xxx i

POLYCYSTIC
OVARY
SYNDROME
 POLYCYSTIC
OVARY
SYNDROME

Editor
Dilip Kumar Dutta
MD MAMS FICOG FICMCH MAGH (USA)
MAFS (USA) DPS (Germany)
Consulting Gynaecologist
Naihati State General Hospital
24 Parganas (North)
West Bengal
Co-editor
Banani Dutta
Medical Officer
ESI Hospitals
Kalyani, Nadia
West Bengal-741 235

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Polycystic Ovary Syndrome

© 2004, Dilip Kumar Dutta

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 Contributors

Dilip Kumar Dutta

Consultant Gynaecologist
Naihati State General Hospital
24, Parganas (North)
West Bengal

Gakul Chandra Das

Associated Professor
Guwahati Medical College and Hospital
Guwahati, Assam

Banani Dutta
Medical Officer
ESI Hospital
Kalyani, Nadia
West Bengal 741 235
 Preface

PCOS is complex and heterogeneous disease. In spite of accumu-

lated literature and remarkable advances in the understanding of
Polycystic ovary syndrome, the aetiology of the PCOS is not clear
and the primary mechanism is not known. Evidence suggests that
Granulosa cells of PCOS contain high level of EGF receptors indi-
cating that hypersensivity of these cells to EGF/TAFα, particularly
in terms of suppression of aromatase activity and LH receptor
formation.
Broadly treatment depends in the symptoms expressed and
whether the therapy is for aesthetic regions in patient not desiring
pregnancy, for infertility or even to prevent long-term complica-
tions.
This book is not only focused recent concept of pathophysiology,
diagnosis and long-term sequelae of PCOS but also highlighted
treatment protocol in details. I hope and firmly believe that this
book will be highly accepted by gynaecologist practicing infertility
and reproductive medicine. It will also be helpful to undergraduate
and postgraduate medical students for the preparation of their final
examination.

Dilip Kumar Dutta

 Contents

1. Overview ............................................................................. 1
DK Dutta
2. Historical Review ............................................................... 3
DK Dutta, B Dutta
3. Pathophysiology ................................................................. 6
DK Dutta, GC Das
4. Diagnosis ........................................................................... 11
DK Dutta, B Dutta
5. Long-term Sequelae ......................................................... 16
DK Dutta, B Dutta
6. Management ..................................................................... 20
DK Dutta, GC Das

Index ................................................................................... 35
 POLYCYSTIC
OVARY
SYNDROME

Polycystic Ovarian Syndrome (PCOS) is a heterogenous condition

that still defies absolute rigid definition but is certainly recognizable.
Several studies have estimated the prevalence to be approximately
20% (Polson et al 1988) in normal adult women, but can be as high
as 50% in women undergoing IVF treatment (Kyei-Mensah et al
1998).
Polycystic ovaries are related to metabolic sequelae. Amongst
the late ones are obesity, diabetes mellitus that is associated with
hyperinsulinemia cardiovascular disease, high LDL and
hypertension (Balen 2001). These conditions represent a significant
health problem in women. Familial aggregates of PCOS are well
recognized (Legro et al 1995). There is evidence of the involvement
of at least two genes in the aetiology of PCOS, the steroid synthesis
gene CYP 11a and the insulin gene VNTR regulatory polymorphism.
Apart from the association with infertility and endometrial cancer,
the epidemiology of the cluster of metabolic sequelae of PCO could
suggest that such sequelae are the result of PCO being present at
a younger pre-menopausal age. Intriguingly, it has been suggested
that PCO and PCOS can also be inherited from the father’s side
(Bennett et al 1997). The implications are therefore that we are
dealing with a condition that has serious Public Health consequences
and has a wide range of medical implications.
Author has highlighted the various aspects of PCOS including
defination, pathophysiology, diagnosis, long-term sequelae and
management of PCOS.
Very useful for practising gynaecologist interested in ART, and
reproductive medicine.

Authors previous publication

• Unsafe Abortion
• Early Pregnancy Haemorrhange
• Antepartum Haemorrhage
• Post partum Haemorrhage
• Caesarean Delivery
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 POLYCYSTIC OVARY SYNDROMEOverview 1

DK Dutta

1 Overview

From our present state of knowledge about PCOS it was very

difficult to make final consensus regarding defination, patho-
physiology, clinical manifestations and treatment modalities. Since
last few years various concepts have emerged which have received
agreement.
Concensus now agreed as regards defination that it should better
defined as syndrome rather than disease since actual cause or causes
of disease is still not known.1
Till date there is no supporting evidence regarding the patho-
physiology of PCOS although recently familial cluster of PCOS is
reported–suggesting a major Component of its etiology. Study was
done intensively (Steven Franks) to find the Zenes involved in
androgen production and secretion and action of Insulin. The results
of both linkage and association studies suggest the involvement of
two key genes in the aetiology of PCOS, the steroid synthesis gene
CYP11a and insulin gene–Variable number tandem repeats
(VNTR).
Urbanck et al2 concluded from his study that follistatin gene,
found to have the strongest linkage with PCOS from 37 genes, but
failed to confirm this finding in large series.
Helen Mason has scientifically setout the possible reasons for
the increased follicular number and attenuated apoptosis.
Robert Rosenfield proposes that of dysregulation of androgen
secretion accounts for this abnormality, probably due to hyper-
activity of on enzyme, cytochrome P450c 17. A single genetic defect
enhancing.Serine phosphorylation, which would decreased the
activity of the insulin receptor activity could account for both the
hyperandrogenism and the insulin resistance of PCOS.
2 Polycystic Ovary Syndrome

As Regards Clinical Menifestation

The concept of wide spectrum of signs (Adam Balen), ranging from
single finding of polycystic ovarian morphology (detected by USG),
to obesity, menstrual irregularities, infertility, cardiovascular
diseases–all are due to metabolic disturbances involving increased
level of LH, insulin and androgen and dyslipidemia.
Clomiphene citrate (CC) is still the first line of treatment for
anovulatory women with PCOS who desire pregnancy. Chronic
low-dose step-up protocol using follicle stimulating hormone (FSH)
is advocated either in CC resistance or failure to conceive with CC
with reasonable time.
The use of GnRH analogues and laparoscopic ovarian puncture
can also be used alternatively or if low-dose FSH failed to conceive
pregnancy.
Last resort of treatment is IVFαET (if all other treatment failed,)
for which excellent results have been reported.
In conclusion the research into the causes of PCOS should focus
in the mechanism underlying the hyperfunction at capacity of PCO
and the factor that tiggers this hyperactivity. Hope in future an
experimental animal model may be required to assist such
investigations.2

REFERENCES
1. Roy Homburg. Polycystic ovary syndrome consensus and controversy, PCOS
edited by Roy Homburg, 2001;1-9.
2. Urbanek, Legro RS, Driscoll Da, et al. Thirty-seven candidate genes for
polycystic ovary syndrome. Strongest evidence for a linkage is with Follistatin.
Proc Natl Sci USA 1999;96:8573-78.
 Historical Review 3
POLYCYSTIC OVARY SYNDROME
DK Dutta, B Dutta

2 Historical Review

The history of PCOS continues to challenge gynaecologist due to

lack of evidence. Historical review includes diagnosis and treatment
of PCOS.

