Clinical Science Session (CSS)

*Kepaniteraan Klinik Senior/ G1A219129

** Pembimbing/ dr. Ade Permana, Sp. OG (K)

Polycystic ovary Syndrome in Adolescents: Pitfalls

in Diagnosis and Management

Zevia Adeka Rhamona, S.Ked*

dr. Ade Permana, Sp.OG (K)**

KEPANITERAAN KLINIK SENIOR

BAGIAN OBSTETRI DAN GINEKOLOGI
FAKULTAS KEDOKTERAN DAN ILMU
KESEHATAN UNIVERSITAS JAMBI
2021
Sindrom Ovarium Polikistik (PCOS) pada Remaja : Kesalahan Dalam
Diagnosis dan Tatalaksana

Abstrak
Tujuan Peninjauan Sindrom ovarium polikistik (PCOS) adalah gangguan endokrin yang
paling umum selama masa reproduksi wanita, dengan kriteria diagnostik dan strategi
terapeutik yang terdokumentasi dengan baik pada orang dewasa; hal yang sama belum
tentu berlaku untuk remaja. Tujuan dari tinjauan ini adalah untuk mengidentifikasi
kesalahan yang sering terjadi dalam diagnosis dan manajemen PCOS selama masa
remaja. Temuan Terbaru Meskipun tidak ada konsensus global mengenai definisi
tersebut, sebagian besar ahli menyimpulkan adanya oligo/amenore dan
hiperandrogenisme (klinis dan/atau biokimia), sebagai prasyarat untuk diagnosis pada
remaja. Kriteria sebelumnya meliputi: (a) interval menstruasi berturut-turut > 90 hari
bahkan pada tahun pertama setelah menarche; (b) interval menstruasi yang menetap < 21
atau > 45 hari selama 2 tahun setelah menarche; atau (c) tidak menstruasi pada usia 15
atau 2-3 tahun setelah pubertas. Namun, pola ketidakteraturan menstruasi ini mungkin
tumpang tindih dengan entitas umum lainnya pada remaja, seperti perdarahan uterus
yang sering atau jarang atau anovulasi karena ketidakmatangan sumbu hipotalamus-
hipofisis-ovarium. Tanda-tanda klinis hiperandrogenisme tidak jelas, tanpa kriteria yang
tervalidasi dengan baik. Akhirnya, kriteria morfologi polikistik tidak dapat digunakan
dengan aman pada remaja, sebagian besar karena keterbatasan teknis USG
transabdominal. Kecuali untuk kemanjuran intervensi gaya hidup pada remaja yang
kelebihan berat badan dan obesitas dengan PCOS, data yang terbatas dan berkualitas
rendah ada mengenai obat-obatan yang tersedia, seperti kontrasepsi oral, metformin, dan
anti-androgen. Ringkasan Manajemen individual, dipandu oleh pengalaman klinis dan
data penelitian dan pemantauan ketat muncul sebagai pendekatan yang paling efektif
dalam populasi PCOS ini untuk kontrol optimal dari hasil reproduksi dan
metabolismenya. Penelitian yang berfokus pada mekanisme genetik dan molekuler
PCOS dapat menjelaskan strategi diagnostik dan terapeutik apa yang paling tepat pada
remaja dengan PCOS di masa depan.

Keywords: Oligomenorrhea, Hyperandrogenism, Adolescence, Diagnosis

Pendahuluan
Sindrom ovarium polikistik (PCOS) merupakan gangguan endokrin yang paling
umum pada wanita usia reproduksi. terhitung 70-80% dari semua kasus dengan
hiperandrogenisme.2 Prevalensinya diperkirakan 6-8% dari populasi umum pra
menopause2, tergantung pada kriteria yang digunakan, dapat mencapai hingga 20% 3,4.
PCOS dianggap sebagai sindrom multifaktorial yang penyebabnya tidak diketahui.
Sekresi gonadotropin yang tidak teratur dengan peningkatan luteinizing hormone (LH),
hiperandrogenisme ovarium, dan resistensi insulin merupakan komponen kunci dari
sindrom ini5. Etiopatogenesisnya melibatkan interaksi antara faktor genetik dan
lingkungan. Studi telah berfokus pada mutasi pada gen yang berpartisipasi dalam
biosintesis dan aksi androgen, metabolisme glukosa, seperti gen reseptor insulin dan
insulin, dan Inflamasi sistemik, seperti CYP11A1, CYP17A, CYP19, CYP21,
HSD17B5, HSD17B6, INS, INSR , IRS-1, IRS-2, IGF, PPAR-γ, tumor necrosis factor-
alpha (TNF-α), dan gen interleukin-6 (IL-6)6. Selain komponen genetik yang kuat,
komponen epigenetik tampaknya memainkan peran penting2. Berkenaan dengan
komponen lingkungan, telah dihipotesiskan bahwa dalam intrauterine growth restriction
(IUGR) atau paparan androgen dalam rahim dapat mengakibatkan perkembangan PCOS
pada wanita dewasa 5,7.
Secara umum, ada heterogenitas dalam presentasi klinis PCOS, yang bervariasi
dengan usia, berat badan, etnis, dan pengaruh faktor lingkungan, seperti obat-obatan8.
Diagnosis sindrom, yang merupakan hasil dari penyingkiran penyebab lain dari
ketidakteraturan menstruasi dan kelebihan androgen, menjadi tantangan setelah
mempertimbangkan bahwa evolusi ciri-cirinya dapat terjadi setiap saat sepanjang umur
wanita9. Berdasarkan kriteria American Society for Reproductive Medicine
(ASRM)/European Society of Human Reproduction and Embryology (ESHRE)
(“Rotterdam”), yang paling banyak diterapkan, setidaknya dua dari tiga kriteria berikut
diperlukan untuk mengkonfirmasi diagnosis PCOS: disfungsi ovulasi,
hiperandrogenisme (klinis atau biokimia), dan morfologi ovarium polikistik (PCOM)
pada USG3,4. Namun, presentasi klinis lebih tidak jelas pada remaja dibandingkan
dengan orang dewasa, memperumit pendekatan diagnostik dan terapeutik.
Tujuan dari tinjauan naratif ini adalah untuk fokus pada PCOS pada masa remaja,
dalam upaya untuk mengidentifikasi perangkap yang sering terjadi dalam diagnosis dan
manajemennya.

Gambaran Diagnostik PCOS pada Orang Dewasa Ketidakteraturan Menstruasi

dan Disfungsi
Ovulasi Ketidakteraturan menstruasi terjadi pada > 75% wanita dewasa dengan
PCOS. Oligomenore didefinisikan sebagai interval> 6-8 minggu antara menstruasi.
Adrenal ((non-classical congenital adrenal Hyperplasia (NCCAH)), tiroid
(hipotiroidisme, hyperthyroidism), dan gangguan hipofisis (hiperprolaktinemia) harus
dikeluarkan[10].

Kelebihan Androgen

Androgen dapat berupa biokimia atau klinis. Hiperandrogenemia biokimia terjadi

pada 60-80% orang dewasa dengan PCOS, terutama disebabkan oleh produksi androgen
berlebih oleh ovarium, sedangkan kelenjar adrenal dan jaringan adiposa perifer
berkontribusi pada tingkat yang kecil [10]. Kelebihan androgen secara klinis dapat
bermanifestasi sebagai hirsutisme (yaitu, kelebihan rambut wajah dan tubuh), jerawat,
atau alopecia (pola kebotakan pria) [11]. Meskipun demikian, penilaian klinis dari
hiperandrogenisme (hirsutism, jerawat, alopecia) memiliki keterbatasan, seperti yang
sering subjektif, sangat spesifik, atau standar dan bervariasi antara kelompok etnis.
Selain itu, > 90% wanita berusia 18 tahun memiliki beberapa bentuk jerawat [12].

Selain itu, hiperandrogenemia biokimia tidak didefinisikan dengan jelas,

tergantung pada androgen mana yang diukur, konsentrasi serum normal atas dan metode
penilaian. Kegunaan serum total testosteron sebagai penanda pengganti
hiperandrogenisme wanita rendah karena akurasi dan sensitivitas yang buruk dari
immunoassay tradisional pada kisaran wanita [13, 14]. Selanjutnya, total konsentrasi
testosteron menunjukkan variabilitas intra dan inter individu yang tinggi dan variasi
protein yang mengikat, seperti albumin dan sex hormone-binding globulin (SHBG); oleh
karena itu, tepat nilai referensi tidak dapat ditentukan [1]. Sebaliknya, serum free
testoterone (fT) adalah penanda hiperandrogenisme yang lebih sensitif dibandingkan
dengan testosteron total [15, 16]; meskipun metode pilihan untuk pengukurannya,
dialisis ekuilibrium, memakan waktu, dan tidak tersedia di seluruh dunia. Oleh karena
itu, pengukuran tidak fT indirect, free androgen index (FAI), dihitung sebagai hasil bagi
100 × total testosteron/SHBG (keduanya dinyatakan dalam nmol/l), telah diusulkan [16].
Sebagai catatan, telah dilaporkan bahwa hanya 50% wanita dengan PCOS dan fenotipe
hiperandrogenik yang memiliki konsentrasi testosteron tinggi > persentil 95th dari nilai
referensi, sedangkan hampir 90% dari mereka memiliki konsentrasi FT > persentil 95th
[17]. Utilitas diagnostik androgen kurang kuat lainnya, seperti
dehydroepiandrosterone(DHEAS) dan sulfateandrostenedion pada PCOS, terbatas
karena produksi adrenalnya yang hampir eksklusif [10].

Namun, banyak pasien dengan PCOS hadir dengan tanda-tanda klinis

hiperandrogenisme tetapi tanpa hiperandrogenisme biokimia. Hal ini mungkin
disebabkan oleh peningkatan metabolisme androgen perifer dari androgen atau
peningkatan konversi testosteron menjadi dihidrotestosteron poten (DHT) pada folikel
rambut dan kelenjar sebasea, melalui aksi enzim 5α-reduktase. Androgen yang
diproduksi secara perifer bertindak dengan cara intrakrin yang tidak tercermin dalam
konsentrasi darah [2]. Selain itu, kelebihan androgen dapat mempengaruhi siklus
menstruasi dan kesuburan, melalui disregulasi ovarium dan gangguan pematangan
folikel yang mengakibatkan anovulasi dan subfertilitas [2].

Policystic Ovarian Morphology

PCOM, didefinisikan sebagai adanya 12 folikel (berdiameter 2–9 mm di setiap

ovarium) atau peningkatan volume ovarium (> 10 ml), telah diperkenalkan sebagai salah
satu kriteria diagnostik Rotterdam untuk PCOS dan telah menerima kritik. untuk
memperluas definisi PCOS. PCOM telah dikaitkan dengan menstruasi yang tidak teratur
dan hiperandrogenisme [18].

Kontroversi tetap ada sehubungan dengan kriteria yang direkomendasikan untuk

diagnosis PCOS yang akurat, karena kriteria yang diusulkan oleh konsensus National
Institutes of Health (NIH) pada tahun 1990 untuk PCOS pada wanita dewasa
memerlukan ketidakteraturan menstruasi dan kelebihan androgen [19]. Kriteria NIH
yang diusulkan pada tahun 2012 sesuai dengan kriteria Rotterdam [20]. Sebaliknya,
Androgen Excess and PCOS Society (AEPCOS) memerlukan adanya
hiperandrogenisme dalam kombinasi dengan ketidakteraturan menstruasi atau PCOM
untuk diagnosis PCOS [10]

Tantangan Diagnostik pada Remaja

Kriteria Diagnostik
Meskipun tidak ada konsensus mengenai definisi PCOS pada remaja, menurut
kelompok ilmiah internasional tersebut, kriteria diagnostik yang sama dapat
diekstrapolasikan pada populasi remaja [3, 4]. Namun, kelemahan utama dalam kasus ini
adalah kenyataan bahwa banyak remaja menunjukkan ketidakteraturan menstruasi
fisiologis dan tanda-tanda kelebihan androgen peripubertal [2, 21]. Selanjutnya,
morfologi ovarium remaja tumpang tindih dengan wanita dengan PCOS [22, 23].
Meskipun tidak ada konsensus global tentang definisi PCOS yang tepat pada remaja,
diagnosis disarankan didasarkan pada adanya hiperandrogenisme klinis dan/atau biokimia
secara bersamaan dengan oligomenore persisten [4, 24, 25]. Kriteria berikut telah
diusulkan untuk yang terakhir: (a) interval menstruasi berturut-turut > 90 hari, bahkan
dari tahun pertama setelah menarche; (b) interval menstruasi yang menetap < 21 atau >
45 hari selama 2 tahun setelah menarche; atau (c) kurangnya menstruasi pada usia 15 atau
2-3 tahun setelah pubertas (perkembangan kuncup payudara) [25]. Berkenaan dengan
prevalensi PCOS pada remaja, meta-analisis baru-baru ini melaporkan tingkat 11,0%
(95% confidence interval (CI), 6,8-16,1), 3,4% (95% CI, 0,3-9,5), dan 8,0% (95 % CI,
6.2–10.0), menurut kriteria Rotterdam, NIH, atau AEPCOS [26•].

