1

Q: A 17-year-old unmarried girl presented to the gynaecology OPD with complaints of irregular menstrual cycle
acne, and excessive hair growth on the face and body for the past two years. Her periods occurred every two
months, with her last menstrual period being 45 days ago. She reached her menarche at the age of 14. Her urine
pregnancy test was negative. She had no significant past or family history. How will you manage this case?

Answer:
Competencies covered

OG30.1 Describe and discuss the etiopathogenesisa, clinical featuresb, differential diagnosisc, investigationsd,
managemente, and complicationsf of PCOS
OG30.2 Enumerate the causesg and describe the investigationsh and managementi of hyperandrogenism

Introduction
PCOS (polycystic ovarian syndrome) is a syndrome associated with anovulation with prevalence of 5-20%. It is
the second most common cause of secondary amenorrhea after pregnancy and one of the most common
endocrinopathies, affecting 4-6% of women of childbearing age. The syndrome is also called Stein-Leventhal
syndrome, after Irving F. Stein and Michael L. Leventhal, who were the first gynaecologists to describe the
syndrome of anovulation as amenorrhea, hirsutism and enlarged polycystic ovaries. Interestingly, polycystic
ovarian morphology(PCOM) can be seen in a third of females with a normal ovulatory cycle.
PCOS is a leading cause of female infertility. It is also associated with obesity, insulin resistance, type 2 diabetes
mellitus, dyslipidemia, and metabolic syndrome.

Definition
The diagnostic criteria for PCOS has been revised over the years. Table 1 provides an overview of changes in the
diagnostic criteria of PCOS over the last few decades

Table 1: Diagnostic criteria of PCOS over decades

Criteria
1. Irregular periods (≤ 8 menses per year)
2. Elevated serum androgens or hyperandrogenism (characterized by hirsutism, acne and/or androgenic
alopecia)
3. Polycystic ovarian morphology (PCOM) or polycystic ovaries (ovarian volume >10 mL3 and/or > 12
follicles between 2 to 9 mm size in at least one ovary)
National Institute of Child Health and Human (In the order of relevance) 2, 1 and exclusion of
Development (NICHD), 1990 other endocrinopathies having similar clinical
presentation
Rotterdam criteria, 2003 (co-sponsored by the Any two of the above three criteria; Differential
European Society of Human Reproduction and diagnosis that can mimic clinical presentation must
Embryology (ESHRE) and the American Society for be excluded
Reproductive Medicine (ASRM)) at the Rotterdam,
the Netherlands.
Androgen Excess and PCOS Criteria 2 and 1 OR 3; Differential diagnosis that can
Society (AE-PCOS) Task Force mimic clinical presentation must be excluded
Criteria, 2004
AE-PCOS Criteria, 2006 Criteria 2 and 1 OR ovarian volume >10 mL3 and/or
Androgen Excess > 25 follicles between 2 to 9 mm size in at least one
and PCOS ovary; Differential diagnosis that can mimic clinical
presentation must be excluded. It excluded the non-
hyperandrogenic phenotypes of PCOS.
AE-PCOS Consensus, 2014 Criteria 2 and 1 OR and ovarian volume >10 mL3
and/or ≥ 25 follicles < 10 mm in diameter per ovary.
Centre for Research Excellence in Polycystic Ovary Ultrasound should not be used for the diagnosis of
Syndrome (CREPCOS)-ESHRE-ASRM evidence-based PCOS up to 8 years of menarche.
guidelines, 2018 PCOM is >20 follicles and/or an ovarian volume of ≥
10 mL3 per ovary ultrasound (preferably using a
transvaginal 8 MHz transducer where appropriate)
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Salient features of the International evidence-based guideline for the assessment and management of
polycystic ovary syndrome 2018:
1. Primary amenorrhea: May be seen in PCOS but, is uncommon. It is defined as no menses by the age 15, or
more than three years after thelarche.
2. Irregular cycles within a year of reaching menarche is considered normal.
3. Irregular cycles are:
• Cycles less than 21 days or more than 45 days in length between one and less than three years after
attainment of menarche, OR
• Cycles less than 21 days or more than 35 days in length, or fewer than 8 cycles per year three years
after attainment of menarche, OR
• Cycles longer than 90 days one year after attainment of menarche
4. An ovary can be called as ‘polycystic’ on ultrasound only after the gynaecological age limit of 8 years after
menarche. Diagnosis of PCOM should be preferably done using a transvaginal 8 MHz transducer, where
appropriate. PCOM is >20 follicles and/or an ovarian volume of ≥ 10 mL3 per ovary.
5. Use the clinical modified Ferriman-Gallwey scoring system (discussed later) for hirsutism (a level ≥4–6
indicating hirsutism) and alopecia using the Ludwig visual scores for hyperandrogenemia. There is no
universally accepted visual assessment method for grading acne.