DIAGNOSIS
1844 : Chereau described Selerocystic changes in the human
ovary.
1935 : Stein and Leventhal described PCO.
1958 : Elevated Luteinizing hormone (LH) concentration were
first reported.
1971 : Introduction of radioimmunoassays for a biochemical
diagnosis.
1962 : Established wide variety of clinical presentation in PCOS.
1976 : Rebar R et al studied the concept of PCOS with normal
LH concentrations.
1976 : Khan et al studied discovery of the association of PCOS
and insulin resistance.
1980 : Burghon et al studied correlation of hyperandrogenism with
hyperinsulinism in polycystic ovarian disease.
1981 : Swanson et al first described the ultrasound findings of
women with PCOS.
1985 : Adam et al refined and cirtically defined diagnostic criteria
following ultrasonographic diagnosis of PCO.
1999 : VR Banek M et al described Follistation gene, found to
have the strongest linkage with PCOS from 37 genes.
4 Polycystic Ovary Syndrome

TREATMENT–MEDICAL
CC
1982 : Gyslen et al described CC regimen including its effects on
the postcoital test.
1982 : Labo RA et al use of CC and dexamethasone in
unresponsive to CC.
1989 : Polson et al use of CC in women with PCOS the difference
between responders and nonresponder.
2003 : Dutta DK et al use of Letrozole (Aromatase Inhibitor) in
CC resistant cases of PCOS.

Low Dose of FSH

1984 : Seibel MM et al treatment of PCO with chronic low dose
FSH.
1987 : Polson WW et al ovulation of a single dominant follicle
during treatment with low dose pulsatile follicle stimulating
hormone in women with PCOS.
1989 : Polson DW et al use of low dose FSH in the treatment of
PCOS: A comparison of pulsatile subcutaneous with daily
intramuscular therapy.
1991 : Shoham Z et al PCOS safety and effectiveness of stepwise
and low dose administration of purified FSH.
1992 : Dale PO et al PCOS in low dose FSH.
1994 : Strowi Tzki T et al PCOS with low dose FSH for
anovulation associated with PCOS.
1995 : Homburg R et al chronic low dose FSH for anovulation
associated PCOS.
1997 : Yong EL et al Responses of PCOS and related variants to
low dose FSH.
1998 : Van der Meer M et al a somatostatin analogue, alters
ovarian sensivity to gonadotrophin stimulation as measured
by the FSH threshold in PCOS.

GnRH Agonists
1987 : Charbonel B et al use of luteinizing hormone-releasing
hormone analog and exogenous gonodotrophins in PCOS.
 Historical Review 5

1989 : Schoemaker J et al PCOD: Treatment with LH-RH

analogues.
1990 : Homburg R et al LH-RH + Exogenous Gonadotrophins
for infertility associated with PCOD.
1995 : EL Kind–Hirsch KE et al use of GnRH agonist + OC pill
for Hirsute women with ovarian hyper androgenism.
1996 : Taskin O et al use of Ovarian cauterization and GnRH
agonist and OC pill on endocrine changes in PCOS.
1998 : Ben–Arie A et al effect of gonadotrophin releasing
hormone against treatment on growth hormone secretion
in women with polycystic ovarian syndrome.

GnRH Antagonists
1993 : Dubourdieu S et al GnRH antagonist and pulsatile GnRH
normalizes LH secretion in PCOS but fail to induce
follicular maturation.
1994 : Died Rich K et al use of GnRH–Antagonist cetrorelix to
suppress endogenous LH.
2000 : Albane C, Felberbaum RE, Smitz et al phase III European
study comparing the LH-RH–antagonist (cetrorelix) and
LH-RH agonist (buserelin).

IVF
1995 : Olivennes F et al GnRH antagonist (cetrorelix) on day 8
of invitro fertilization cycles-a pilot study.

Laparoscopic Ovarian puncture

1972 :
Neuwirth RS bilateral ovarian biopsy by laparoscopy.
1984 :
Gjonnaess H Electro cautery through the laparoscope.
1989 :
Daniell KF et al laser vaporization through the laparoscope.
1989 :
Kojima E et al ovarian wedge resection with contact Nd:
YAG laser irradiation by laparoscopically.
1996 : Donesky BW et al ovarian diathermy in PCOS.
1995 : Farhi J et al laparoscopic ovarian eletrocautery on ovarian
response and out come of treatment with gonadotrophins
CC resistant patients with polycystic ovary syndrome.
6 Polycystic Ovary Syndrome
POLYCYSTIC OVARY SYNDROME
DK Dutta, GC Das

3 Pathophysiology

The pathogenic mechanisms of PCO are still not known. It has

been suggested that PCOS1 represents a wide range of disorders
rather than a single entity. Hyperandrogenism is however, the most
endocrine features in women with polycystic ovary. The ovary,
rather then the adrenal gland is the major source of excessive
androgen.
The vicious cycle probably begins as a result of excessive andro-
gen production in the adrenal cortex during puberty and adolescent
period. Androgens are then aromatized, particularly in the sub-
cutaneous adipose tissue. This leads to an increase of estrogens,
which exert a positive feedback on LH but a negative feedback to
FSH concentrations. LH leads to excessive androgen production
in Theca cells surrounding the follides. Normally FSH maintains
aromatase activity in the granulosa cells. When the concentrations
of FSH are low, androgens cannot converted to estrogen. Conse-
quently, excessive amounts of androgen of ovarian origin inter the
circulation and the vicious cycle continues.
Basically pathogenesis of PCOS are divided into:
a. Follicle arrest upto 10 mm in diameter
b. Hypersecretion of LH
c. Hypersecretion of androgen
d. Hypersecretion of insulin
a. The large number of follicles up to 10 mm in diameter that
have been arrested in their development may be due to a number
of factors; hyperfunction of EGF/TGFα, Follistatin, Inhibin-
B all of which would interfere with the action of Endogenous
(Fig. 3.1).
 Pathophysiology 7

PCO follicles

Arrest of development Attenuated apoptosis

Interfering with FSH action Hyperexpression of

TGFα/EGF + mdm 2

Follistatin + bFGF

Steroid feedback + BCL 2

Inhibin-B + TGFα/EGF +

Inhibition of

Growth differentiating factor 9 deficiency p53

Early development of LH receptors + BAX

APO/FAS

Fig. 3.1: Possible factors influencing the morphological changes

in the polycystic ovary

b. An increased number LH receptors and increasing the sensi-

vity of LH may be due a deficiency of growth differentiating
factor 9.
c. The abnormal ovarian steroidogenesis results excess production
of androgens by PCO thecal cells which may originate from
several possible sources either alone or in combination (Fig.
3.2).
1. An intrinsic Hyper function of CYP11A encoding for
cholesterol side chain cleavage.
2. Increased stimulation of enzyme P450c17 and by LH
mediated by insulin and IGF-I.
d. A post receptor genetic, unique to PCO, causing abnormality
of serine phosphorylation of the insulin receptor2 may be source
of insulin hypersecretion on resistance (Figs 3.3 and 3.4) which
may be responsible for increased androgen production, reduced
transport of testosterone, menstrual irregularity anovulation and
in long run factors for increased cardiovascular risk.
8 Polycystic Ovary Syndrome

cholesterol

Insulin + P450scc +
serine
phosphorylation + pregnenolone

free IGF-I

17, 20-lyase
P450c Androstenedione +++
17α
17-hydroxylase TGFα/EGF +

FSH – ––
LH

Follistatin +
Fig. 3.2: Possible factors influencing the increased ovarian androgen accumulation
in the polycystic ovary (Source: PCOS, page 99, Edited by Roy Homburg)