Ketidakteraturan Menstruasi dan Disfungsi Ovulasi pada Masa Remaja

Ketidakteraturan menstruasi seringkali merupakan manifestasi klinis paling awal
dari PCOS pada masa remaja [27]. Ini dapat bermanifestasi sebagai oligomenore atau
perdarahan uterus yang berlebihan [25], yang biasanya sembuh dalam waktu 2 tahun
pasca-menarche. Dalam beberapa kasus, bagaimanapun, menstruasi yang teratur dapat
terjadi di kemudian hari, tanpa penyebab patologis [28]. Oligomenore pada usia 15 tahun
bertahan selama 3 tahun lebih pada 51% kasus; di antara lain, hanya 2% remaja dengan
siklus menstruasi yang teratur mengalami oligomenore di kemudian hari [29]. Dengan
demikian, oligomenore pada usia 15 tahun dapat menjadi prediktor oligomenorea dalam 3
tahun. Selain itu, PCOS telah dilaporkan sebagai diagnosis utama pada remaja rawat inap
dengan perdarahan uterus yang berlebihan, terhitung 33% dari kasus [30].

Anovulasi juga sering terjadi pada awal pubertas karena imaturitas aksis
hipotalamus-hipofisis-ovarium dan melibatkan sekitar 40-50% gadis remaja [31]. Oleh
karena itu, diferensiasi antara anovulasi fisiologis selama masa remaja dan disfungsi
ovulasi merupakan tantangan.
Kelebihan Androgen pada Masa Remaja
Meskipun jerawat dapat dikaitkan dengan hiperandrogenisme yang mendasarinya,
jerawat tidak dapat digunakan sebagai satu-satunya kriteria untuk hiperandrogenisme
klinis, karena prevalensinya yang tinggi (hingga 90%) pada masa remaja [32]. Hirsutisme
dianggap sebagai penanda hiperandrogenisme yang lebih andal pada remaja
dibandingkan dengan jerawat. Ini menjadi lebih menonjol di masa dewasa karena durasi
paparan androgen meningkat [33]. Menurut konsensus internasional tahun 2003 [34],
hirsutisme sedang hingga berat dianggap sebagai gambaran klinis kelebihan androgen,
serta jerawat yang persisten. Sebaliknya, hirsutisme ringan dianggap normal segera
setelah menarche [25]. Sistem penilaian Ferriman-Gallwey diterapkan untuk kuantifikasi
hirsutisme (skor 8-15 menunjukkan hirsutisme ringan dan skor > 15 menunjukkan
hirsutisme sedang atau berat, meskipun ambang batas yang sama digunakan pada orang
dewasa dan remaja). Ada kekurangan data mengenai androgenic alopecia pada remaja.

Sejak tanda-tanda klinis hiperandrogenisme tidak dapat diandalkan pada masa

remaja, hiperandrogenemia biokimia tetap menjadi ciri khas PCOS pada populasi ini
[17], meskipun fisiologis peningkatan konsentrasi androgen selama remaja. Peningkatan
fT yang dihitung adalah temuan biokimia yang paling umum, meskipun testosteron total
dan DHEAS juga dapat meningkat [17]. S ampai saat ini, tidak ada ambang batas yang
jelas untuk konsentrasi androgen yang disesuaikan untuk masa remaja. Seperti pada
orang dewasa, uji testosteron sensitif tetap menjadi hal yang mutlak untuk hasil yang
akurat. Masyarakat AEPCOS merekomendasikan spektrometri massa sebagai metode
optimal untuk menilai konsentrasi testosteron total dan bebas [35].

PCOM pada Masa Remaja

Kehadiran ovarium multifollicular (kista ≥ 6, diameter 4-10 mm, dan ukuran
normal atau sedikit meningkat) sering terjadi pada remaja [34] dan dapat mencapai
57,9% pada remaja dengan ketidakteraturan menstruasi [36]; dengan demikian,
signifikansi klinis dan keandalan diagnostik kriteria ini pada masa remaja dipertanyakan.
PCOM dan peningkatan volume ovarium adalah ciri-ciri pubertas fisiologis dan
selanjutnya dapat mereda dengan timbulnya siklus menstruasi yang teratur [37]. Oleh
karena itu, direkomendasikan bahwa gambaran ultrasonografi tidak boleh dimasukkan
dalam kriteria diagnostik PCOS selama masa remaja, karena belum divalidasi untuk
kelompok usia ini [31].
Ada beberapa laporan dalam literatur yang berkaitan dengan PCOM pada remaja.
Diperkirakan bahwa 10-48% remaja tanpa PCOS memiliki kemungkinan penampilan
polikistik ovarium mereka, menunjukkan tumpang tindih dalam morfologi ovarium
antara remaja dengan PCOS dan remaja kontrol [21, 38, 39]. Juga telah dilaporkan bahwa
sepertiga dari anak perempuan dengan berat badan normal atau kelebihan berat badan
mungkin memiliki PCOM tanpa disfungsi ovulasi dalam 2-4 tahun setelah menarche [23,
40].
Pada konsep yang sama, PCOM mungkin ada pada sepertiga remaja dengan
hiperandrogenisme [41], serta pada 9 dan 28% dari mereka dengan menstruasi yang
teratur dan tidak teratur (panjang siklus rata-rata 22-41 hari), masing-masing, dan pada
45%. remaja dengan oligomenore dan peningkatan konsentrasi androgen [42]. Namun,
pola menstruasi awal merupakan prediksi dari yang terlambat [29]; oleh karena itu,
oligomenore yang bertahan 2 tahun setelah menarche harus dievaluasi sebagai tanda
klinis awal PCOS. Kelemahan lain dari PCOM pada remaja adalah bahwa USG
transabdominal, yang merupakan alat pencitraan utama yang digunakan dalam populasi
ini (dapat menggunakan USG transvaginal), dapat membatasi akurasi diagnostik dan
kegunaan modalitas pencitraan ini pada remaja kelebihan berat badan atau obesitas.
Magnetic resonance imaging (MRI) telah disarankan sebagai pendekatan yang lebih
akurat, tetapi tidak digunakan secara rutin [43].
Studi lebih lanjut dalam populasi yang lebih besar selama dekade kedua
kehidupan diperlukan untuk kesimpulan yang aman untuk ditarik. Dengan keterbatasan
ini, diagnosis PCOS bergantung pada bukti kelebihan androgen dan disfungsi ovulasi,
daripada pencitraan ovarium [25].

Pendekatan Diagnostik PCOS pada Masa Remaja

Riwayat kesehatan yang menyeluruh harus diperoleh, termasuk dalam riwayat
konsumsu obat eksogen, seperti steroid androgen dan anti-epilepsi. Sebagai catatan, fitur
PCOS mungkin ditutupi oleh obat yang digunakan untuk mengobati jerawat [44]. Selain
itu, memperoleh riwayat keluarga diperlukan, karena komponen genetik mungkin ada.
Pemeriksaan fisik yang rinci juga penting. Akantosis nigrikans dan obesitas truncal dapat
dideteksi sebagai tanda klinis resistensi insulin. Derajat hirsutisme dapat dinilai dengan
skor Ferriman-Gallwey [45], dan tingkat keparahan jerawat dapat dinilai berdasarkan
jenis dan jumlah lesi [8].
Pemeriksaan biokimia pada PCOS terutama harus mencakup glukosa plasma
puasa, profil lipid [46], dan konsentrasi FT total atau dihitung (atau FAI), sebaiknya di
pagi hari [3]. Jika pengobatan telah dimulai untuk sementara, konsentrasi androgen dapat
diubah, dan ini harus dipertimbangkan oleh dokter [10, 11, 46, 3]. Untuk membedakan
antara penyebab hiperandrogenemia atau ketidakteraturan menstruasi yang berbeda,
pengujian tambahan mungkin termasuk DHEAS,4-an drostenedione, 17-
hydroxyprogesterone [17(OH)P], thyroid stimulating hormone (TSH), prolaktin, LH,
FSH, dan estradiol dari hari ke-3 sampai ke-5 dari siklus menstruasi. Pada remaja dengan
morning baseline 17(OH)P > 200 mg/dl, tes stimulasi cosyntropin harus dilakukan untuk
menyingkirkan NCCAH [47]. Tes kehamilan sangat penting.
Meskipun ultrasonografi panggul tidak direkomendasikan secara universal untuk
memastikan diagnosis PCOS pada remaja[25],USG panggul mungkin berguna kecuali
memiliki patologi, terutama androgen-mensekresi tumor dalam kasus hyperandrogenemia
dan anovulasi[48, 49].

Komplikasi PCOS
Bukti kumulatif mendukung bahwa PCOS dikaitkan dengan konsekuensi jangka
panjang, termasuk gangguan kesehatan reproduksi, disfungsi psikologis, disregulasi
homeostasis glukosa impaired glucose tolerance (IGT) or type 2 diabetes mellitus
(T2DM)), non-alcoholic fatty liver disease (NAFLD), dyslipidemia, metabolic syndrome
(MetS),, penyakit kardiovaskular, dan peningkatan risiko kanker endometrium, payudara,
dan ovarium [50–52]. Obesitas memperburuk disregulasi metabolik terkait PCOS [53,
54]. Selanjutnya, insulin merangsang sintesis androgen ovarium [55] dan menghambat
produksi SHBG di hati [56]. Akibatnya, konsentrasi androgen bebas yang bersirkulasi
meningkat. Meskipun disregulasi metabolik ini merupakan kelainan inti pada PCOS,
perubahan metabolisme "Fisiologis" ini juga menonjol selama masa pubertas. Memang,
penurunan sensitivitas insulin dan hiperinsulinemia cukup umum terjadi pada remaja
yang sehat [57]. Telah dilaporkan bahwa sensitivitas insulin menurun 50% selama masa
pubertas, dikompensasikan dengan dua kali lipat sekresi insulin [56].
Namun, remaja yang didiagnosis dengan PCOS harus diskrining untuk gangguan
metabolisme, karena sekitar sepertiga dari mereka memenuhi kriteria MetS, seperti
obesitas sentral, hipertensi arteri, dislipidemia aterogenik, dan intoleransi glukosa,
dibandingkan dengan hanya 5% dari mereka yang tidak PCOS. [58, 59]. Sebagai catatan,
kriteria diagnostik untuk MetS berbeda pada populasi remaja. Secara khusus, tiga dari
lima berikut diperlukan untuk menetapkan diagnosis: (i) konsentrasi glukosa darah puasa
> 100 mg/dl; (ii) high-density lipoprotein cholesterol (HDL-C) < 40 mg/dl; (iii)
trigliserida 110 mg/dl; (iv) lingkar pinggang > percentil 90th untuk usia dan jenis
kelamin; dan (v) tekanan darah > persentil 90th untuk usia dan jenis kelamin [60].
Kelainan ini dapat muncul pada awal perjalanan PCOS [61]. Obesitas telah
terbukti memperburuk kelainan metabolik ini pada remaja dengan PCOS [62•]. Meskipun
PCOS menimbulkan risiko tinggi untuk MetS, terlepas dari indeks massa tubuh (BMI),
prevalensi MetS lebih tinggi dengan adanya obesitas [59], terutama obesitas perut [63].
Menariknya, meskipun obesitas dianggap sebagai prediktor MetS yang lebih umum
dibandingkan dengan kelebihan androgen [kelebihan androgen64, 65],sebaliknya dapat
meningkatkan risiko obesitas terlepas dari BMI [59, 66].
PCOS mungkin merupakan tanda inflamasi sistemik, karena peningkatan
konsentrasi IL-6 dan penurunan konsentrasi adiponektin telah ditemukan pada remaja
kurus dengan hiperandrogenisme dibandingkan dengan remaja tanpa hiperandrogenisme
[67]. Konsentrasi adiponektin yang rendah telah berkorelasi dengan resistensi insulin dan
adipositas viseral [68]. Sehubungan dengan dislipidemia, peningkatan trigliserida dan
konsentrasi lipoprotein densitas rendah (LDL-C) telah dilaporkan pada remaja dengan
PCOS dan kelebihan androgen [66]. Komplikasi lain PCOS pada masa remaja yang harus
diperhatikan adalah pengaruhnya terhadap kualitas hidup (QoL). Memang, meta-analisis
telah menunjukkan bahwa kualitas hidup, sebagian besar mengacu pada profil psikologis,
terganggu pada pasien remaja dengan PCOS, dengan obesitas sangat memediasi efek ini
[69•].
Follow up PCOS pada Remaja
Follow up yang teratur sangat penting untuk mencatat tingkat keparahan dan
perkembangan hirsutisme, jerawat, dan gangguan menstruasi. Selain itu, pemantauan
untuk komorbiditas terkait PCOS, seperti adanya gangguan metabolisme, seperti
dijelaskan di atas, juga penting [25, 59, 70].
Tes toleransi glukosa oral 2 jam (OGTT) adalah tes skrining standar emas untuk
mendiagnosis gangguan regulasi glukosa dan skrining berkala menggunakan tes ini telah
disarankan [49]. Peningkatan prevalensi MetS pada usia yang begitu muda
menggarisbawahi pentingnya skrining rutin pada populasi ini untuk mengurangi risiko
diabetes dan penyakit arteri koroner di masa depan.
Dampak psikologis PCOS pada pasien remaja juga harus ditangani secara berkala.
Depresi dan kecemasan terlihat pada populasi ini dengan prevalensi yang meningkat,
dan bimbingan ahli mungkin diperlukan dalam kasus-kasus tertentu [71, 72]. Gangguan
makan lazim terjadi pada remaja dengan PCOS, dan dokter harus waspada [73].

