: changes and challenges. Nat
Rev Endocrinol 2013;9:607–614.
211 Haedersdal M, Gotzsche PC: Laser and pho-
toepilation for unwanted hair growth. Co-
chrane Database Syst Rev 2006;4:CD004684.
212 Haedersdal M, Wulf HC: Evidence-based
review of hair removal using lasers and light
sources. J Eur Acad Dermatol Venereol
2006;20:9–20.
213 Sadighha A, Mohaghegh Zahed G: Meta-
analysis of hair removal laser trials. Lasers
Med Sci 2009;24:21–25.
214 Clayton WJ, Lipton M, Elford J, Rustin M,
Sherr L: A randomized controlled trial of la-
ser treatment among hirsute women with
polycystic ovary syndrome. Br J Dermatol
2005;152:986–992.
Ibáñez et al.
215 McGill DJ, Hutchison C, McKenzie E, Mc-
Sherry E, Mackay IR: A randomized, split-
face comparison of facial hair removal with
the alexandrite laser and intense pulsed light
system. Lasers Surg Med 2007;39:767–772.
216 Somani N, Turvy D: Hirsutism: an evidence-
based treatment update. Am J Clin Dermatol
2014;15:247–266.
217 Vissing AC, Taudorf EH, Haak CS, Philip­
sen PA, Hædersdal M: Adjuvant eflorni-
thine to maintain IPL-induced hair reduc-
tion in women with facial hirsutism: a ran-
domized controlled trial. J Eur Acad
Dermatol Venereol 2016;30:314–319.
218 Wang T, McNeill AM, Chen Y, Senderak M,
Shankar RR: Metformin prescription pat-
terns among US adolescents aged 10–19
years: 2009–2013. J Clin Pharm Ther 2016;
41:229–236.
219 Naderpoor N, Shorakae S, de Courden B,
Misso ML, Moran LJ, Teede HJ: Metformin
and lifestyle modification in polycystic ovary
syndrome: systematic review and meta-anal-
ysis. Hum Reprod Update 2015;21:560–574.
220 Ladson G, Dodson WC, Sweet SD, Ar-
chibong AE, Kunselman AR, Demers LM,
Lee PA, Williams NI, Coney P, Legro RS: Ef-
fects of metformin in adolescents with poly-
cystic ovary syndrome undertaking lifestyle
therapy: a pilot randomized double-blind
study. Fertil Steril 2011;95:2595–2598.e1–e6.
221 Allen HF, Mazzoni C, Heptulla RA, Murray
MA, Miller N, Koenigs L, Reiter EO: Ran-
domized controlled trial evaluating response
to metformin versus standard therapy in the
treatment of adolescents with polycystic
ovary syndrome. J Pediatr Endocrinol Metab
2005;18:761–768.
222 Al-Zubeidi H, Klein KO: Randomized clini-
cal trial evaluating metformin versus oral
contraceptive pills in the treatment of ado-
lescents with polycystic ovarian syndrome. J
Pediatr Endocrinol Metab 2015;28:853–858.
223 Bridger T, MacDonald S, Baltzer F, Rodd C:
Randomized placebo-controlled trial of
metformin for adolescents with polycystic
ovary syndrome. Arch Pediatr Adolesc Med
2006;160:241–246.
224 El Maghraby H, Nafee T, Guiziry D, El-
nashar A: Randomized controlled trial of the
effects of metformin versus combined oral
contraceptives in adolescent PCOS women
through a 24 month follow up period. Mid-
dle East Fertil Soc J 2015;20:131–137.
225 Ibáñez L, Potau N, Ferrer A, Rodriguez-Hi-
erro F, Marcos MV, de Zegher F: Anovula-
tion in eumenorrheic, nonobese adolescent
girls born small for gestational age: insulin
sensitization induces ovulation, increases
lean body mass, and reduces abdominal fat
excess, dyslipidemia, and subclinical hyper-
androgenism. J Clin Endocrinol Metab
2002;87:5702–5705.
226 Ibáñez L, Valls C, Ferrer A, Marcos MV, Ro-
driguez-Hierro F, de Zegher F: Sensitization
to insulin induces ovulation in nonobese ad-
olescents with anovulatory hyperandrogen-
Update: PCOS Pathophysiology,
Diagnosis, and Treatment
ism. J Clin Endocrinol Metab 2001;86:3595–
3598.
227 Al Khalifah RA, Florez ID, Dennis B, Tha-
bane L, Bassilious E: Metformin or oral con-
traceptives for adolescents with polycystic
ovarian syndrome: a meta-analysis. Pediat-
rics 2016;137:e20154089.
228 Swiglo BA, Cosma M, Flynn DN, Kurtz DM,
Labella ML, Mullan RJ, Erwin PJ, Montori
VM: Clinical review: Antiandrogens for the
treatment of hirsutism: a systematic review
and meta-analyses of randomized con-
trolled trials. J Clin Endocrinol Metab 2008;
93:1153–1160.
229 Moghetti P, Tosi F, Tosti A, Negri C, Miscia-
li C, Perrone F, Caputo M, Muggeo M, Cas-
tello R: Comparison of spironolactone, flu-
tamide, and finasteride efficacy in the treat-
ment of hirsutism: a randomized, double
blind, placebo-controlled trial. J Clin Endo-
crinol Metab 2000;85:89–94.
230 de Zegher F, Ibáñez L: Low-dose flutamide
for hirsutism: into the limelight, at last. Nat
Rev Endocrinol 2010;6:421–422.