IGF-II
Selection IGFBPs

IGFBP
protease(s)

arrested
development
IGF-II

IGFBPs

no selection IGFBP
protease(s) atresia

Fig. 3.3: Changes in the IGF system in human ovary that correspond with follicle
selection and no selection, and the enigma of what controls whether an androgen-
dominant follicle will become atretic or will persit in an arrested state of development
(as in PCOS) (Source: PCOS, page 84, Edited by Roy Homburg, Martin Dunit-2)

GENETIC FACTORS IN THE AETIOLOGY OF PCOS

Two key genes are found to be causative factor for PCOS. The
results of both linkage and association studies suggest that the
 Pathophysiology 9

Insulin secretion Insulin resistance Insulin clearance

Beta Target Hepatic

cell cell clearance

Exaggerated • Binding (a) receptor defect Decreased

reactivity post (b) autoantibodies hepatic
glucose stimulation • Tyrosine serine phosphorylation degradation
VNTR regulatory site • Postreceptor defect

OBESITY + HYPERINSULINEMIA

Synergistic effect

Fig. 3.4: The different pathways that can cause hyperinsulinemia in women with
PCOS. Obesity has a synergistic effect, thus increasing hyperinsulinemia and insulin
resistance. Changes in the VNTR regulatory site are strongly associated with PCOS.
A postreceptor insulin signaling defect is found in approximately 50% of patients
with PCOS. In these women the insulin receptor is constantly serine phosphorylated,
which in turn decreases its tyrosine kinase activity (Source: PCOS, page 99, Edited
by Roy Homburg)

(a) steroid synthesis gene CYP11a3 and (b) Insulin VNTR4 (Variable
number tandem repeats) regulatory polymorphism are important
factors in the genetic basis of PCOS and may explain, in part, the
heterogeneity of the syndrome.
Thus, differences in expression of CYP11a could account for
variation in androgen production in women who have PCO. Women
carrying class III alleles at the insulin gene VNTR locus may be
more likely to be hyperinsulinaemic and to suffer from menstrual
disturbances.
10 Polycystic Ovary Syndrome

Environmental factors can aiter the clinical and biochemical

presentation in those with a genetic predisposition to PCOS.5 This
is illustrated by the effect of obesity on serum insunil lends, insulin
sensivity and menstrual funltion.
REFERENCES
1. Franks S. Medical progress article: Polycystic ovary syndrome. N Engl J
Med 1995;301-25.
2. Dunaif A. Insulin resistance and ovarian dysfunction. In: Moller D (Ed.):
Insulin resistance John Wiley: New York, 1993;301-25.
3. Gharanin, Wather Worth DM, Battyental association of the steroid synthesis
gene CYP11a with polycystic ovary syndrome and hyperandorogenism. Hum
Mol Genet 1997;6:397-402.
4. Wather Worth DM, Bennetist, Gharani, et al. Linkage and association of
insulin gene VNTR regulatory polymorphism with polycystic ovary
syndrome. Lancet 1997;349:986-89.
5. Holte J, Bergh T, Berne C, et al. Restored insulin sensivity but persistently
increased early insulin secreation after weight loss in obese women with
polycystic ovary sundrome. J Clin Endocrinol Metab 1995;80:2586-93.
 Diagnosis 11
POLYCYSTIC OVARY SYNDROME
DK Dutta, B Dutta

4 Diagnosis

HISTORY
1. Medical history A history of headaches or blurred vision
(indicating pituitary tumor), any signs or symptoms of thyroid
dysfunction (as a differential diagnosis of amenorrhea), or
clinical sings of diabetes (indicating adrenal tumor) need to be
elicited. History of acne, hirsutism, deepening of the voice,
and increase in muscle mass (without exercise). A rapid onset
of these symptoms is rare in a PCOS patient, but if present,
they suggest a need for an urgent work-up, as an ovarian tumor
or adrenal tumor needs to be ruled out. Also, masculinization
is uncommon with PCOS patients and is more suggestive of
congenital adrenal hyperplasia.
2. Family history PCOS tends to run in families; it is important
to ask about family history. Some believe that if a mother has
PCOS and her daughter is showing sings of it, she should be
evaluated by her pediatrician or by an endocrinologist.
3. Social/cultural history Ethnic factors must be considered in
the evaluation of women who are hirsute. Northern European
white women and women of Asia usually have small amount
of hair on their face, torso, and extremities. However, Medi-
terranean white women will frequently have hair on their upper
lip, chin, and have dark hair on their arms and legs. Also, certain
conditions like pregnancy and menopause can cause transient
hirsutism. An important caveat to remember is the patient may
not appear hirsute at the time of the examination as she may be
using cosmetic procedures like waxing, shaving, or electrolysis
to control it.
12 Polycystic Ovary Syndrome

4. Menstrual history In addition to obtaining a thorough medical

and surgical history, elicit a completed menstrual history,
including menarche and family history of PCOS. A history of
hirsutism, acne, alopecia, menstrual irregularies, or infertility,
especially in the patient’s mother, is very important. A diagnosis
of PCOS may often be made with a complete history. Particular
attention to the onset of menstrual irregularities, as this will
usually date back to menarche. Inquire about recent pregnancy
status and other reproductive history such as miscarriages.
5. Drug history In addition to asking about the patient’s current
medications it is important to remember that there are certain
medications and classes of medications that can cause transient
hirsutism. Examples of these are phenytoin (Dilantin),
diazoxide, glucocorticoids, and the phenothiazines.

CLINICAL FEATURES
1. Evaluate the skin for evidence of hirsutism, acne, alopecia, fat
distribution, and pigment changes in the skin, specifically
acanthosis nigricans. Hirsutism can be defined as hair in
locations in women where it is usually not found. Examples of
these locations are upper lip, chin, midline of the body, and in
the intermammary region. Hirsutism can be graded using the
Ferriman-Gallowey scoring system. This scoring system
evaluates 9 key anatomic sites. These sites can be graded from
0 (no terminal hair growth) to 4 (maximal growth).1 The
maximum score is 36. A score of 8 greater suggests and
androgen excess.2,3
Even when a PCOS patient has increased levels of andro-
gens, hirsutism may not be present unless there is an increase
in peripheral androgen metabolism. This is why some women
with PCOS are hirsute and others are not. Temporal balding is
usually seen after prolonged exposure to androgens. Frontal
balding is associated with a virilizing ovarian or adrenal tumor.
2. Central obesity with a ration of > 0.85 is associated with
cardiovascular disease and is marker for PCOS. A “buffalo
hump” on the back or purple striae on the abdomen might
suggest Cushing’s syndrome.
 Diagnosis 13

3. During the pelvic examination, assess for clitoromegaly and

pelvic masses. Bilateral pelvic masses would be more consistent
with PCOS whereas a unilateral pelvic mass may be more
consistent with a neoplasia. Remember, too, that the pelvic
exam may not reveal any masses in a patient with PCOS.