Manajemen PCOS pada Remaja

Tujuan dan Prinsip Manajemen
Tujuan pengobatan PCOS adalah untuk meningkatkan kualitas hidup dan
mengurangi risiko hasil kesehatan jangka panjang [11]. Perawatan individual
berdasarkan presentasi klinis, kebutuhan dan preferensi setiap pasien sangat penting.
Inisiasi pengobatan untuk PCOS tidak memerlukan diagnosis pasti dari sindrom, karena
dapat menurunkan risiko komorbiditas di masa depan [25].

Modifikasi Hidup Modifikasi

Modifikasi gaya hidup untuk menghindari kenaikan berat badan pada pasien non-
obesitas atau untuk mengurangi berat badan dalam kasus kelebihan lemak tubuh tetap
menjadi andalan pengobatan [3, 4]. Penurunan berat badan bermanfaat untuk
ketidakteraturan menstruasi terkait PCOS, kelebihan androgen, dan risiko
kardiometabolik. Menariknya, tampaknya tidak bermanfaat pada wanita dengan berat
badan normal dengan PCOS [3, 4]. Ini adalah pembatasan kalori itu sendiri dari jenis diet
(yaitu, kandungan protein) yang berdampak pada reproduksi dan memenuhi profil abolik
[3, 4, 74]. Intervensi gaya hidup juga dapat memperbaiki profil lipid pada remaja dengan
PCOS [75].
Meskipun 40-70% remaja dengan PCOS kelebihan berat badan atau obesitas,
kepatuhan terhadap intervensi gaya hidup adalah suboptimal dan obat yang digunakan
untuk menurunkan berat badan pada orang dewasa belum disetujui pada populasi ini.
Selanjutnya, diet yang optimal belum ditentukan [76].
Beberapa data yang ada mengenai pengaruh modifikasi gaya hidup pada profil
metabolisme dan reproduksi pada remaja. Dalam sebuah studi prospektif (59 obesitas
PCOS perempuan, berusia 12-18 tahun), intervensi gaya hidup (modifikasi diet ditambah
olahraga teratur), terjadinya penurunan BMI rata-rata 3,9 kg / m2 setelah 1 tahun,
ameliorate profil lipid (meingkat HDL-C dan berkurangnya konsentrasi trigliserida), dan
berkurangnya index resistensi insulin dan tekanan darah. Ini juga mengurangi prevalensi
oligo- dan amenore, masing-masing sebesar 42 dan 19%. Menariknya, carotid intima
media thickness (cIMT) menurun, serta konsentrasi testosteron [77]. Pada catatan yang
sama, uji coba terkontrol secara acak (RCT) pada remaja obesitas dengan PCOS (n = 60)
menunjukkan bahwa program diet intensif dengan pembatasan kalori konvensional
menyebabkan peningkatan pola menstruasi dan skor hirsutisme, dibandingkan dengan
diet sehat. , tanpa pembatasan energi [78]. Dalam penelitian ini, modifikasi gaya hidup
pada remaja dengan PCOS menghasilkan penurunan lingkar pinggang, yang
menunjukkan penurunan resistensi insulin [78].

Kontrasepsi Oral

Oral kombinasi kontrasepsi (COC) direkomendasikan sebagai pengobatan medis

lini pertama untuk manajemen ketidakteraturan menstruasi dan tanda-tanda klinis
kelebihan androgen pada wanita dengan PCOS [3, 4]. Kombinasi estrogen dan
progesterone memiliki efek supresi pada aksis hipotalamus-hipofisis ovarium (HPO),
dengan menghalangi produksi androgen ovarium. Selanjutnya, COCs meningkatkan
konsentrasi SHBG, sehingga semakin mengurangi kelebihan androgen [79]. Progesterone
komponen COC mencegah kerja estrogen dan mengurangi risiko hiperplasia
endometrium [11]. COC diindikasikan untuk semua bentuk ketidakteraturan menstruasi,
termasuk amenore, oligomenore, menoragia, dan perdarahan uterus abnormal [4, 45].
Efek positif COC pada menstruasi terbukti 2-3 bulan setelah memulai pengobatan.
 Meskipun durasi pengobatan dengan COC tidak didefinisikan dengan baik, satu
tahun atau lebih adalah periode yang disarankan untuk pemulihan sumbu HPO dan
potensi resolusi ketidakteraturan menstruasi [11]. COC juga mungkin berkhasiat untuk
pengelolaan jerawat dan hirsutisme [11].

Efek samping umum yang terkait dengan penggunaan COC termasuk mual, nyeri
payudara, sakit kepala, dan perubahan suasana hati, yang dikurangi setelah bulan-bulan
pertama pemberian [80]. Studi pada orang dewasa dengan PCOS menunjukkan bahwa
COC mungkin memiliki dampak negatif atau netral pada profil lipid dan metabolisme
glukosa, sebagian besar tergantung pada dosis estrogen dan jenis progestin; data berasal
dari studi ukuran sampel kecil dan durasi pendek [80]. Menurut meta-analisis Cochrane,
tidak ada efek COC pada berat badan pada wanita dengan PCOS [81]. Meta-analisis
terbaru telah menunjukkan bahwa potensi efek samping terkait COC kardiometabolik
dapat berkurang ketika COC dikombinasikan dengan metformin atau modifikasi gaya
hidup [82, 83].

Mengenai remaja, buktinya tidak kuat untuk kesimpulan yang aman. Sebuah
penelitian di Yunani telah menunjukkan bahwa 30 μg/hari etinil-estradiol dikombinasikan
dengan 150 mg/hari desogestrel, selama 21 hari per siklus 28 hari, dapat mengurangi
konsentrasi androgen tanpa memperburuk profil lipid, berat badan, atau pinggang-ke-
rasio pinggul [79]. Namun, beberapa data menunjukkan peningkatan peradangan
sistemik, seperti yang dinilai oleh konsentrasi protein C-reaktif sensitivitas tinggi dan
cIMT, dengan penggunaan COC [84, 85]. Kontraindikasi, seperti riwayat deep vein
thrombosis (DVT) atau migrain, harus sangat dipertimbangkan sebelum memulai COC
[80].

Metformin

Secara umum, metformin, sebagai sensitizer insulin, direkomendasikan sebagai

modalitas terapi lini kedua pada pasien dengan PCOS dan gangguan metabolisme
glukosa (IGT atau T2DM) di mana intervensi gaya hidup tidak efektif atau yang memiliki
kontra indikasi atau tidak toleran terhadap COC.3, 4]. Penggunaan sensitizer insulin
lainnya, seperti inositol atau thiazolidinediones, tidak dianjurkan untuk pengobatan
PCOS [3, 4]. Metformin dapat meningkatkan profil kardiometabolik dan ketidakteraturan
menstruasi pada wanita dengan PCOS, meskipun dengan efek yang dapat diabaikan pada
hiperandrogenisme klinis [3, 4]. Menariknya, ini mungkin memperbaiki fungsi
reproduksi terlepas dari resistensi insulin dan IGT [86].
Beberapa studi non-RCT, dengan ukuran sampel kecil dan durasi pendek ada pada
penggunaan metformin pada remaja dengan PCOS. Dalam satu studi prospektif pada
remaja non-obesitas dengan PCOS (n = 18, rata-rata BMI 21,4 kg / m2)dengan
hiperandrogenisme hyperinsulinemic dan anovulasi persisten, metformin 1275 mg / hari
selama 6 bulan, dikembalikan ketidakteraturan menstruasi pada semua pasien[87].Induksi
ovulasi dicapai pada hampir 80% pasien dalam 6 bulan. Dalam studi yang sama,
metformin meningkatkan hiperandrogenemia klinis dan biokimia dan menghasilkan
profil yang kurang aterogenik, ditandai dengan penurunan konsentrasi kolesterol total,
trigliserida, dan LDL-C [87]. Hal ini juga terjadi dalam penelitian lain pada remaja
dengan PCOS dan IGT, di mana metformin (850 mg, dua kali sehari), meningkatkan
sensitivitas insulin dan hiperandrogenemia biokimia dan mengurangi respons
steroidogenik adrenal terhadap hormon adrenokortikotropik [88]. Dalam studi ini, efek
metformin pada BMI menguntungkan [88] atau netral [87].
Studi tambahan menunjukkan bahwa kombinasi metformin dengan diet rendah
karbohidrat menghasilkan normalisasi siklus menstruasi dan pemulihan ovulasi pada
remaja dengan PCOS dalam beberapa bulan [89, 90]. Beberapa bulan terapi metformin
juga menyebabkan normalisasi toleransi glukosa, pengurangan konsentrasi testosteron
total dan bebas, dan peningkatan BMI, komposisi tubuh, dan sensitivitas insulin pada
remaja [88].
Beberapa data komparatif ada sehubungan dengan penggunaan metformin vs.
COC pada remaja. Sebuah meta-analisis dari empat RCT (n = 170), yang diterbitkan
pada tahun 2016, menunjukkan bahwa penggunaan COC menginduksi perbaikan
sederhana dalam pola menstruasi dan skor jerawat. Sebaliknya, metformin menyebabkan
penurunan BMI yang lebih besar dan peningkatan disregulasi glukosa, kolesterol total,
dan konsentrasi LDL-C pada remaja dengan PCOS. Tidak ada perbedaan dalam
hirsutisme dan konsentrasi HDL-C atau trigliserida yang diamati antar kelompok [91].
Namun, data yang tersedia berkualitas buruk. Studi tambahan diperlukan mengenai
pengelolaan PCOS pada remaja. Efek samping gastrointestinal (mual, sakit perut, diare)
merupakan kekurangan yang paling umum dengan penggunaan metformin, yang dapat
terjadi pada hingga 30% remaja dengan PCOS [92].

Anti-androgen
Obat-obatan ini disarankan pada kasus denganklinis yang parah
hiperandrogenemia, tidak berhasil dikelola dengan KOK atau, di mana KOK merupakan
kontraindikasi. Prasyarat penggunaannya adalah penerapan kontrasepsi yang efektif
padaaktif secara seksual remaja yang, karena tindakan teratogenik yang potensial.
Secara umum, anti-androgen efektif dalam memperbaiki tandatanda klinis kelebihan
androgen, profil psikologis, dan kualitas hidup pada wanita dengan PCOS [3, 4].
Data pada remaja terbatas. Spironolakton, antagonis reseptor aldosteron dan
androgen, dapat memperbaiki gangguan menstruasi dan manifestasi kulit dari
hiperandrogenisme tetapi tidak pada gangguan metabolisme [93]. Ini dapat digunakan
sebagai tambahan untuk pengobatan dengan KOK atau metformin, dengan dosis 50-200
mg/hari [93, 94]. Sehubungan dengan remaja populasidengan PCOS,kombinasi tiga
dosis rendah spironolakton(50 mg/hari)/pioglitazone (7,5 mg/hari)/ metformin (850
mg/hari) (SPIOMET) memberikan efek yang sebanding dengan KOK pada
penguranganbiokimia hiperandrogenemiadan distribusi lemak tubuh. Selanjutnya,
SPIOMET mengurangi insulin dan meningkatkan konsentrasi adiponektin dan tingkat
ovulasi hingga tiga kali lipat selamapasca perawatan periode (setelah 12 bulan)
dibandingkan dengan KOK [95]. Flutamide adalah anti-androgen lain, bekerja pada
tingkat reseptor androgen [96]. Selain tindakan anti-androgenik pada orang dewasa
dengan PCOS, telah terbukti kemanjuran dalamklinis hiperandrogenismedan biokimia
pada remaja non-obesitas dengan PCOS, dengan dosis 250 mg/hari. Namun,
obattersebut tidak berpengaruh pada keteraturan menstruasi daninsulin resistensi[97].
Juga, dokter harus memperhatikan potensi toksisitas hati [3, 4].
Cyproterone acetate (CPA) adalah anti-androgen lain yang paling umum
digunakan dalam pil kontrasepsi, pada dosis 2 mg dalam kombinasi dengan 35 mg etinil-
estradiol atau pada dosis 50-100 mg/hari sebagai terapi adjuvant untuk KOK [3, 4]. Pada
wanita dewasa dengan PCOS, CPA mengurangi skor hirsutisme di lebih dari 50% dari
mereka dan meningkatkan jerawat [98, 99]. Namun, hal itu dapat meningkatkan
konsentrasi trigliserida [79] dan risiko DVT [100]. Selanjutnya, finasteride, penghambat
isoenzim 5α-reduktase, pada dosis rendah (2,5mg setiap 3 hari), telah diuji coba dalam
studi percontohan dan ditemukan efektif untuk pengobatan hirsutisme pada remaja
[101].