231 Ganie MA, Khurana ML, Eunice M, Gupta
N, Gulati M, Dwivedi SN, Ammini AC:
Comparison of efficacy of spironolactone
with metformin in the management of poly-
cystic ovary syndrome: an open-labeled
study. J Clin Endocrinol Metab 2004; 89:
2756–2762.
232 Ganie MA, Khurana ML, Nisar S, Shah PA,
Shah ZA, Kulshrestha B, Gupta N, Zargar
MA, Wani TA, Mudasir S, Mir FA, Taing S:
Improved efficacy of low-dose spironolac-
tone and metformin combination than ei-
ther drug alone in the management of wom-
en with polycystic ovary syndrome (PCOS):
a six-month, open-label randomized study.
J Clin Endocrinol Metab 2013; 98: 3599–
3607.
233 Ibáñez L, Valls C, Ferrer A, Ong K, Dunger
DB, de Zegher F: Additive effects of insulin-
sensitizing and anti-androgen treatment in
young, nonobese women with hyperinsulin-
ism, hyperandrogenism, dyslipidemia, and
anovulation. J Clin Endocrinol Metab 2002;
87:2870–2874.
234 Keleştimur F, Everest H, Unlühizarci K,
Bayram F, Sahin Y: A comparison between
spironolactone and spironolactone plus fin-
asteride in the treatment of hirsutism. Eur J
Endocrinol 2004;150:351–354.
235 Mastorakos G, Koliopoulos C, Creatsas G:
Androgen and lipid profiles in adolescents
with polycystic ovary syndrome who were
treated with two forms of combined oral
contraceptives. Fertil Steril 2002; 77: 919–
927.
236 Mastorakos G, Koliopoulos C, Deligeoro-
glou E, Diamanti-Kandarakis E, Creatsas G:
Effects of two forms of combined oral con-
traceptives on carbohydrate metabolism in
adolescents with polycystic ovary syndrome.
Fertil Steril 2006;85:420–427.
237 Battaglia C, Mancini F, Fabbri R, Persico N,
Busacchi P, Facchinetti F, Venturoli S: Poly-
Horm Res Paediatr
DOI: 10.1159/000479371
cystic ovary syndrome and cardiovascular
risk in young patients treated with drospire-
none-ethinylestradiol or contraceptive vagi-
nal ring. A prospective, randomized, pilot
study. Fertil Steril 2010;94:1417–1425.
238 Bhattacharya SM, Jha A: Comparative study
of the therapeutic effects of oral contracep-
tive pills containing desogestrel, cyproter-
one acetate, and drospirenone in patients
with polycystic ovary syndrome. Fertil Steril
2012;98:1053–1059.
239 Ibáñez L, del Río L, Díaz M, Sebastiani G,
Pozo OJ, López-Bermejo A, de Zegher F:
Normalizing ovulation rate by preferential
reduction of hepato-visceral fat in adoles-
cent girls with polycystic ovary syndrome.
J Adolesc Health 2017, DOI: 10.1016/j.
jadohealth.2017.04.010.
240 Ibáñez L, de Zegher F, Potau N: Anovulation
after precocious pubarche: early markers
and time course in adolescence. J Clin Endo-
crinol Metab 1999;84:2691–2695.
241 US Medical Eligibility Criteria for Contra-
ceptive Use, 2010. MMWR Recomm Rep
2010;59:1–86.
242 Bonny AE, Ziegler J, Harvey R, Debanne
SM, Secic M, Cromer BA: Weight gain in
obese and nonobese adolescent girls initiat-
ing depot medroxyprogesterone, oral con-
traceptive pills, or no hormonal contracep-
tive method. Arch Pediatr Adolesc Med
2006;160:40–45.
243 Harel Z, Johnson CC, Gold MA, Cromer B,
Peterson E, Burkman R, Stager M, Brown
R, Bruner A, Coupey S, Hertweck P, Bone
H, Wolter K, Nelson A, Marshall S, Ba-
chrach LK: Recovery of bone mineral den-
sity in adolescents following the use of de-
pot medroxyprogesterone acetate contra-
ceptive injections. Contraception 2010; 81:
281–291.
244 Francis JKR, Gold MA: Long-acting revers-
ible contraception for adolescents. A review.
JAMA Pediatr 2017;171:694–701.
245 Palomba S, de Wilde MA, Falbo A, Koster
MP, La Sala GB, Fauser BC: Pregnancy com-
plications in women with polycystic ovary
syndrome. Hum Reprod Update 2015; 21:
575–592.
246 Kuchenbecker WK, Groen H, van Asselt SJ,
Bolster JH, Zwerver J, Slart RH, Vd Jagt EJ,
Muller Kobold AC, Wolffenbuttel BH, Land
JA, Hoek A: In women with polycystic ova-
ry syndrome and obesity, loss of intra-ab-
dominal fat is associated with resumption of
ovulation. Hum Reprod 2011; 26: 2505–
2512.
247 Jones H, Sprung VS, Pugh CJ, Daousi C, Ir-
win A, Aziz N, Adams VL, Thomas EL, Bell
JD, Kemp GJ, Cuthbertson DJ: Polycystic
ovary syndrome with hyperandrogenism is
characterized by an increased risk of hepatic
steatosis compared to nonhyperandrogenic
PCOS phenotypes and healthy controls, in-
dependent of obesity and insulin resistance.
J Clin Endocrinol Metab 2012; 97: 3709–
3716.
25