LABORATORY STUDIES
Blood Profile
1. Glucose testing. Glucose tolerance testing is important. As may
as 35 to 45 percent of PCOS patients will have impaired glucose
testing and about 7 to 10 percent will have type 2 diabetes
mellitus. A fasting glucose to fasting insulin ration less than 4.5
is predictive of insulin resistance. Values on the 2HR glucose
tolerance test are as follow: 2H < 140 mg/dl (normal); 140-199
mg/dl (impaired glucose); and > 200 mg/dl (type 2 diabetes).
Cardiac risk profile. Because PCOS patients have hyper-
androgenism, they are at an increased risk of cardiovascular
disease. It is imperative, than the patients are screened for an
abnormal HDL, cholesterol, and triglycerides at 35 years of
age. Normal results should be repeated in 3-5 years. If these
results are abnormal, these entities can be treated early, thus
reducing the risk of cardiovascular disease.
2. Endocrine screening. Prolactin and thyroid-stimulating
hormone (TSH) levels are tested to rule out pituitary or thyroid
disease as an etiology of anovulation. LH and follicle-
stimulating hormone (FSH) may be analyzed, and they are
usually seen in a ration of >2.5 to 3. However, a normal LH/
FSH ratio does not exclude the diagnosis of PCOS. An FSH
level will also help rule out premature ovarian failure in a
woman with amenorrhea.
Total testosterone and dehydroepiadrosterone sulfate
(DHEAS) are evaluated to rule out an androgen-producing
neoplasm. Total testosterone levels of 200 ng/dl are not
generally seen in PCOS and suggest a virilizing tumor. DHEAS
is a weak androgen that primarily comes from the adrenal
glands. A level greater than 800 mcg/dl suggests a virilizing
adrenal tumor.
14 Polycystic Ovary Syndrome

17-hydroxyprogesterone (17OH-progesterone) is useful

screen for late-onset congenital adrenal hyperplasia (LOCAD).
170H-progesterone levels less than 2 mg/ml are normal. A level
> 5 mg/ml is diagnostic for LOCAD. A value between 2 mg/
ml and 5 mg/ml should prompt an investigation with an
adrenocorticotropic hormone stimulation test. If there is a
suspicion for Cushing’s syndrome, may get a 24 hours urine
for free cortisol or can do a 1-mg dexamethasone suppression
test overnight.
ENDOMETRIAL ASPIRATION AND BIOPSY
Many PCOS patients have unopposed estrogen stimulation for
prolonged periods of time and are thus a risk for endometrial
hyperplasia or endometrial carcinoma. Any PCOS patient with
prolonged oligomenorrhea or amenorrhea or a patient with PCOS
who is older than aged 35 years and has irregular bleeding should
have endometrial aspiration or Biopsy to rule out endometrial
carcinoma. An important point to remember is that advancing age
is not a factor in deciding to obtain endometrial aspiration in patients
with PCOS as it is in non-PCOS patients.
RADIOLOGIC STUDIES
An enlarged uterus or enlarges ovaries palpated on pelvic exami-
nation suggests a need for pelvic ultrasound to distinguish uterine
fibroids from an adnexal masss. If a patient has elevated DHEAS,
adrenal imaging is indicated. An important caveat to remember is
that polycystic ovaries can been seen in a number of healthy women
who do not have PCOS, and women with PCOS do not always
have radiographically demonstrated polycystic ovaries. By
ultrasound, 25 percent of “normal”ovulating women would have
polycystic-appearing ovaries. Typical USG findings of PCOS ITC
(i) no of cyst = >10mm, pushed/phenipheny (Necklace pattern),
(ii) Abnormal stroma, (iii) Uterine width: ovarian length = <1. (iv)
Increased ovarian roundness index = >0.7.
DIFFERENTIAL DIAGNOSIS
Premature ovarian failure, rapid weight loss, extreme physical
exertion, low body mass index (BMI) as in anorexia nervosa, and
 Diagnosis 15

pregnancy will cause abnormal menstrual cycles. Discontinuation

of oral contraceptives may also cause amenorrhea. The letter is
called post-pill amenorrhea. A pituitary adenoma, hyperthyroidism,
or hypothyroidism will also cause a change in the menstrual cycle.
Other important etiologies to consider include congential adrenal
hyperplasia, late-oneset adrenal hyperplasia, and Cushing’s syn-
drome. Tumors of the adrenal gland or the ovaries may also present
with menstrual irregularies.

REFERENCES
1. Mac Pannill, MPAS, PA-C; Polycystic ovary syndrome. An overview topics
in Advanced Practice Nursing Journal 2(3), 2002.
2. Slowey MJ. Polycystic ovary syndrome; New Perspective on an old problem.
South Med J, 2001; 94:190-96.
3. DR, Stenchever MA, Droege muellen W, Henbst AL. Chapter 39.
Comprehensive Gynaecology. Third Edition, St. Lonsmo: Mosby; 1997:1087-
1112.
16 Polycystic Ovary Syndrome
POLYCYSTIC OVARY SYNDROME
DK Dutta, B Dutta

5 Long-term Sequelae

Long-term sequelae in polycystic ovary is still confused due to

lack of evidence, since the cause of disease or syndrome is still not
known. However, it is important to know its long-term sequelae
because (a) Higher incidence of PCOS in adolescent (20%) and
postmenopausal women (37-44%) detected by USG1 (b) Woman
having PCOS want to know its significance in future reproductive
years.

THE NATURAL HISTORY OF PCO

The natural history of PCO is not known, PCO or PCOS have found
in young girls and adolescents by USG.2 During reproductive period
it was occasionally found during routine USG at assisted pre-
productive clinic, otherwise ovary becomes quiescence during
lactation, Oral contraceptive use, GnRH analogue use and hypo-
thalamic gonadism. During postmenopausal period PCO is found
in 37 to 44 percent having larger ovaries, higher endometrial thick-
nes. Higher serum concentration of testosterone and Triglycerols
compared with postmenopausal women with normal ovaries. Post-
menopausal women with PCO were found to require lipid modi-
fying drugs more frequently than postmenopausal women with
normal ovaries and were more hirsute. The high prevalence of
polycystic ovaries found in post menopousal women, who had histry
of chest pain and were undergoing coronary angiography by USG.
Complication
a. Short-term sequelae
b. Long-term sequelae
 Long-term Sequelae 17

Short-term Sequelae
Obesity, hirsutism, menstrual irregularities (oligomenorrhea,
Amenorrhoea) and infertility were short-term sequelae due to persis-
tant anovulation caused by high level androgen, estrogen, lower
level of progesterone, low FSH, High LH, and insulin resistant etc.

Long-term Sequelae
Diabetic, cardiovascular disease, osteoporosis and cancer may
develop in PCO women if not treated early.

Diabetic
Untreated hyperinsulamic women with PCOS may develop diabetes
in long run.

Cardiovascular Disease
There have been many reports of metabolic abnormalities in women
(both lean and obese) with polycystic ovaries. These include raised
serum concentrations of1 Triaglycerol and low-density lipoproteins
cholesterol, lowered serum concentrations of high density
lipoproteins (HDL) cholesterol3 and evidence of insulin resistance4
which are all recognized cardiac risk factors. Obese women with
PCOs tending to have higher systolic blood pressure is also reported.