Perawatan Lokal/Perawatan Kosmetik Perawatan

hirsutisme termasuk aplikasieflornithine secara krimlokal; durasi pengobatan
tidak didefinisikan dengan jelas, karena data pada remaja terbatas. Pendekatan
pengobatan non-farmasi, menawarkAn hasil langsung, juga tersedia, termasuk hair
removal mekanis dengan laser atau elektrolisis [11]. Kombinasieflornithine dengan terapi
laser lebih berkhasiat dibandingkan dengan pendekatan masing-masing saja; lagi,lebih
banyak data diperlukan[102, 103].

Kesimpulan
Diagnosis PCOS pada remaja tidak mudah, karena tingkat variabilitas fenotipikal
yang tinggi dalam presentasinya. Gangguan menstruasi pada remaja, yang
dimanifestasikan sebagai perdarahan uterus yang sering atau jarang, serta tingginya
prevalensi tanda-tanda klinis hiperandrogenisme dan PCOM, tumpang tindih dengan
gejala dan tanda-tanda PCOS, semakin memperumit proses penegakan diagnosis.
Ketidakteraturan menstruasi sebagai ekspresi klinis PCOS sulit dibedakan dari anovulasi
karena imaturitas aksis HPO. Selanjutnya, nilai klinis dari tanda-tanda
hiperandrogenisme rendah; oleh karena itu, peningkatan konsentrasi serum androgen
merupakan penanda kelebihan androgen. Selain itu, nilai PCOM, kriteria kunci untuk
menetapkan diagnosis pada wanita dewasa, rendah pada remaja, karena perubahan
tampilan ovarium danteknis keterbatasan USG transabdominal. Akibatnya, indeks
kecurigaan yang tinggi dan tindak lanjut yang ketat diperlukan untuk menegakkan
diagnosis PCOS.
Mengenai pengobatan, manajemen individual diperlukan untuk mengubah riwayat
alami dari hasil reproduksi dan metabolisme dari kondisi yang kompleks ini. Intervensi
gaya hidup pada remaja yang kelebihan berat badan dan obesitas dapat mengurangi
komplikasi jangka panjang terkait PCOS, seperti DMT2 dan penyakit kardiovaskular.
Kemanjuran dan keamanan pendekatan farmasi didokumentasikan dengan baik pada
orang dewasa dengan PCOS tetapi terbatas pada remaja. Oleh karena itu, lebih banyak
data dari RCT diperlukan untuk menetapkan strategi terapeutik. Tutup pemantauan
derangements formetabolic, evaluasi proses penyakit dan eksklusi PCOS-meniru lainnya
penyakit sangat penting pada populasi ini.

Kepatuhan dengan Standar Etika

Konflik Kepentingan Penulis tidak memiliki konflik kepentingan untuk
diungkapkan. Hak Asasi Manusia dan Hewan dan Informed Consent Artikel ini tidak
berisi penelitian apapun dengan subyek manusia atau hewan yang dilakukan oleh salah
Current Obesity Reports
https://doi.org/10.1007/s13679-020-00388-9

METABOLISM (M DALAMAGA, SECTION EDITOR)

Polycystic ovary Syndrome in Adolescents: Pitfalls

in Diagnosis and Management
Eirini Kostopoulou 1 & Panagiotis Anagnostis 2 & Julia K. Bosdou 3 & Bessie E. Spiliotis 1 & Dimitrios G. Goulis 2

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder during a woman’s reproductive
lifespan, with well-documented diagnostic criteria and therapeutic strategies in adults; the same is not necessarily true for
adolescents. The purpose of this review was to identify frequent pitfalls in PCOS diagnosis and management during adolescence.
Recent Findings Although there is no global consensus on the definition, most experts converge to the presence of both oligo/
amenorrhea and (clinical and/or biochemical) hyperandrogenism, as a prerequisite for diagnosis in adolescents. The former
criterion includes: (a) consecutive menstrual intervals > 90 days even in the first year after menarche; (b) menstrual intervals
persistently < 21 or > 45 days for ≥ 2 years after menarche; or (c) lack of menses by the age of 15 or 2–3 years after pubarche.
However, these menstrual irregularity patterns may overlap with other common entities in adolescents, such as frequent or
infrequent uterine bleeding or anovulation due to immaturity of the hypothalamic-pituitary-ovarian axis. Clinical signs of
hyperandrogenism are obscure, without well-validated criteria. Finally, the criterion of polycystic morphology cannot be safely
used in adolescents, mostly due to technical limitations of the transabdominal ultrasound. Except for the efficacy of lifestyle
intervention in overweight and obese adolescents with PCOS, limited and low-quality data exist regarding the available medi-
cations, such as oral contraceptives, metformin, and anti-androgens.
Summary Individualized management, guided by clinical experience and research data and close monitoring appear the most
effective approach in this PCOS population for optimal control of its reproductive and metabolic outcomes. Research focusing on
PCOS genetic and molecular mechanisms may elucidate what diagnostic and therapeutic strategies will be most appropriate in
adolescents with PCOS in the future.

Keywords Oligomenorrhea . Hyperandrogenism . Adolescence . Adolescents . Diagnosis

Introduction

Polycystic ovary syndrome (PCOS) constitutes the most com-

This article is part of the Topical Collection on Metabolism
* Panagiotis Anagnostis
pan.anagnostis@gmail.com
1
Division of Pediatric Endocrinology and Diabetes, Department of
Pediatrics, University of Patras School of Medicine, 265
00 Patras, Greece
2
Unit of Reproductive Endocrinology, 1st Department of Obstetrics
and Gynecology, Medical School, Aristotle University of
Thessaloniki, Thessaloniki, Greece
3 biosynthesis and action, glucose metabolism, such as the in-
Unit for Human Reproduction, 1st Department of Obstetrics and
Gynecology, Medical School, Aristotle University of Thessaloniki,
Thessaloniki, Greece
mon endocrine disorder in females of reproductive age [1],
accounting for 70–80% of all cases with hyperandrogenism
[2]. Its prevalence is estimated to 6–8% of the general pre-
menopausal population [2], depending on the criteria used, it
may reach up to 20% [3, 4]. PCOS is considered a multifac-
torial syndrome of unknown cause. Disordered gonadotropin
secretion with elevated luteinizing hormone (LH), ovarian
hyperandrogenism, and insulin resistance are key components
of the syndrome [5]. Its etiopathogenesis involves an interac-
tion between genetic and environmental factors. Studies have
focused on mutations in genes that participate in androgen
sulin and insulin receptor genes, and systemic inflammation,
such as the CYP11A1, CYP17A, CYP19, CYP21, HSD17B5,

HSD17B6, INS, INSR, IRS-1, IRS-2, IGF, PPAR-γ, the tumor
necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) genes
[6]. Besides the strong genetic component, an epigenetic com-
ponent seems to play a significant role [2]. With regard to the
environmental component, it has been hypothesized that in-
trauterine growth restriction (IUGR) or exposure to androgens
in utero may result in the development of PCOS in adult
women [5, 7].
In general, there is heterogeneity in the clinical presentation
of PCOS, which varies with age, body weight, ethnicity, and
the influence of environmental factors, such as medications
[8]. The diagnosis of the syndrome, which is the result of the
exclusion of other causes of menstrual irregularity and andro-
gen excess, becomes challenging after taking into consider-
ation that the evolution of its features may occur any time
throughout a woman’s lifespan [9]. Based on the American
Society for Reproductive Medicine (ASRM)/European
Society of Human Reproduction and Embryology (ESHRE)
(“Rotterdam”) criteria, which are the most widely applied, the
presence of at least two of the following three criteria are
needed to confirm the diagnosis of PCOS: ovulatory dysfunc-
tion, hyperandrogenism (clinical or biochemical), and poly-
cystic ovarian morphology (PCOM) on ultrasound [3, 4].
However, the clinical presentation is more obscure in adoles-
cents compared with the adults, complicating the diagnostic
and therapeutic approach.
The purpose of this narrative review is to focus on PCOS in
adolescence, in an attempt to identify frequent pitfalls in its
diagnosis and management.
Diagnostic Features of PCOS in Adults
Menstrual Irregularity and Ovulatory Dysfunction
Menstrual irregularity is present in > 75% of adult women
with PCOS. Oligomenorrhea is defined as intervals of > 6–8
weeks between menses. Adrenal (non-classical congenital ad-
renal hyperplasia (NCCAH)), thyroid (hypothyroidism, hy-
perthyroidism), and pituitary disorders (hyperprolactinemia)
should be excluded [10].
Androgen Excess
Androgen excess may be either biochemical or clinical.
Biochemical hyperandrogenemia is present in 60–80% of
adults with PCOS, mainly attributed to excess androgen pro-
duction by the ovaries, whereas the adrenal glands and periph-
eral adipose tissue contribute to a small degree [10]. Androgen
excess may clinically manifest as hirsutism (i.e., excess facial
and body hair), acne, or alopecia (male-pattern baldness) [11].
Nonetheless, clinical assessment of hyperandrogenism (hir-
sutism, acne, alopecia) has limitations, as it is often subjective,
Curr Obes Rep
poorly specific, or standardized and varies among ethnic
groups. Moreover, > 90% of 18-year-old women have some
form of acne [12].
In addition, biochemical hyperandrogenemia is not clearly
defined, depending on which androgen is measured, its upper
normal serum concentrations and the method of assessment.
The usefulness of serum total testosterone as a surrogate mark-
er of female hyperandrogenism is low due to the poor accura-
cy and sensitivity of traditional immunoassays in the female
range [13, 14]. Furthermore, total testosterone concentrations
exhibit a high intra- and inter-individual variability and are
subject to variations of the binding proteins, such as albumin
and sex hormone-binding globulin (SHBG); therefore, precise
reference values cannot be determined [1]. In contrast, serum-
free testosterone (fT) is a more sensitive marker of
hyperandrogenism compared with total testosterone [15, 16];
albeit the method of choice for its measurement, equilibrium
dialysis, is time consuming, and not available worldwide.
Therefore, an indirect measurement of fT, the free androgen
index (FAI), calculated as the quotient 100 × total
testosterone/SHBG (both expressed in nmol/l), has been pro-
posed [16]. Of note, it has been reported that only 50% of
women with PCOS and hyperandrogenic phenotype have to-
tal testosterone concentrations > 95th percentile of the refer-
ence values, whereas nearly 90% of them have fT concentra-
tions > 95th percentile [17]. The diagnostic utility of other
less-potent androgens, such as dehydroepiandrosterone sul-
fate (DHEAS) and Δ4-androstenedione in PCOS, is limited
due to their almost exclusive adrenal production [10].
However, many patients with PCOS present with clinical
signs of hyperandrogenism but without biochemical
hyperandrogenism. This may be attributed to increased pe-
ripheral androgen metabolism of androgens or increased con-
version of testosterone to the potent dihydrotestosterone
(DHT) at the hair follicles and sebaceous glands, through the
action of the enzyme 5α-reductase. Peripherally produced an-
drogens act in an intracrine way that is not reflected in blood
concentrations [2]. Moreover, androgen excess may affect the
menstrual cycle and fertility, through ovarian dysregulation
and impaired follicular maturation that result in anovulation
and subfertility [2].
Polycystic Ovarian Morphology
PCOM, defined as the presence of ≥ 12 follicles (2–9 mm in
diameter in each ovary) or increased ovarian volume (> 10
ml), has been introduced as one of the Rotterdam diagnostic
criteria for PCOS and has received criticism for broadening
the definition of PCOS. PCOM has been associated with both
irregular menses and hyperandrogenism [18].
Controversy persists with regard to the recommended
criteria for an accurate diagnosis of PCOS, since the criteria
proposed by the National Institutes of Health (NIH) consensus
Curr Obes Rep
in 1990 for PCOS in adult women require menstrual irregu-
larity and androgen excess [19]. The NIH criteria proposed in
2012 are in agreement with the Rotterdam criteria [20]. By
contrast, the Androgen Excess and PCOS Society (AEPCOS)
requires the presence of hyperandrogenism in combination
with either menstrual irregularity or PCOM for the diagnosis
of PCOS [10].
Diagnostic Challenges in Adolescence
Diagnostic Criteria
Although there is no consensus on the definition of PCOS in
adolescents, according to the aforementioned international
scientific groups, the same diagnostic criteria can be extrapo-
lated in the adolescent population [3, 4]. However, the main
shortcoming in these cases is the fact that many adolescents
exhibit physiologic menstrual irregularity and signs of andro-
gen excess peripubertal [2, 21]. Furthermore, adolescent ovar-
ian morphology overlaps with that of women with PCOS [22,
23]. Although there is no global consensus on the exact PCOS
definition in adolescents, the diagnosis is suggested to be
based on the concomitant presence of clinical and/or biochem-
ical hyperandrogenism with persistent oligomenorrhea [4, 24,
25]. The following criteria have been proposed for the latter:
(a) consecutive menstrual intervals > 90 days, even from the
first year after menarche; (b) menstrual intervals persistently <
21 or > 45 days for ≥ 2 years after menarche; or (c) lack of
menses by the age of 15 or 2–3 years after pubarche (devel-
opment of breast budding) [25]. With regard to PCOS preva-
lence in adolescents, a recent meta-analysis reported rates of
11.0% (95% confidence interval (CI), 6.8–16.1), 3.4% (95%
CI, 0.3–9.5), and 8.0% (95% CI, 6.2–10.0), according to the
Rotterdam, NIH, or AEPCOS criteria [26•].
Menstrual Irregularity and Ovulatory Dysfunction in
Adolescence
Menstrual irregularity is often the earliest clinical manifestation
of PCOS in adolescence [27]. It may manifest as oligomenor-
rhea or excessive uterine bleeding [25], which usually resolve
within 2 years post-menarche. In some cases, however, regular
menses might be established later on, without any pathological
cause [28]. Oligomenorrhea at the age of 15 years persists for 3
years more in 51% of the cases; on the other hand, only 2% of
adolescents with regular menstrual cycles develop oligomenor-
rhea later on [29]. Thus, oligomenorrhea at 15 years of age may
be a good predictor of oligomenorrhea in 3 years. Moreover,
PCOS has been reported as the predominant diagnosis in hos-
pitalized adolescents with excessive uterine bleeding, account-
ing for 33% of the cases [30].
Anovulation is also common at the beginning of puberty
due to the immaturity of the hypothalamic-pituitary-ovarian
axis and involves approximately 40–50% of adolescent girls
[31]. Therefore, differentiation between physiological
anovulation during adolescence and ovulatory dysfunction is
challenging.
Androgen Excess in Adolescence
Although acne may be associated with underlying
hyperandrogenism, it cannot be used as the sole criterion for
clinical hyperandrogenism, due to its high prevalence (up to
90%) in adolescence [32]. Hirsutism is considered a more
reliable marker of hyperandrogenism in adolescents compared
with acne. It becomes more prominent in adulthood as the
duration of exposure to androgens is increasing [33].
According to the international consensus of 2003 [34],
moderate-to-severe hirsutism is considered a clinical feature
of androgen excess, as well as persistent acne. In contrast,
mild hirsutism is considered to be normal soon after menarche
[25]. The Ferriman-Gallwey scoring system is applied for the
quantification of hirsutism (a score of 8–15 indicates mild
hirsutism and a score of > 15 indicates moderate or severe
hirsutism, although the same thresholds are used in adults
and adolescents). There is a paucity of data concerning andro-
genic alopecia in adolescents.
Since clinical signs of hyperandrogenism are not reliable in
adolescence, biochemical hyperandrogenemia remains a defin-
ing feature of PCOS in this population [17], despite the phys-
iological increase in androgen concentrations during adoles-
cence. Increased calculated fT is the most prevalent biochemi-
cal finding, although total testosterone and DHEAS may also
be increased [17]. To date, there are no well-defined thresholds
for androgen concentrations adjusted for adolescence. As in
adults, a sensitive testosterone assay remains the sine qua non
for accurate results. The AEPCOS Society recommends mass
spectrometry as the optimal method for assessing total and free
testosterone concentrations [35].
PCOM in Adolescence
The presence of multifollicular ovaries (≥ 6 cysts, 4–10 mm in
diameter, and of normal or slightly increased size) is frequent
in adolescents [34] and may reach 57.9% in adolescents with
menstrual irregularities [36]; thus, the clinical significance and
diagnostic reliability of this criterion in adolescence are
questioned. PCOM and increased ovarian volume are features
of physiologic puberty and may subsequently subside with the
onset of regular menstrual cycles [37]. Hence, it is recom-
mended that the ultrasonographic picture should not be in-
cluded in the diagnostic criteria of PCOS during adolescence,
as it has not been validated for this age group [31].