CANCER
Breast Cancer
A study has examined the association between breast cancer and
PCO.7 A count of 34835 cancer free women aged 55-69 years was
assembled in 1986 and followed until 1992. A total of 472 (1.35%)
women reported a history of PCOS at baseline. During the follow
up period 883 women develop breast cancer, 14 of whom had PCOS,
but this study does not entirely answer the question as to whether,
any association exist between breast cancer and PCO, because pre
menopausal women were not included and the prevalence of PCOS
was found to be only 1 percent.
18 Polycystic Ovary Syndrome

Endometrial Cancer
The endometrial cancer that are reported in association with PCO
tend to occur in women at the severe end of the PCO septrum and
are generally associated with a favorable prognosis,5 although the
exact risk is probably small. Long episodes of amenorrhoea in PCOS
may be the risk of endometrial cancer in untreated cases.

Ovarian Cancer
Ovarian cancer risk was found to be increased 2.5 fold (95% CI,
1.1 to 5.9) among women with PCOS,6 but this study did not use a
histological definition of PCOS. Therefore more research is needed
to confirm its association with PCOS. Dehlgren from Sweden
showed that PCO was a definite risk factor for myocardial
infarction, and his group estimates that myocardial in facts would
be seven times more common in women with PCOS compared
with the general population. Mary Bindsall group from Auckland
reported that PCO were diagnosed in 42 percent of the women and
were associated with hirsutism, previous hysterectory, higher free
testosterone, Triaglycerol and C-peptid levels and lower HDL
cholesterol levels and the number of segments with more than
50 percent stenosis was 1.7 (95% CI, 1.1 to 2.3) compared with
0.82 (CI, 0.54 to 1.1); P < 0.01. However, this study did not answer
the question as to whether women with PCO died more frequently
of cardiovascular disease.

Osteoporosis
Women with PCO with history of amenorrhoea or oligomenorrhoea,
with anovulation, with anoexia nervosa, hypothalamic ameno-
rrhoea, exercise induced amenorrhoea on hyperprolactinemia
anemia, may be at increased risk of osteoporosis. Reassuring
evidence shows that women with PCO do not have an increased
risk of ostoporosis,19 may be due to secondary PCO secrete
significant quantities of testosterone, oestrone and oestradiol, all
of which preventive against bone loss.
 Long-term Sequelae 19

PCO and Mortality

A study was conducted on 842 British women with diagnosis of
PCOS, followed until the age of 75 years of age, confirmed that
there were fewer deaths than expected in women with PCOS, less
circulatory disease as a cause of death and fewer neosplasms causing
death but more cases of diabetes were recorded.18 This findings
conclude that PCOS may be protective against cardiac disease
because of excess oestrogen in the blood.

CONCLUSION
Association with PCOS and its long-term sequelae is still confused
since the reported is scanty. Association with breast and ovarian
cancer is still doubtful but long episodes of amenorrhoea in PCOS
may be risk endometrial cancer if not treated early. As regard osteo-
porosis and mortality no substantial evidence is reported till date.

REFERENCES
1. Farquhar CM, Bindshall MA, Manning P, Mitchell J, France JT. The
prevalence of polycystic ovaries on ultrasound scanning in a population of
randomly selected women. Aust NZJ. obstet. Gynaecol (1994) 34(i): 67-72.
2. Bridges NA, Hindmansh PC, Cooke A, Brook CGD, Healthy MJR. Standards
for ovarian volume in childhood and pulesty. Fentil steril (1993) 60: 456-60.
3. Wild RA, Alaupovic P, Parken IJ. Lipid and apolipo protein alnormalities in
hinsute women 1. The association with in sulin resistance. Am J obstet
Gynecol (1992) 166:1191-7.
4. Banobieni RL. Polycystic ovarian disease. Annu Rev Med (1991) 42:199-
204.
5. Jafani K, Javaheni G, Ruiz G: Endometrial adeno cancinoma and the stein-
leventhal syndrome. Obst Gynec (1978) 51:97-100.
6. Schildknaut JM, Schwing L PJ, Bastos E, Evanoff A, Hughes C. Epithelial
ovarian Cancer risk among women with polycystic ovary syndrome. Obst
Gynec (1996) 88: 554-9.
7. Anderson KE, Sellers TA, Chen PL, Rich SS, Hong CP, Folsom AR.
Association of Stein leventhal syndrome with the incidence of post-
menopausal breast cancer in a large prospective study of women in lowa.
Cancer (1997) 79:494-9.
20 Polycystic Ovary Syndrome
POLYCYSTIC OVARY SYNDROME
DK Dutta, G Das

6 Management

Till date, PCOS was diagnosed as a syndrome of ovarian hyper-

function; influence by genetic defect causing intrinsic ovarian
dysfunction whose degree of symptomatology is largely influenced
by extraovarian factors. Causative genes, although small number,
involved have yet to be delineated. Due to above facts treatment of
PCOS remains almost symptomatic.5
Basically treatment depends upon various factors:
• Age of women
• Presence or absence of obesity, hirsutism, Acne.
• Menstrual irregularity
• Presence or absence of hyperinsulinaemia or hyperandrogenism
or high LH
• Infertility
• Prevention of long-term sequelae
Prime importance of treatment:
a. Reduction of weight loss
b. Reduction of insulin level
c. Lowering of LH secretion
d. Lowering of androgen secretion
e. Treatment of hirsutism, ACNE if any.
Treatment were devided into:
A. Weight reduction and diet
B. Medical
1. Ovulation induction (Conventional approach)
2. Ovulation induction (Modern approach)
3. Treatment of ACNE and Hirsutism
 Management 21

C. Surgical
1. Wedge Resection of ovary
2. Laparoscopic ovarian puncture
D. In vitro fertilization
A. WEIGHT REDUCTION AND DIET
Weight reduction12 often has beneficial effect on menstrual abnor-
malities and hirsutism.
Short-term (4 weeks) very low–energy diets in women with
PCOS resulted in a reduction in (a) Serum free testosterone (b)
Insulin and insulin like growth factor I (IGF-I) and increase in
SHBG levels. It has been shown that weight loss decreased Ovarian
P450c 17a activity and reduced scrum free testosterone concen-
tration in obese women with PCOS, but in obese ovulatory
women.20
Weight loss then decreases both hyperinsulinaemia and insulin
resistance increases SHBG and results in overall reduction of hyper-
androgenism.19 There fore low energy diet and exercise should be
encouraged as a form of first line therapy.
B. MEDICAL
Ovulation Induction (Conventional Approach)
a. Clomiphene citrate (CC)13 CC alone or in combination weight
loss, continues to be the first line of treatment for anovulatory
infertility associated with polycystic ovary syndrome (PCOS)
How CC acts–By binding to hypothalamic oestrogen recep-
tors, CC displaces endogenous oestrogen from the receptor,
leading to a decrease in negative feedback exerted by endo-
genous oestrogen and reduced replenishment of estrogen
receptors. As a result, gonadotrophin-releasing hormone (Gn
RH) secretion appears to increase, followed by GnRH mediated
luteinizing hormone (LH) and follicle stimulating hormone
(FSH) secretion. As gonadotrophins level increase, peak
ovarian follicular development and oestradiol secretion became
evident approximately 5-10 days after the last tablet.21,11,24
Rising oestradiol levels than appear to trigger the mid cycle
LH Surge and ovulation.
22 Polycystic Ovary Syndrome

Why Conception Failures

Consideration discrepancy exists between ovulation rates (70-90%)
and conception rates (40-50%) during CC treatment. This is
probably due to antiestrogenic action of CC-may adversely affect
the vaginal cornfication, cervical mucus and endometrial thickness,
thus potentially affecting sperm transport, sperm survival, early
implantation. In addition to the potential antiestrogenic effects of
CC, ovulation induction in women with PCOS occurs in an
environment characterised by high basal LH and androgen
concentrations, both of which may be exacerbated during CC
treatment and may have a negative impact on outcome. This
suboptimal environment may affect oocyte quality and fertilization
rates, as seen during in vitro-fertilization cycles in women with
PCOS or it may increase the likelihood of an early pregnancy loss.
In CC failures cases ovulation has been by induced the duration
CC administration to 7 day or more in women who were unrespon-
sive to the conventional 5 day administration.