There are several reports in the literature with regard to
PCOM in adolescents. It has been estimated that 10–48% of
adolescents without PCOS may have a polycystic appearance
of their ovaries, suggesting an overlap in ovarian morphology
between adolescents with PCOS and control adolescents [21,
38, 39]. It has also been reported that one third of normal
weight or overweight girls may have PCOM without ovulato-
ry dysfunction within 2–4 years after menarche [23, 40].
On the same concept, PCOM may exist in one third of
adolescents with hyperandrogenism [41], as well as in 9 and
28% of those with regular and irregular menses (average cycle
length 22–41 days), respectively, and in 45% of adolescents
with oligomenorrhea and increased androgen concentrations
[42]. However, the early menstrual pattern is predictive of the
late one [29]; therefore, oligomenorrhea that persists 2 years
beyond menarche should be evaluated as an early clinical sign
of PCOS. Another shortcoming of PCOM in adolescents is
that transabdominal ultrasound, which is the primary imaging
tool used in this population (instead of transvaginal ultra-
sound), may limit the diagnostic accuracy and usefulness of
this imaging modality in overweight or obese adolescents.
Magnetic resonance imaging (MRI) has been suggested as a
more accurate approach, but it is not routinely used [43].
Further studies in larger populations during the second de-
cade of life are needed for safe conclusions to be drawn. With
these limitations, the diagnosis of PCOS hinges on the evi-
dence of androgen excess and ovulatory dysfunction, rather
than ovarian imaging [25].
Diagnostic Approach of PCOS in Adolescence
Α thorough medical history has to be obtained, including in-
formation on exogenous medication intake, such as androgen-
ic steroids and anti-epileptics. Of note, PCOS features may be
covered by medications used to treat acne [44]. Furthermore,
obtaining a family history is required, since a genetic compo-
nent may be present. A detailed physical examination is also
important. Acanthosis nigricans and truncal obesity may be
detected as clinical signs of insulin resistance. The degree of
hirsutism can be assessed by the Ferriman-Gallwey score [45],
and the severity of acne can be graded based on lesion type
and count [8].
Biochemical workup in PCOS should mainly include
fasting plasma glucose, lipid profile [46], and total or calcu-
lated fT concentrations (or FAI), preferably in the morning
[3]. If treatment has been initiated in the interim, androgen
concentrations may be altered, and this should be taken into
consideration by the clinicians [10, 11, 46, 3]. To discriminate
between different causes of hyperandrogenemia or menstrual
irregularity, additional testing may include DHEAS, Δ4-an-
drostenedione, 17-hydroxyprogesterone [17(OH)P], thyroid-
stimulating hormone (TSH), prolactin, LH, FSH, and estradiol
from the 3rd to 5th day of the menstrual cycle. In adolescents
Curr Obes Rep
with baseline morning 17(OH)P > 200 mg/dl, a cosyntropin
stimulation test should be performed to exclude NCCAH [47].
A pregnancy test is essential.
Although pelvic ultrasonography is not universally recom-
mended for setting the diagnosis of PCOS in adolescents [25],
a pelvic ultrasound may be useful for excluding other under-
lying pathology, particularly androgen-secreting tumors in
cases of hyperandrogenemia and anovulation [48, 49].
Complications of PCOS
Cumulative evidence supports that PCOS is associated with
long-term consequences, including impaired reproductive
health, psychological dysfunction, dysregulation of glucose
homeostasis (impaired glucose tolerance (IGT) or type 2 dia-
betes mellitus (T2DM)), non-alcoholic fatty liver disease
(NAFLD), dyslipidemia, metabolic syndrome (MetS), cardio-
vascular disease, and increased endometrial, breast, and ovar-
ian cancer risk [50–52]. Obesity exacerbates PCOS-associated
metabolic dysregulation [53, 54]. Furthermore, insulin stimu-
lates ovarian androgen synthesis [55] and inhibits the produc-
tion of SHBG in the liver [56]. As a result, circulating free
androgen concentrations are increased. Although this meta-
bolic dysregulation is a core defect in PCOS, these “physio-
logic” metabolic changes are also prominent during puberty.
Indeed, reduced insulin sensitivity and hyperinsulinemia are
quite common in healthy adolescents [57]. It has been report-
ed that insulin sensitivity decreases by 50% during puberty,
compensated by doubling of insulin secretion [56].
However, adolescents diagnosed with PCOS should be
screened for metabolic disorders, as approximately one third
of them meet the criteria for MetS, such as central obesity,
arterial hypertension, atherogenic dyslipidemia, and glucose
intolerance, as opposed to only 5% of those without PCOS
[58, 59]. Of note, the diagnostic criteria for MetS differ in the
adolescent population. In particular, three of the following five
are required for setting the diagnosis: (i) fasting blood glucose
concentrations > 100 mg/dl; (ii) high-density lipoprotein cho-
lesterol (HDL-C) < 40 mg/dl; (iii) triglycerides ≥ 110 mg/dl;
(iv) waist circumference ≥ 90th percentile for age and sex; and
(v) blood pressure ≥ 90th percentile for age and sex [60].
These abnormalities may present early in the course of the
PCOS [61]. Obesity has shown to exacerbate these metabolic
abnormalities in adolescents with PCOS [62•]. Although
PCOS poses a heightened risk for MetS, independently of
body mass index (BMI), the prevalence of MetS is higher in
the presence of obesity [59], especially abdominal obesity
[63]. Interestingly, although obesity is considered a better pre-
dictor of MetS compared with androgen excess [64, 65], the
latter may conversely increase the risk of obesity independent-
ly of BMI [59, 66].
Curr Obes Rep
PCOS may be a sign of systemic inflammation, since in-
creased concentrations of IL-6 and reduced adiponectin con-
centrations have been found in lean adolescents with
hyperandrogenism compared with adolescents without
hyperandrogenism [67]. Low adiponectin concentrations have
been correlated with insulin resistance and visceral adiposity
[68]. With respect to dyslipidemia, increased triglyceride and
low-density lipoprotein- cholesterol (LDL-C) concentrations
have been reported in adolescents with PCOS and androgen
excess [66]. Another complication of PCOS in adolescence
that should be taken into account is its effect on the quality of
life (QoL). Indeed, a meta-analysis has shown that QoL, most-
ly referring to a psychological profile, is impaired in adoles-
cent patients with PCOS, with obesity strongly mediating this
effect [69•].
Follow-up of PCOS in Adolescence
Regular follow-up is of utmost importance to record the
severity and progression of hirsutism, acne, and men-
strual disturbances. Additionally, monitoring for PCOS-
associated comorbidities, such as the presence of meta-
bolic disturbances, as described above, is also crucial
[25, 59, 70].
A 2-h oral glucose tolerance test (OGTT) is the gold-
standard screening test for diagnosing impaired glucose regu-
lation and periodic screening using this test has been sug-
gested [49]. The increased prevalence of MetS at such a young
age underscores the importance of regular screening of this
population to decrease the future risk of diabetes and coronary
artery disease.
The psychological impact of PCOS in adolescent patients
should also be addressed at regular intervals. Depression and
anxiety are seen in this population at an increased prevalence,
and expert guidance may be needed in specific cases [71, 72].
Eating disorders are prevalent in adolescents with PCOS, and
physicians should be aware [73].
Management of PCOS in Adolescence
Goals and Principles of Management
The goals of PCOS treatment are to improve QoL and
reduce the risk of long-term health outcomes [11].
Individualized treatment based on the clinical presentation,
needs and preferences of each patient is imperative. The
initiation of treatment for PCOS does not require a defini-
tive diagnosis of the syndrome, as it may decrease the risk
for future comorbidities [25].
Lifestyle Modifications
Lifestyle modifications to avoid weight gain in non-obese
patients or to reduce body weight in cases of excess body fat
remain the mainstay of treatment [3, 4]. Weight loss is bene-
ficial for PCOS-associated menstrual irregularity, androgen
excess, and cardiometabolic risk. Interestingly, it seems to
be of no benefit in normal-weight women with PCOS [3, 4].
It is the calorie restriction itself rather than the type of diet (i.e.,
protein content) that has an impact on reproductive and met-
abolic profile [3, 4, 74]. Lifestyle intervention may also ame-
liorate the lipid profile in adolescents with PCOS [75].
Although 40–70% of adolescents with PCOS are over-
weight or obese, adherence to lifestyle intervention is subop-
timal and drugs used for weight loss in adults have not been
approved in this population. Furthermore, the optimal diet has
not been defined [76].
Few data exist regarding the effect of lifestyle modification
on the metabolic and reproductive profile in adolescents. In a
prospective study (59 obese PCOS girls, aged 12–18 years),
lifestyle intervention (diet modification plus regular exercise),
leading to a mean BMI reduction of 3.9 kg/m2 after 1 year,
ameliorated lipid profile (increased HDL-C and reduced tri-
glyceride concentrations), and reduced insulin resistance in-
dex and blood pressure. It also reduced the prevalence of
oligo- and amenorrhea, by 42 and 19%, respectively.
Interestingly, carotid-intima media thickness (cIMT) de-
creased, as well as testosterone concentrations [77]. On the
same note, a randomized-controlled trial (RCT) in obese ado-
lescents with PCOS (n = 60) showed that intensive dietary
program with conventional calorie restriction led to an im-
provement in menstrual pattern and hirsutism score, compared
with a healthy diet, without energy restriction [78]. In this
study, lifestyle modification in adolescents with PCOS result-
ed in a decrease in waist circumference, denoting a decrease in
insulin resistance [78].
Oral Contraceptives
Combined oral contraceptives (COCs) are recommended as a
first-line medical treatment for the management of menstrual
irregularity and clinical signs of androgen excess in women
with PCOS [3, 4]. The combination of estrogen and proges-
terone has a suppressive effect on the hypothalamus-pituitary-
ovarian (HPO) axis, by blocking the ovarian androgen pro-
duction. Furthermore, COCs increase SHBG concentrations,
thereby further reducing androgen excess [79]. The progester-
one component of the COC prevents estrogen action and de-
creases the risk of endometrial hyperplasia [11]. COCs are
indicated for all forms of menstrual irregularity, including
amenorrhea, oligomenorrhea, menorrhagia, and abnormal
uterine bleeding [4, 45]. The positive effect of COCs in men-
struation is evident 2–3 months after initiation of treatment.

Although the duration of treatment with COCs is not well
defined, one or more years is the suggested period for HPO
axis recovery and potential resolution of menstrual irregularity
[11]. COCs may also be efficacious for the management of
acne and hirsutism [11].
Common adverse effects associated with COC use include
nausea, breast tenderness, headaches, and mood changes,
which are mitigated after the first months of administration
[80]. Studies in adults with PCOS indicate that COCs may
have either negative or neutral impact on lipid profile and
glucose metabolism, mostly dependent on the dose of estro-
gen and type of progestin; data are derived from studies of
small sample size and short duration [80]. According to a
Cochrane meta-analysis, there is no effect of COCs on body
weight in women with PCOS [81]. Recent meta-analyses have
shown that potential cardiometabolic COC-related adverse ef-
fects may be blunted when COCs are combined with metfor-
min or lifestyle modification [82, 83].
Regarding adolescents, the evidence is not robust for safe
conclusions. A Greek study has shown that 30 μg/day of
ethinyl-estradiol combined with 150 mg/day of desogestrel,
for 21 days per cycle of 28 days, may reduce androgen con-
centrations without worsening the lipid profile, weight, or
waist-to-hip ratio [79]. However, some data suggest an in-
crease in systemic inflammation, as assessed by high-
sensitivity C-reactive protein concentrations and cIMT, with
the use of COCs [84, 85]. Contra-indications, such as a history
of deep vein thrombosis (DVT) or migraine, should be strong-
ly taken into consideration before the initiation of COCs [80].
Metformin
In general, metformin, as an insulin sensitizer, is recommended
as a second-line therapeutic modality in patients with PCOS
and disordered glucose metabolism (IGT or T2DM) in whom
lifestyle intervention was ineffective or who have contra-
indications or are intolerant to COCs [3, 4]. The use of other
insulin sensitizers, such as inositols or thiazolidinediones, is not
recommended for the treatment of PCOS [3, 4]. Metformin
may improve the cardiometabolic profile and menstrual irreg-
ularity in women with PCOS, although with a negligible effect
on clinical hyperandrogenism [3, 4]. Interestingly, it may ame-
liorate the reproductive function regardless of insulin resistance
and IGT [86].
A few non-RCTs, of small sample size and short duration
studies exist on metformin use in adolescents with PCOS. In
one prospective study in non-obese adolescents with PCOS (n
= 18, mean BMI 21.4 kg/m 2 ) with hyperinsulinemic
hyperandrogenism and persistent anovulation, metformin
1275 mg/day for 6 months, restored menstrual irregularity in
all patients [87]. Ovulation induction was achieved in almost
80% of patients in 6 months. In the same study, metformin
improved clinical and biochemical hyperandrogenemia and
Curr Obes Rep
resulted in a less atherogenic profile, characterized by a reduc-
tion in total cholesterol, triglyceride, and LDL-C concentra-
tions [87]. This was also the case in another study in adoles-
cents with PCOS and IGT, in which metformin (850 mg,
twice daily), improved insulin sensitivity and biochemical
hyperandrogenemia and mitigated the adrenal steroidogenic
response to adrenocorticotropic hormone [88]. In these stud-
ies, the effect of metformin on BMI was either beneficial [88]
or neutral [87].
Additional studies have shown that the combination of
metformin with a low-carbohydrate diet resulted in normali-
zation of menstrual cycles and restoration of ovulation in ad-
olescents with PCOS within a few months [89, 90]. A few
months of metformin therapy has also led to normalization
of glucose tolerance, reduction in total and free testosterone
concentrations, and improvement of BMI, body composition,
and insulin sensitivity in adolescents [88].
A few comparative data exist with regard to metformin use
vs. COCs in adolescents. A meta-analysis of four RCTs (n =
170), published in 2016, showed that COC use induced a
modest amelioration in menstrual pattern and acne scores. In
contrast, metformin led to greater BMI reduction and im-
provement in glucose dysregulation, total cholesterol, and
LDL-C concentrations in adolescents with PCOS. No differ-
ence in hirsutism and HDL-C or triglyceride concentrations
were observed between groups [91]. However, available data
were of poor quality. Additional studies are needed regarding
the management of PCOS in adolescents. Gastrointestinal ad-
verse effects (nausea, stomach upset, diarrhea) constitute the
most common shortcoming with metformin use, which may
occur in up to 30% of adolescents with PCOS [92].
Anti-androgens
These medications are suggested in cases with severe clinical
hyperandrogenemia, not successfully managed with COCs or,
in which, COCs are contra-indicated. Prerequisite of their use
is the application of effective contraception in sexually active
adolescents, due to their potential teratogenic action. In gen-
eral, anti-androgens are effective in improving clinical signs
of androgen excess, psychological profile, and QoL in women
with PCOS [3, 4].
Data in adolescents are limited. Spironolactone, an
aldosterone- and androgen-receptor antagonist, may improve
menstrual disturbances and cutaneous manifestations of
hyperandrogenism but not metabolic disorders [93]. It can
be used as an adjunct to treatment with COCs or metformin,
at doses of 50–200 mg/day [93, 94]. With respect to the ado-
lescent population with PCOS, low dose of the triple combi-
nation spironolactone (50 mg/day)/pioglitazone (7.5 mg/day)/
metformin (850 mg/day) (SPIOMET) exerted comparable ef-
fect with COCs on the reduction in biochemical
hyperandrogenemia and body fat distribution. Furthermore,
Curr Obes Rep
SPIOMET reduced insulin and increased adiponectin concen-
trations and ovulation rates up to threefold during the post-
treatment period (after 12 months) compared with COCs [95].
Flutamide is another anti-androgen, acting at the level of
the androgen receptor [96]. In addition to its anti-androgenic
action in adults with PCOS, it has proven efficacy in clinical
and biochemical hyperandrogenism in non-obese adolescents
with PCOS, at the dose of 250 mg/day. However, the medi-
cation had no effect on the menstrual regularity and insulin
resistance [97]. Also, clinicians should be mindful of its po-
tential liver toxicity [3, 4].
Cyproterone acetate (CPA) is another anti-androgen most
commonly used in a contraceptive pill, at the dose of 2 mg in
combination with 35 mg ethinyl-estradiol or at doses of 50–
100 mg/day as adjuvant therapy to COC [3, 4]. In adult wom-
en with PCOS, CPA reduced hirsutism score in more than
50% of them and improved acne [98, 99]. However, it may
increase triglyceride concentrations [79] and DVT risk [100].
Furthermore, finasteride, an inhibitor of 5α-reductase isoen-
zyme, at low doses (2.5 mg every 3 days), has been trialed in a
pilot study and was found to be effective for the treatment of
hirsutism in adolescents [101].
Local Treatment/Cosmetic Treatment
Treatment of hirsutism includes local application of eflornithine
cream; the duration of treatment is not clearly defined, as data in
adolescents are limited. Non-pharmaceutical treatment ap-
proaches, offering immediate results, are also available, includ-
ing mechanical hair removal by laser or electrolysis [11]. The
combination of eflornithine with laser therapy is more effica-
cious compared with each approach alone; again, more data are
needed [102, 103].
Conclusions
The diagnosis of PCOS in adolescents is not straightforward,
due to the high degree of phenotypical variability in its pre-
sentation. The impaired menstruation in adolescents, mani-
fested as frequent or infrequent uterine bleeding, as well as
the high prevalence of clinical signs of hyperandrogenism and
PCOM, overlap with symptoms and signs of PCOS, further
complicating the process of establishing a firm diagnosis.
Menstrual irregularity as a clinical expression of PCOS is
difficult to be distinguished from anovulation due to the im-
maturity of the HPO axis. Furthermore, the clinical value of
signs of hyperandrogenism is low; therefore, increased serum
androgen concentrations represent the best marker of andro-
gen excess. In addition, the value of PCOM, a key criterion for
setting the diagnosis in adult women, is low in adolescents,
due to the changes in ovarian appearance and the technical
limitations of the transabdominal ultrasound. As a result, a
high index of suspicion and close follow-up are necessary
for establishing the diagnosis of PCOS.
Concerning treatment, individualized management is re-
quired to change the natural history of the reproductive and
metabolic outcomes of this complex condition. Lifestyle in-
tervention in overweight and obese adolescents may reduce
PCOS-associated long-term complications, such as T2DM
and cardiovascular disease. The efficacy and safety of the
pharmaceutical approach are well-documented in adults with
PCOS but limited in adolescents. Therefore, more data from
RCTs are needed to establish a therapeutic strategy. Close
monitoring for metabolic derangements, evaluation of the pro-
cess of the disease and exclusion of other PCOS-mimicking
diseases is crucial in this population.
Compliance with Ethical Standards
Conflict of Interest The authors have no conflict of interest to disclose.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
1. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo
R, et al. Consensus on women's health aspects of polycystic ovary
syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored
3rd PCOS Consensus Workshop Group. Fertil Steril.
2012;97(1):28–38e25. https://doi.org/10.1016/j.fertnstert.2011.
09.024.
2. Fanelli F, Gambineri A, Mezzullo M, Vicennati V, Pelusi C,
Pasquali R, et al. Revisiting hyper- and hypo-androgenism by tan-
dem mass spectrometry. Rev Endocr Metab Disord. 2013;14(2):
185–205. https://doi.org/10.1007/s11154-013-9243-y.
3. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-
Morreale HF, Franks S, Gambineri A, et al. The polycystic ovary
syndrome: a position statement from the European Society of
Endocrinology. Eur J Endocrinol. 2014;171(4):P1–29. https://
doi.org/10.1530/EJE-14-0253.
4. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH,
Pasquali R, et al. Diagnosis and treatment of polycystic ovary
syndrome: an Endocrine Society clinical practice guideline. J
Clin Endocrinol Metab. 2013;98(12):4565–92. https://doi.org/10.
1210/jc.2013-2350.
5. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC,
Laven JS, Legro RS. Scientific Statement on the Diagnostic
Criteria, Epidemiology, Pathophysiology, and Molecular
Genetics of Polycystic Ovary Syndrome. Endocr Rev.
2015;36(5):487–525. https://doi.org/10.1210/er.2015-1018.
6. Zhao H, Lv Y, Li L, Chen ZJ. Genetic Studies on Polycystic
Ovary Syndrome. Best Pract Res Clin Obstet Gynaecol.
2016;37:56–65. https://doi.org/10.1016/j.bpobgyn.2016.04.002.