Conventional Clomiphene Administration

CC treatment is usually started between the second and fifth day
of spontaneous or progesterone induced withdrawal bleeding. The
usual starting dose is 50g to 100 mg per day for 5 days for 3 to 6
cycles. The dose may increase upto 250 mg for days in rare cases.
Among women with various ovulatory disorders including PCOS,
approximately 25 percent will remain an ovulatory at a dose of
150 mg while upto 15 percent remain anovulatory despite 250 mg
of CC for 5 days.6,29,2
CC non-responders tend to hope significantly larger ovarian
volumes with significantly more intermediate sized follicles than
CC responders and normal controls, although considerable overlap
exists. As well increasing levels of LH elevated total or free
testosterone concentrations, fasting hyperinsulinemia or insulin
resistance and decreasing concentration of sex hormone blinding
globulin (SHBG) tend to predict poor response to CC. In general
the more severe the hormonal and ultrasonographic abnormalities,
the less likely it is that ovulation will be induced with CC.
 Management 23

Induction of Ovulation (Modern Approach)

a. Lose dose FSH
b. GnRH agonists
c. GnRH antagonist
d. Letrozole (Aromatase inhibitor)

a. Low dose FSH

Low dose FSH26 for induction of ovulation is the method of choice
in clomiphene resistant PCOS. (Failure to achieve pregnancy within
6 ovulatory cycles following 150 g to 250 mg CC for 5 days or 7
days are considered to be clomiphene resistant).
Protocol—Ovarian stimulation is begun with 50 IU or 75 IU27,7
of highly purified FSH preparation on the third day of either a
spontaneous period or progesterone induced withdrawal bleeding.
Stimulation is monitored by USG and oestradiol, LH determi-
nations. Stimulation is continued until the largest follicle is 17 to
19 mm in diameter. At this time 500-1000 IU of hCG are given IM
for final follicle and oocyte maturation and to induce ovulation,
dose of FSH is increased by half on ample if at the end of 10 days
of stimulation no sign of follicular growth is observed. When the
patient does not become pregnant during first cycle, she should
begin her next cycle with a dose that is half an ample less than the
maximum dose pf the previous cycle (The threshold dose). This
dose is maintained for 7 days. Alternatively adjuvant medication
by addition of:
i. Glucocorticoids–May be of benefit to: (a) Women with hyper-
adrogenic anovulation (b) CC resistant women with normal
level of dehydroepiandrosterone sulphate (DHEAS) treatment
begins with dexamethason 0.25-0.5 mg or prednisone
5 mg at bed time together with progestion therapy to induce a
withdrawal bleeding prior to reinstituting CC.
ii. Human chorionic gonadotrophin–The addition of a mid-cycle
hCG injection is logical if endogenous LH surge is truly delayed
or about the routine addition of a mid cycle hcG injection does
not appear to improve luteal phase parameters or conception
rates when compared with cycles in which a spontaneous surge
was documented with urinary LH testing.
24 Polycystic Ovary Syndrome

iii. Pulsatile GnRH–Tan and colleagues recently reported success-

ful ovulation in 66 percent and conception in 17 percent cycles
in women with PCOS who received pulsatile GnRH plus CC
(100 mg for 5 days) after failing to respond to pulsatile GnRH
alone.
iv. Bromocryptine is used in women with anovulation in the pre-
sence of galactorrhoea and/or hyper prolactinemia. No luteal
support is given either by progesterone or by hCG. It is better
to avoid GnRH analogs in combination with low dose step-up
protocol.
b. GnRH Agonists
The use of GnRH agonists in the treatment of patients suffering
from PCOS for ovulation induction has become more and more
standard procedure.17,4
GnRH agonists suppress (i) Excessive LH levels during the folli-
cular phase (ii) The premature LH surge (iii) May be direct effect
on the ovum.
With regard to treatment regimens with luteinizing hormone-
releasing hormone (LH-RH) agonists for ovulation induction there
are in principle three periods during which the use of an agonist
could be of some advantage. First, during the “flare up” (Ovulation)
period, secondly during down regulation (by hMG/FSH/GnRH and
finally during the recovery period (by Pulsatile GnRH, CC, fixed
dose FSH) after discontinuation of the analogue.1
Duirng the flare-up period the GnRH agonist is used for its direct
stimulating effect. During down regulation the agonist is used for
increasing fertility of ovulated oocytes, and finally for facilation
of ovulation the recovery period.
Pusatile GnRH has become an accepted and highly effective
treatment in patients suffering from hypothalamic amenorrhoea and
clomiphene resistance cases with successfully induce ovulation 90-
100 percent. It is premature to conclude that the use of GnRH
agonists to trigger ovulation will protect patients from development
of severe OHSS. The use of a low dose OC seems to be effective in
restoring the follicular environment in woman with PCOS.
 Management 25

c. GnRH Antagonists
Whether GnRH antagonists used in combination with gonado
trophins in ovulation induction give better result with respect to
monofollicular growth and pregnancy rate in PCOS patients has
not yet been studied. hypothetically, GnRH antagonists28 have some
advantages over agonists, since the antagonist suppresses LH
immediately it can be administered in the late follicular phase when
the LH peak is expected.
There are at lease two reasons why GnRH antagonists might be
more beneficial in controlled ovarian hyperstimulation for PCOS
patients (a) A reduced use of gonadotrophins and (b) The potential
use the GnRH agoinst instead of human chorionic gonadotrophins
(hCG) for triggering ovulation.
The GnRH antagonists have the advantage that they don’t need
to be administered until the mid follicular phase, so the follicular
recruitment can take place under low dose step-up FSH treatment
without down regulation which reduces the number of follicles
developing and the oestradiol level. Lower steroid levels in the
luteal phase diminish considerably in the risk of OHSS.
The third generation GnRH antagonists cetrorelix and ganirelix
are new drugs that have proved their safety and efficacy in IVF
protocols with selected patients.
They are easier, safer and theoretically more advantageous to
use than GnRH agonists in PCOS patients, owing to their different
pharmacodynamics.

d. Letrozole
Letrozole (Aromatase Inhibitor) is used very safely for induction
of ovulation in clomiphene citrate registance cases.
How it acts–Release of hypothalamic pituitary axis hormone
from oestrogenic negative feedback gonadotrophic secretion
resulting in stimulation of ovarian development by means of
conversion of androgen subtrate to oestrogen is blocked à
intraovarian androgens high follicular sensivity to FSH high
stimulate insulin like growth factor other endocrine and paracrine
factors, synergic with FSH to promote folliculogenesis.
26 Polycystic Ovary Syndrome

Pregnancy rate 20 percent (4/20) was found when letrozole is

used from day 3 to 7 for 5 days at the dose of 2.5 mg twice daily in
CC resistant cases (Dutta et al, 2003). Encouraging result is found
in PCOS women who have excessive baseline E2. Further research
is required with this drugs.