7. Sir-Petermann T, Hitchsfeld C, Maliqueo M, Codner E, Echiburu
B, Gazitua R, et al. Birth weight in offspring of mothers with
polycystic ovarian syndrome. Hum Reprod. 2005;20(8):2122–6.
https://doi.org/10.1093/humrep/dei009.
8. Rosenfield RL. The diagnosis of polycystic ovary syndrome in
adolescents. Pediatrics. 2015;136(6):1154–65. https://doi.org/10.
1542/peds.2015-1430.
9. Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifac-
eted disease from adolescence to adult age. Ann N Y Acad Sci.
2006;1092:158–74. https://doi.org/10.1196/annals.1365.014.
10. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E,
Escobar-Morreale HF, Futterweit W, et al. Positions statement:
criteria for defining polycystic ovary syndrome as a predominant-
ly hyperandrogenic syndrome: an Androgen Excess Society
guideline. J Clin Endocrinol Metab. 2006;91(11):4237–45.
https://doi.org/10.1210/jc.2006-0178.
11. Kamboj MK, Bonny AE. Polycystic ovary syndrome in adoles-
cence: diagnostic and therapeutic strategies. Transl Pediatr.
2017;6(4):248–55. https://doi.org/10.21037/tp.2017.09.11.
12. Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late
adolescence and in adults. Br Med J. 1979;1(6171):1109–10.
https://doi.org/10.1136/bmj.1.6171.1109.
13. Herold DA, Fitzgerald RL. Immunoassays for testosterone in
women: better than a guess? Clin Chem. 2003;49(8):1250–1.
https://doi.org/10.1373/49.8.1250.
14. Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N,
et al. Testosterone measured by 10 immunoassays and by isotope-
dilution gas chromatography-mass spectrometry in sera from 116
men, women, and children. Clin Chem. 2003;49(8):1381–95.
https://doi.org/10.1373/49.8.1381.
15. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus work-
shop group. Revised 2003 consensus on diagnostic criteria and
long-term health risks related to polycystic ovary syndrome
(PCOS). Hum Reprod. 2004;19(1):41–7. https://doi.org/10.1093/
humrep/deh098.
16. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of
simple methods for the estimation of free testosterone in serum. J
Clin Endocrinol Metab. 1999;84(10):3666–72. https://doi.org/10.
1210/jcem.84.10.6079.
17. Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R.
Phenotypic spectrum of polycystic ovary syndrome: clinical and
biochemical characterization of the three major clinical sub-
groups. Fertil Steril. 2005;83(6):1717–23. https://doi.org/10.
1016/j.fertnstert.2005.01.096.
18. Fernandes AR. de Sa Rosa e Silva AC, Romao GS, Pata MC, dos
Reis RM. Insulin resistance in adolescents with menstrual irregu-
larities. J Pediatr Adolesc Gynecol. 2005;18(4):269–74. https://
doi.org/10.1016/j.jpag.2005.05.006.
19. Zawadzki JKDA. Diagnostic criteria for polycystic ovary syn-
drome: towards a rational approach. In: Dunaif A, Givens JR,
Haseltine F, et al., editors. Polycystic ovary syndrome 1992.
Boston: Blackwell Scientific Publications. p. 377–84.
20. Terry NL, Ryan ME. Polycystic Ovary Syndrome (PCOS).
Bethesda, Md: National Institutes of Health Library. 2012.
Available at: http://prevention.nih.gov/workshops/2012/pcos/
docs/PCOS_Bibliography.pdf. Accessed 27 Mar 2013.
21. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic
ovary syndrome in adolescence. Ann N Y Acad Sci. 2008;1135:
76–84. https://doi.org/10.1196/annals.1429.005.
22. Villarroel C, Merino PM, Lopez P, Eyzaguirre FC, Van Velzen A,
Iniguez G, et al. Polycystic ovarian morphology in adolescents
with regular menstrual cycles is associated with elevated anti-
Mullerian hormone. Hum Reprod. 2011;26(10):2861–8. https://
doi.org/10.1093/humrep/der223.
23. Codner E, Villarroel C, Eyzaguirre FC, Lopez P, Merino PM,
Perez-Bravo F, et al. Polycystic ovarian morphology in
Curr Obes Rep
postmenarchal adolescents. Fertil Steril. 2011;95(2):702–6e1–2.
https://doi.org/10.1016/j.fertnstert.2010.06.015.
24. Pena AS, Witchel SF, Hoeger KM, Oberfield SE, Vogiatzi MG,
Misso M, et al. Adolescent polycystic ovary syndrome according
to the international evidence-based guideline. BMC Med.
2020;18(1):72. https://doi.org/10.1186/s12916-020-01516-x.
25. Witchel SF, Oberfield S, Rosenfield RL, Codner E, Bonny A,
Ibanez L, et al. The diagnosis of polycystic ovary syndrome dur-
ing adolescence. Horm Res Paediatr. 2015;83:376–89. https://doi.
org/10.1159/000375530.
26.• Naz MSG, Tehrani FR, Majd HA, Ahmadi F, Ozgoli G, Fakari
FR, et al. The prevalence of polycystic ovary syndrome in adoles-
cents: a systematic review and meta-analysis. Int J Reprod
Biomed (Yazd). 2019;17(8):533–42. https://doi.org/10.18502/
ijrm.v17i8.4818. This meta-analysis recorded a wide variation
(3.4% to 11%) in the prevalence of PCOS in adolescents, de-
pending on the diagnostic criteria used.
27. Avvad CK, Holeuwerger R, Silva VC, Bordallo MA, Breitenbach
MM. Menstrual irregularity in the first postmenarchal years: an
early clinical sign of polycystic ovary syndrome in adolescence.
Gynecol Endocrinol. 2001;15(3):170–7.
28. Gardner J. Adolescent menstrual characteristics as predictors of
gynaecological health. Ann Hum Biol. 1983;10(1):31–40. https://
doi.org/10.1080/03014468300006161.
29. 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 polycystic ovaries
at age 15 years for oligo-amenorrhoea at age 18 years. Hum
Reprod. 2004;19(2):383–92. https://doi.org/10.1093/humrep/
deh079.
30. Maslyanskaya S, Talib HJ, Northridge JL, Jacobs AM, Coble C,
Coupey SM. Polycystic ovary syndrome: an under-recognized
cause of abnormal uterine bleeding in adolescents admitted to a
children’s hospital. J Pediatr Adolesc Gynecol. 2017;30(3):349–
55. https://doi.org/10.1016/j.jpag.2016.11.009.
31. Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic
ovary syndrome in adolescents. Am J Obstet Gynecol.
2010;203(3):201.e1–5. https://doi.org/10.1016/j.ajog.2010.03.
008.
32. Slayden SM, Moran C, Sams WM Jr, Boots LR, Azziz R.
Hyperandrogenemia in patients presenting with acne. Fertil
Steril. 2001;75(5):889–92. https://doi.org/10.1016/s0015-
0282(01)01701-0.
33. Pfeifer SM, Kives S. Polycystic ovary syndrome in the adolescent.
Obstet Gynecol Clin N Am. 2009;36(1):129–52. https://doi.org/
10.1016/j.ogc.2008.12.004.
34. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment
of the polycystic ovary: international consensus definitions. Hum
Reprod Update. 2003;9(6):505–14. https://doi.org/10.1093/
humupd/dmg044.
35. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E,
Escobar-Morreale HF, Futterweit W, et al. The Androgen
Excess and PCOS Society criteria for the polycystic ovary syn-
drome: the complete task force report. Fertil Steril. 2009;91(2):
456–88. https://doi.org/10.1016/j.fertnstert.2008.06.035.
36. Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N,
Tucker M, et al. Multifollicular ovaries: clinical and endocrine
features and response to pulsatile gonadotropin releasing hor-
mone. Lancet. 1985;2(8469–70):1375–9. https://doi.org/10.
1016/s0140-6736(85)92552-8.
37. Venturoli S, Porcu E, Fabbri R, Pluchinotta V, Ruggeri S, Macrelli
S, et al. Longitudinal change of sonographic ovarian aspects and
endocrine parameters in irregular cycles of adolescence. Pediatr
Res. 1995;38(6):974–80. https://doi.org/10.1203/00006450-
199512000-00024.
Curr Obes Rep
38. Bridges NA, Cooke A, Healy MJ, Hindmarsh PC, Brook CG.
Standards for ovarian volume in childhood and puberty. Fertil
Steril. 1993;60(3):456–60.
39. Mortensen M, Rosenfield RL, Littlejohn E. Functional signifi-
cance of polycystic-size ovaries in healthy adolescents. J Clin
Endocrinol Metab. 2006;91(10):3786–90. https://doi.org/10.
1210/jc.2006-0835.
40. Hart R, Doherty DA, Norman RJ, Franks S, Dickinson JE, Hickey
M, et al. Serum antimullerian hormone (AMH) levels are elevated
in adolescent girls with polycystic ovaries and the polycystic ovar-
ian syndrome (PCOS). Fertil Steril. 2010;94(3):1118–21. https://
doi.org/10.1016/j.fertnstert.2009.11.002.
41. Ibanez L, Lopez-Bermejo A, Callejo J, Torres A, Cabre S, Dunger
D, et al. Polycystic ovaries in nonobese adolescents and young
women with ovarian androgen excess: relation to prenatal growth.
J Clin Endocrinol Metab. 2008;93(1):196–9. https://doi.org/10.
1210/jc.2007-1800.
42. van Hooff MH, Voorhorst FJ, Kaptein MB, Hirasing RA,
Koppenaal C, Schoemaker J. Polycystic ovaries in adolescents
and the relationship with menstrual cycle patterns, luteinizing
hormone, androgens, and insulin. Fertil Steril. 2000;74(1):49–
58. https://doi.org/10.1016/s0015-0282(00)00584-7.
43. Yoo RY, Sirlin CB, Gottschalk M, Chang RJ. Ovarian imaging by
magnetic resonance in obese adolescent girls with polycystic ova-
ry syndrome: a pilot study. Fertil Steril. 2005;84(4):985–95.
https://doi.org/10.1016/j.fertnstert.2005.04.039.
44. Eichenfield LF, Krakowski AC, Piggott C, Del Rosso J, Baldwin
H, Friedlander SF, et al. Evidence-based recommendations for the
diagnosis and treatment of pediatric acne. Pediatrics.
2013;131(Suppl 3):S163–86. https://doi.org/10.1542/peds.2013-
0490B.
45. Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA,
Rosenfield RL, et al. Evaluation and treatment of hirsutism in
premenopausal women: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab. 2008;93(4):1105–20.
https://doi.org/10.1210/jc.2007-2437.
46. Salley KE, Wickham EP, Cheang KI, Essah PA, Karjane NW,
Nestler JE. Glucose intolerance in polycystic ovary syndrome–a
position statement of the Androgen Excess Society. J Clin
Endocrinol Metab. 2007;92(12):4546–56. https://doi.org/10.
1210/jc.2007-1549.
47. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke
DP, et al. Congenital adrenal hyperplasia due to steroid 21-
hydroxylase deficiency: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab. 2010;95(9):4133–60. https://
doi.org/10.1210/jc.2009-2631.
48. Bremer AA. Polycystic ovary syndrome in the pediatric popula-
tion. Metab Syndr Relat Disord. 2010;8(5):375–94. https://doi.
org/10.1089/met.2010.0039.
49. Buggs C, Rosenfield RL. Polycystic ovary syndrome in adoles-
cence. Endocrinol Metab Clin N Am. 2005;34(3):677–705, x.
https://doi.org/10.1016/j.ecl.2005.04.005.
50. Hart R, Doherty DA. The potential implications of a PCOS diag-
nosis on a woman's long-term health using data linkage. J Clin
Endocrinol Metab. 2015;100(3):911–9. https://doi.org/10.1210/jc.
2014-3886.
51. Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian
syndrome (PCOS): Long-term metabolic consequences.
Metabolism. 2018;86:33–43. https://doi.org/10.1016/j.metabol.
2017.09.016.
52. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic
ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev
Endocrinol. 2011;7(4):219–31. https://doi.org/10.1038/nrendo.
2010.217.
53. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence
and predictors of risk for type 2 diabetes mellitus and impaired
glucose tolerance in polycystic ovary syndrome: a prospective,
controlled study in 254 affected women. J Clin Endocrinol
Metab. 1999;84(1):165–9. https://doi.org/10.1210/jcem.84.1.
5393.
54. Sam S. Obesity and polycystic ovary syndrome. Obes Manag.
2007;3(2):69–73. https://doi.org/10.1089/obe.2007.0019.
55. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N,
Medina F. Insulin stimulates testosterone biosynthesis by human
thecal cells from women with polycystic ovary syndrome by acti-
vating its own receptor and using inositolglycan mediators as the
signal transduction system. J Clin Endocrinol Metab. 1998;83(6):
2001–5. https://doi.org/10.1210/jcem.83.6.4886.
56. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR,
Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum
sex hormone-binding globulin levels in obese women with the
polycystic ovary syndrome. J Clin Endocrinol Metab.
1991;72(1):83–9. https://doi.org/10.1210/jcem-72-1-83.
57. Hannon TS, Janosky J, Arslanian SA. Longitudinal study of phys-
iologic insulin resistance and metabolic changes of puberty.
Pediatr Res. 2006;60(6):759–63. https://doi.org/10.1203/01.pdr.
0000246097.73031.27.
58. Alemzadeh R, Kichler J, Calhoun M. Spectrum of metabolic dys-
function in relationship with hyperandrogenemia in obese adoles-
cent girls with polycystic ovary syndrome. Eur J Endocrinol.
2010;162(6):1093–9. https://doi.org/10.1530/EJE-10-0205.
59. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycys-
tic ovary syndrome have an increased risk of the metabolic syn-
drome associated with increasing androgen levels independent of
obesity and insulin resistance. J Clin Endocrinol Metab.
2006;91(2):492–7. https://doi.org/10.1210/jc.2005-1666.
60. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH.
Prevalence of a metabolic syndrome phenotype in adolescents:
findings from the third National Health and Nutrition
Examination Survey, 1988-1994. Arch Pediatr Adolesc Med.
2003;157(8):821–7. https://doi.org/10.1001/archpedi.157.8.821.
61. Roe AH, Dokras A. The diagnosis of polycystic ovary syndrome
in adolescents. Rev Obstet Gynecol. 2011;4(2):45–51.
62.• Li L, Feng Q, Ye M, He Y, Yao A, Shi K. Metabolic effect of
obesity on polycystic ovary syndrome in adolescents: a meta-anal-
ysis. J Obstet Gynaecol. 2017;37(8):1036–47. https://doi.org/10.
1080/01443615.2017.1318840. This meta-analysis highlighted
the importance of preventing/treating obesity for the manage-
ment of PCOS in adolescents.
63. Bruni V, Dei M, Nannini S, Balzi D, Nuvolone D. Polycystic
ovary syndrome in adolescence. Ann N Y Acad Sci. 2010;1205:
175–84. https://doi.org/10.1111/j.1749-6632.2010.05648.x.
64. Fulghesu A, Magnini R, Portoghese E, Angioni S, Minerba L,
Melis GB. Obesity-related lipid profile and altered insulin
incretion in adolescents with polycystic ovary syndrome. J
Adolesc Health. 2010;46(5):474–81. https://doi.org/10.1016/j.
jadohealth.2009.10.008.
65. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al.
Prevalence of metabolic syndrome and related characteristics in
obese adolescents with and without polycystic ovary syndrome. J
Clin Endocrinol Metab. 2008;93(12):4780–6. https://doi.org/10.
1210/jc.2008-1198.
66. Fruzzetti F, Perini D, Lazzarini V, Parrini D, Genazzani AR.
Adolescent girls with polycystic ovary syndrome showing differ-
ent phenotypes have a different metabolic profile associated with
increasing androgen levels. Fertil Steril. 2009;92(2):626–34.
https://doi.org/10.1016/j.fertnstert.2008.06.004.
67. Ibanez L, Valls C, Marcos MV, Ong K, Dunger DB, De Zegher F.
Insulin sensitization for girls with precocious pubarche and with
risk for polycystic ovary syndrome: effects of prepubertal initia-
tion and postpubertal discontinuation of metformin treatment. J