Treatment of Acne and Hirsutism

The individual drugs used in the treatment of hirsutism affect
different aspects of androgen metabolism. Idea is:
1. To decrease androgen production
2. Increase metabolic clearance rate of androgens.
3. Inhibit androgen receptors
4. Inhibit or block enzymes responsible peripheral production of
testosterone or conversion of testosterone to dehydrotesto-
sterone (DHT)
5. Increase the amount of sex hormone binding globulin (SHBG)
Treatment divided into: (1) Medical management, (2) Other
therapies

Medical Management
Combined Oral Contraceptive Pill
Oestrogen/progesterone oral contraceptive pills is the treatment of
choice for mild hirsutism of PCOS. However, 19 nor-testosterone
derivates (norethindrone, norgestrel, ethynodiol diacetate) in OC
is better to avoid as because of androgenic properties. Hence it is
better to choose a combination drug oestrogen plus cyproterone
acetate (CPA) (antiandrogenic effects). Treatment with OC
containing 2 mg of CPA had masked beneficial effects on acne,
seborrhoea and hirsutism. Beneficial effects of low dose combined
oestrogen-antiandrogen preparation in PCOS:
a. On hormonal disturbances
1. Decrease in LH levels
2. Decrease ovarian and adrenal androgen level
3. Increase of SHBG concentration
b. On clinical signs Decrease in hirsutism improvement in acne
and seborrhea good control of menstrual cycle.
 Management 27

c. On ovarian size Decrease in ovarian volume This regime is

found to be better in adolescents with PCOS.

Antiandrogens
Till no antiandrogen has been shown to be superior in well designed
trial on hirsute women. Cyproterone acetate a steroid derived from
17 hydroxyprogesterone has progestational and anti-gonadotrophic
actions in addition to antiandrogen activity A ‘reverse sequential’
regimen is found to be better in CPA (25–100 mg daily is given
orally on 5-15 of the cycle and ethinyl oestradiol–20-30 mg is given
on days 5-26 of the cycle.
CPA (50mg daily for 10 days)10,12,15,3 Combined with an OC is
found to be treatment of choice for women with PCOS as because
it suppress LH androstenedione, an drostenedione levels, and
increases SHBG. This regimen is a highly effective treatment for
severe hirsutism and provided excellent cycle control and
contraception. Monotherapy with CPA for 10days in each cycle or
month could be an option for women who do not tolerate oestrogens
provided adequate contraception is used.
In severe hirsutism, CPA (10 mg) daily can be advocated for 6
month to 1 year, but when satisfactory result is achieved the dose
of CPA may be reduced every 3-6 months, first to 50 mg daily and
then to 25 mg daily for the first 10 days of reverse sequential
regimen. Alternatively, a region with 10 mg CPA during the first
15 days of the OC can be employed in cases of re-curence or less
severe hirsutism. When a sates factory clinical reduction in
hirsutism is observed it is justifiable to continue treatment with a
lower dose preparation containing 20 mg of CPA and 35 mg of
ethinyl oestradiol with no added CPA.
Side effects of CPA include weight gain, loss of libido, headache
and fatigue and mood changes but when ethinyl oestradiol is added
to CPA these complaints diminish in frequency often hyperinsu-
linaemia and glucose tolerance hepatotoxicity are reported.

Spironolactone
In clinical practice does of spironolactone range from 50 to 200
mg daily but most patients require at least 100 mg. This dosage has
28 Polycystic Ovary Syndrome

been associated with significant improvement in 70-75 percent of

hirsute women ofter 6 months.
Serum levels of SHBG, DHEAS and DHEA are unaltered by
this regime but testosterone levels will drop with a few days of
treatment. Side effects are gastrointestinal (20%) menstrual
irregularities (27%), increase fasting blood insulin concentrations.
It should be avoided in women using drugs such as angiotensin
converting enzyme inhibitors or angiotensin II receptor blockers.

Flutamide
Doses of 250 mg three times daily for 3-6 months.30 It induces a
significant reduction in total free testosterone, 5-dihydro
testosterone, DHEA, DHEAS and androstanedione levels and a
favorable effect on lipid profile. Side effects include nausea,
vomiting, deterioration in liver function tests, cholestetic joundice
and hepatic necrosis.

Finasteride
Five mg daily has clinical effect on hirsutism similar to that of
spironolactone and flutamide the drug is well tolerated and no side
effects have been noted in human.23

GnRH Agonists
GnRH agonists such as Nafarelin, leuprolide or buserelin decrease
ovarian steroid production by suppressing LH and FSH secretion.
This treatment is highly effective (i) in women with PCOS (ii)
ovarian hyperthecosis (iii) sever premenstrual syndrome.
Combination of GnRH agonists with oestrogen–can prevent bone
loss and coronary heart disease (due to decreased level of
oestrogen). It acts by suppressing androgen and increasing SHBG
concentrations.

Ketoconazole
400 mg per day in PCOS as well as with 1000 mg per day in stromal
hyperthecosis side effects are nausea, vomiting, pruritus and
 Management 29

atternations with hepatic functions.

Metformin
Metforming 500 mg three times a day for 6 months is used in the
treatment of PCOS. It significantly reduces hyperinsulinaemia and
hyperandrogenism independent of changes in body weight (obesity).
1. Other Therapies
a. Cosmetic procudures All forms of hormonal treatment will
benefit form concurrent mechanical hair removal.
b. Antibiotic and topical therapies Tetracycline, erythromycin
and tetracycline with conjunction with androgen therapy are
the mainstays of therapy of acne.
c. Psychological in treventions Psychological treatment in the
form of group therapy has important beneficial effects on
the management of obese women with PCOS because hirsute
women have increased levels of anxiety and depression.

C. SURGICAL
i. Wedge resection of ovary
ii. Laparoscopic ovarian puncture
Wedge Resection of Ovary
Stein and leventhal described resection of half to three quarters of
both of the enlarged ovaries. Out of 1766 patients whose results
were published between 1935 and 1983 there was an overall
pregnancy rate of 58.8 percent with results ranging from stein’s
high of 86.7 percent to a low of 25 percent bilateral wedge resection8
of the ovaries are abandoned long ago because of problems
associated with postoperative adhesions.25

Laparoscopic Ovarian Puncture

The methods described range from: (i) multiple ovarian biopsy to
remove 0.5-1 mm of tissue, (ii) electrocautery14 using a unipolar
coagulating current, (iii) puncture of the ovarian surface with a
laser.
With KTP and carbon dioxide lasers: As with electro coutery,
the ovarian cortex over follicles is vaporized; the number of
30 Polycystic Ovary Syndrome

punctures is however increased compared with electro cautery.9

With the Nd: YAG laser, coagulation rather than vaporization is
the goal and a wedge of various tissue is coagulated to a depth of
4-10 mm without opening the ovarian cortex.
The laparoscopic ovarian puncture is best indicated:
a. Clomiphene resistant women who are slim
b. Anovulatory
c. LH high
d. Recurrent miscarriage
e. Women undergoing medical induction or WHO develop solitary
cyst formation. This procedure is contraindicated: (a) obesity,
(b) infertility that cannot be accounted for by an ovulation.
The most striking benefit of ovarian electrocautery in women
with PCOS is that in contrast to medical induction of ovulation
there is no increased risk of multiple pregnancy.
Only question is, if there is good ovulation but no pregnancy,
will the patient benefit from ovarian drill or shall we consider if as
unexplained infertility and move to COH with or without IU or
IVF.