Clin Endocrinol Metab. 2004;89(9):4331–7. https://doi.org/10.
1210/jc.2004-0463.
68. Athyros VG, Tziomalos K, Karagiannis A, Anagnostis P,
Mikhailidis DP. Should adipokines be considered in the choice
of the treatment of obesity-related health problems? Curr Drug
Targets. 2010;11(1):122–35. https://doi.org/10.2174/
138945010790030992.
69.• Kaczmarek C, Haller DM, Yaron M. Health-related quality of kife
in adolescents and young Adults with Polycystic Ovary
Syndrome: A Systematic Review. J Pediatr Adolesc Gynecol.
2016;29(6):551–7. https://doi.org/10.1016/j.jpag.2016.05.006.
This meta-analysis showed a significant impairment in the
quality of life of adolescent girls with PCOS. Body weight
and BMI mediated this association.
70. Glueck CJ, Morrison JA, Friedman LA, Goldenberg N, Stroop
DM, Wang P. Obesity, free testosterone, and cardiovascular risk
factors in adolescents with polycystic ovary syndrome and regu-
larly cycling adolescents. Metabolism. 2006;55(4):508–14.
https://doi.org/10.1016/j.metabol.2005.11.003.
71. Dokras A, Clifton S, Futterweit W, Wild R. Increased risk for
abnormal depression scores in women with polycystic ovary syn-
drome: a systematic review and meta-analysis. Obstet Gynecol.
20 1 1 ; 1 1 7 ( 1 ) : 14 5– 52 . h t t ps : / / do i . o rg / 10 . 10 9 7 / A O G .
0b013e318202b0a4.
72. Dokras A, Clifton S, Futterweit W, Wild R. Increased prevalence
of anxiety symptoms in women with polycystic ovary syndrome:
systematic review and meta-analysis. Fertil Steril. 2012;97(1):
225–30 e2. https://doi.org/10.1016/j.fertnstert.2011.10.022.
73. Bernadett M, Szeman NA. Prevalence of eating disorders among
women with polycystic ovary syndrome. Psychiatr Hung.
2016;31(2):136–45.
74. Toscani MK, Mario FM, Radavelli-Bagatini S, Wiltgen D, Matos
MC, Spritzer PM. Effect of high-protein or normal-protein diet on
weight loss, body composition, hormone, and metabolic profile in
southern Brazilian women with polycystic ovary syndrome: a ran-
domized study. Gynecol Endocrinol. 2011;27(11):925–30. https://
doi.org/10.3109/09513590.2011.564686.
75. Salmi DJ, Zisser HC, Jovanovic L. Screening for and treatment of
polycystic ovary syndrome in teenagers. Exp Biol Med
(Maywood). 2004;229(5):369–77. https://doi.org/10.1177/
153537020422900504.
76. Vatopoulou A, Tziomalos K. Management of obesity in adoles-
cents with polycystic ovary syndrome. Expert Opin Pharmacother.
2020;21(2):207–11. https://doi.org/10.1080/14656566.2019.
1701655.
77. 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 adoles-
cent girls. J Clin Endocrinol Metab. 2011;96(11):3533–40. https://
doi.org/10.1210/jc.2011-1609.
78. Marzouk TM, Sayed Ahmed WA. Effect of Dietary Weight Loss
on Menstrual Regularity in Obese Young Adult Women with
Polycystic Ovary Syndrome. J Pediatr Adolesc Gynecol.
2015;28(6):457–61. https://doi.org/10.1016/j.jpag.2015.01.002.
79. 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(5):919–27. https://doi.org/10.1016/s0015-
0282(02)02993-x.
80. Yildiz BO. Approach to the patient: contraception in women with
polycystic ovary syndrome. J Clin Endocrinol Metab.
2015;100(3):794–802. https://doi.org/10.1210/jc.2014-3196.
81. Gallo MF, Lopez LM, Grimes DA, Carayon F, Schulz KF,
Helmerhorst FM. Combination contraceptives: effects on weight.
Cochrane Database Syst Rev. 2014;1:CD003987. https://doi.org/
10.1002/14651858.CD003987.pub5.
Curr Obes Rep
82. Wang A, Mo T, Li Q, Shen C, Liu M. The effectiveness of met-
formin, oral contraceptives, and lifestyle modification in improv-
ing the metabolism of overweight women with polycystic ovary
syndrome: a network meta-analysis. Endocrine. 2019;64(2):220–
32. https://doi.org/10.1007/s12020-019-01860-w.
83. Luque-Ramirez M, Nattero-Chavez L, Ortiz Flores AE, Escobar-
Morreale HF. Combined oral contraceptives and/or antiandrogens
versus insulin sensitizers for polycystic ovary syndrome: a system-
atic review and meta-analysis. Hum Reprod Update. 2018;24(2):
225–41. https://doi.org/10.1093/humupd/dmx039.
84. Harmanci A, Cinar N, Bayraktar M, Yildiz BO. Oral contraceptive
plus antiandrogen therapy and cardiometabolic risk in polycystic
ovary syndrome. Clin Endocrinol. 2013;78(1):120–5. https://doi.
org/10.1111/j.1365-2265.2012.04466.x.
85. Ibanez L, Diaz M, Sebastiani G, Marcos MV, Lopez-Bermejo A,
de Zegher F. Oral contraception vs insulin sensitization for 18
months in nonobese adolescents with androgen excess: posttreat-
ment differences in C-reactive protein, intima-media thickness,
visceral adiposity, insulin sensitivity, and menstrual regularity. J
Clin Endocrinol Metab. 2013;98(5):E902–7. https://doi.org/10.
1210/jc.2013-1041.
86. Pasquali R, Gambineri A. Glucose intolerance states in women
with the polycystic ovary syndrome. J Endocrinol Investig.
2013;36(8):648–53. https://doi.org/10.1007/BF03346757.
87. Ibanez L, Valls C, Ferrer A, Marcos MV, Rodriguez-Hierro F, de
Zegher F. Sensitization to insulin induces ovulation in nonobese
adolescents with anovulatory hyperandrogenism. J Clin
Endocrinol Metab. 2001;86(8):3595–8. https://doi.org/10.1210/
jcem.86.8.7756.
88. Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy
in obese adolescents with polycystic ovary syndrome and im-
paired glucose tolerance: amelioration of exaggerated adrenal re-
sponse to adrenocorticotropin with reduction of insulinemia/
insulin resistance. J Clin Endocrinol Metab. 2002;87(4):1555–9.
https://doi.org/10.1210/jcem.87.4.8398.
89. Glueck CJ, Aregawi D, Winiarska M, Agloria M, Luo G, Sieve L,
et al. Metformin-diet ameliorates coronary heart disease risk fac-
tors and facilitates resumption of regular menses in adolescents
with polycystic ovary syndrome. J Pediatr Endocrinol Metab.
2006;19(6):831–42. https://doi.org/10.1515/jpem.2006.19.6.831.
90. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L.
Metformin to restore normal menses in oligo-amenorrheic teenage
girls with polycystic ovary syndrome (PCOS). J Adolesc Health.
2001;29(3):160–9. https://doi.org/10.1016/s1054-139x(01)
00202-6.
91. Al Khalifah RA, Florez ID, Dennis B, Thabane L, Bassilious E.
Metformin or oral contraceptives for adolescents with polycystic
ovarian syndrome: a meta-analysis. Pediatrics. 2016;137(5).
https://doi.org/10.1542/peds.2015-4089.
92. Al-Zubeidi H, Klein KO. Randomized clinical trial evaluating
metformin versus oral contraceptive pills in the treatment of ado-
lescents with polycystic ovarian syndrome. J Pediatr Endocrinol
Metab. 2015;28(7–8):853–8. https://doi.org/10.1515/jpem-2014-
0283.
93. Ganie MA, Khurana ML, Eunice M, Gupta N, Gulati M, Dwivedi
SN, et al. Comparison of efficacy of spironolactone with metfor-
min in the management of polycystic ovary syndrome: an open-
labeled study. J Clin Endocrinol Metab. 2004;89(6):2756–62.
https://doi.org/10.1210/jc.2003-031780.
94. Zulian E, Sartorato P, Benedini S, Baro G, Armanini D, Mantero
F, et al. Spironolactone in the treatment of polycystic ovary syn-
drome: effects on clinical features, insulin sensitivity and lipid
profile. J Endocrinol Investig. 2005;28(1):49–53. https://doi.org/
10.1007/bf03345529.
95. Ibanez L, Diaz M, Garcia-Beltran C, Malpique R, Garde E, Lopez-
Bermejo A, et al. Toward a Treatment Normalizing Ovulation
Curr Obes Rep
Rate in Adolescent Girls With Polycystic Ovary Syndrome. J
Endocr Soc. 2020;4(5):bvaa032. https://doi.org/10.1210/jendso/
bvaa032.
96. Simard J, Luthy I, Guay J, Belanger A, Labrie F. Characteristics of
interaction of the antiandrogen flutamide with the androgen recep-
tor in various target tissues. Mol Cell Endocrinol. 1986;44(3):
261–70. https://doi.org/10.1016/0303-7207(86)90132-2.
97. Ibanez L, Potau N, Marcos MV, de Zegher F. Treatment of hir-
sutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and
hyperinsulinism in nonobese, adolescent girls: effect of flutamide.
J Clin Endocrinol Metab. 2000;85(9):3251–5. https://doi.org/10.
1210/jcem.85.9.6814.
98. Golland IM, Elstein ME. Results of an open one-year study with
Diane-35 in women with polycystic ovarian syndrome. Ann N Y
Acad Sci. 1993;687:263–71. https://doi.org/10.1111/j.1749-6632.
1993.tb43875.x.
99. Sahin Y, Dilber S, Kelestimur F. Comparison of Diane 35 and
Diane 35 plus finasteride in the treatment of hirsutism. Fertil
Steril. 2001;75(3):496–500. https://doi.org/10.1016/s0015-
0282(00)01764-7.
100. Seaman HE, de Vries CS, Farmer RD. Venous thromboembolism
associated with cyproterone acetate in combination with
ethinyloestradiol (Dianette): observational studies using the UK
General Practice Research Database. Pharmacoepidemiol Drug
Saf. 2004;13(7):427–36. https://doi.org/10.1002/pds.896.
101. Tartagni MV, Alrasheed H, Damiani GR, Montagnani M, De
Salvia MA, De Pergola G, et al. Intermittent low-dose finasteride
administration is effective for treatment of hirsutism in adolescent
girls: a pilot study. J Pediatr Adolesc Gynecol. 2014;27(3):161–5.
https://doi.org/10.1016/j.jpag.2013.09.010.
102. Hamzavi I, Tan E, Shapiro J, Lui H. A randomized bilateral
vehicle-controlled study of eflornithine cream combined with la-
ser treatment versus laser treatment alone for facial hirsutism in
women. J Am Acad Dermatol. 2007;57(1):54–9. https://doi.org/
10.1016/j.jaad.2006.09.025.
103. Smith SR, Piacquadio DJ, Beger B, Littler C. Eflornithine cream
combined with laser therapy in the management of unwanted fa-
cial hair growth in women: a randomized trial. Dermatol Surg.
2006;32(10):1237–43. https://doi.org/10.1111/j.1524-4725.2006.
32282.x.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.