IVF–PCOS
Inspite of different therapeutic options, such as CC (Cumulative
pregnancy rate 40–50%), Human Gonadotrophins (CPR–30%,
multiple pregnancy 30% high-risk-OHSS), Pulsatile gonadotrophin
releasing hormone (GnRH) (CPR–14.6%) and surgical treatment
for the infertility and an ovulation status associated with PCO still
there is a group of patients in whom pregnancy is not achived in
the absence of any other infertility cause.
The available evidence indicates that IVF16 offers women with
PCO attractive possibilities of achieving a pregnancy when other
techniques have failed.31
The protocol that offers the best results in these women as in
most IVF patients is based on pituitary down regulation to inhibit
endogenous FSH and LH secretion. Thus reducing the deleterious
effects based on elevated LH levels characteristic in these patients
prior to ovarian hyperstimulation.
 Management 31

Pregnancy outcome of IVF in patients with PCO are reported

by Homburg et al (Cumulative Pregnancy Rate (CPR) = 34 out of
68 patients. MacDougal et al (CPR–16 out of 76 patients) and Own
et al (CPR–12 out of 58 patients) are encouraging.18
In the near future new recombinant gonadotrophins the use of
GnRH antagonists and the attractive possibility of in vitro oocyte
maturation may simplify the therapeutic attractive is these patients.

REFERENCES
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study group. Ovarian stimulation with hMG: Results of a prospective
randomized phase III European study comparing the luteinizing hormone-
releasing hormone (LH-RH)-antagonist cetrorelix and the LH-RH-agonist
buserelin. Hum Reprod 2000;15:526-31.
2. Bateman BG, Nunley WCJ, Kolp LA. Exogenous estrogen therapy for
treatment of clomiphene citrate-induced cervical mucus abnormalities: Is it
effective? Fertil Steril 1990;54:557-80.
3. Belisle S, Love EJ. Clinical efficacy and safety of cyproterone acetate in
severe hirsutism: Results of a multicentred Canadian study. Fertil Steril
1986;46:689-99.
4. Charbonel B, Krempf M, Blanchard P, Dano F, Delage C. Induction of
ovulation in polycystic ovary syndrome with a combination of luteinizing
hormone-releasing hormone analog and exogenous gonadotropin. Fertil Steril
1987;47:920-26.
5. Conway GS, Honour JW, Jacobs HS. Heterogeneity of the polycystic ovary
syndrome: Clinical, endocrine and ultrasound features in 556 patients. Clin
Endocrinol 1989;40:459-70.
6. Dupon C, Rosenfield R, Cleary R. Sequential changes in total and free
testosterone and androstenedione in plasma during spontaneous and clomid-
induced ovulatory cycles. Am J Obstet Gynecol 1973;115:478-53.
7. Dale PO, Tanbo T, Haug E, Abyholm T. Polycystic ovary syndrome: Low
dose follicle stimulating hormone administration is a safe stimulation regimen
even in previous hyperresponsive patients. Hum Reprod 1992;7:1085-89.
8. Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic
ovary syndrome: Wedge resection revisited in the age of laparoscopy. Fertil
Steril 1995;63:439-63.
9. Daniell KF, Miller W. Polycystic ovaries treated by laser vaporization. Fertil
Steril 1989;51:232-36.
10. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853-61.
11. Ficicioglu C, Api M, Ozden S. The number of follicles and ovarian volume
in the assessment of response to clomiphene citrate treatment in polycystic
ovarian syndrome. Acta Obstet Gynecol Scand 1996;75:917-21.
32 Polycystic Ovary Syndrome

12. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences
of weight loss in obese, hyperandrogenic women before and after weight
loss. J. Cline Endocrinol Metab 1989;68:173-79.
13. Gysler M, March CM, Mishell DR, Bailey EJ. A decade’s experience with
an individualized colmiphene treatment regimen including its effects on the
postcoital test. Fertil Steril 1982;37:161-67.
14. Gjonnacss H. Polycystic ovary syndrome treated by electrocautery through
the laparoscope. Fertil Steril 1984;41:20-25.
15. Hammerstein J, Meckies J, Leo-Rossberg I, et al. Use of cyproterone acetate
(CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem
1975;6:827-36.
16. Homburg R, Bwerkowitz D, Levy T, Feldberg D, Ashkenazi J, Ben-Rafael
Z. In vitro fertilization and embryo transfer for the treatment of infertility
associated with polycystic ovary syndrome. Fertil Steril 1993;60:858-63.
17. Homburg R, Eshel A, Kilborn J, Adams J, Jacobs HS. Combined luteinizing
hormone releasing hormone analogue and exogenous gonadotrophins for
the treatment of infertility associated with polycystic ovaries. Hum Reprod
1990;5:32-35.
18. Homburg R, Berkovitz D, Levy T, Ferldberg D, Ashkenazi J, Ben-Rafael Z.
In vitro fertilization and embryo transfer for the treatment of infertility
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Low dose follicle-stimulating hormone in the treatment of polycystic ovary
 Management 33

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 Index 35

Index

A Follistatin 3
Follistatin Gene 3
ACNE 20
Adolescence 17
G
Adrenal androgen production 6
Aromastase Inhibitor 25 Genirelix 25
GnRH agonist 23
B GnRH antagonists 24
Bilateral ovarian wedge resection 29 Granulosa cell 6
Body Mass Index 14, 22
Breast Cancer 17 H
Hirsutism 20
C Hyper insulinaemia 9
Cardiovascular disease 17 17-Hydroxylase 8
Cetrorelix 25 Hyperandrogenism 8
Clomiphene Resistance 23
Clomiphene citrate 21 I
Contraception 26 IGFBP Proteases 8
Coronary Angiography 16 IGF-I Level 8
CYP 11A 7 Inhibin 6
Cypro terone Acetate 27 Insulin 9
Cyto Chrome P450c 17 2, 9 Invitro fertilization 30

D L
Diathermy 30 Laparoscope ovarian puncture 29
Dominent Follicle 8 Laparoscopic diathermy 29
Luteinising hormone 9
E
M
Electro cautery 30
Endometrial Cancer 18 Metformin 29
Myocaridal infart 16
F O
Fertilisation 22 Obesity 29
Follicle Development 8 Oestradiol 18
Follicle Stimulating Hormone 21 Oocyte 31
Follicular Atresia 8, 10 Ovarian dysfunction 21
36 Polycystic Ovary Syndrome

Ovarian morphology 21 U
Ovarian wedge resection 29 Ultrasonographi 14, 15
Ovulation induction 20
P V

Polycystic ovary 3 Variable number tandem repeats 9

Pulsatile GnRH agonist 24 Variable number tandem repeats
(VNTR) Gene 9
T
W
Theca Cells 6
Triacylglycenol 17 Wedge bilopsy 29
 Index 37

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