Phenotypic classification of PCOS

There are four phenotypes of PCOS, namely A, B, C, and D. (Table.2)

1. Phenotype A (full blown PCOS) is most prevalent. It includes presence of hyperandrogenaemia, ovulatory
dysfunction and PCOM.
2. Phenotype B (non-PCO-PCOS) includes hyperandrogenism and ovulatory dysfunction. PCOM is not a part of
this phenotype.
3. Phenotype C (ovulatory PCOS) includes hyperandrogenism and PCOM. It excludes ovulatory dysfunction.
4. Phenotype D (non-hyperandrogenic PCOS) includes ovulatory dysfunction and polycystic ovaries. It is
associated with least metabolic risk.

Table.2 Phenotypic classification of PCOS

Parameters Phenotype A Phenotype B Phenotype C Phenotype D
PCOS Hyperandrogenism + Hyperandrogenism Hyperandrogenism Ovulatory
features Ovulatory Dysfunction + + + PCOM dysfunction +
PCOM Ovulatory PCOM
Dysfunction

HYPERANDROGENISM

PHENOTYPE B PHENOTYPE C

PHENOTYPE A

OVULATORY PCOM
DYSFUNCTION
PHENOTYPE D

Diagrammatic representation of Phenotypic classification of PCOS

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Aetiopathogenesis of PCOSs

Three factors, namely hypothalamic-pituitary dysfunction, peripheral insulin resistance and ovarian/adrenal
hyperandrogenism are implicated in pathogenesis of PCOS.

PITUITARY

Figure .1 Pathophysiology of PCOS

A. Hypothalamic-pituitary dysfunction:

In a normal female, the thecal cells are responsible for production of androgens under the influence of
luteinizing hormone (LH) and the granulosa cells aromatize androgens to oestrogens under the effect of Follicle
stimulating hormone (FSH). This is known as the two-cell theory.
1. Women with PCOS have higher serum levels of LH, low to normal levels of FSH, and an elevated LH to
FSH ratio (≥2). However, an altered gonadotropin level is not diagnostic of PCOS.
2. Elevated LH levels result in thecal hyperplasia, increased ovarian androgen production and follicular
arrest in the preantral stage.
3. An inadequate response of granulosa cells to FSH leads to reduced aromatization and oestrogen
production. Since oestrogen is of primal importance in development and selection of dominant follicles,
this imbalance produces the classic polycystic ovarian morphology.
4. The excess androgen reaches the circulatory system, inappropriately activates the hypothalamic-
pituitary axis producing excess LH compared to FSH inciting a vicious cycle. This disproportionately
raised LH in these women is secondary to an increased GnRH pulse rate and higher LH pulse frequency
compared to pulse amplitude. (Figure.1)
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B. Peripheral insulin resistance:

1. The prevalence rate of insulin resistance in PCOS is between 50 and 70%.

2. Thirty-five percent of PCOS patients have impaired glucose tolerance and 7-10% type 1 diabetes mellitus.
3. Insulin resistance in PCOS is mostly confined to skeletal muscles.
4. The incidence of insulin resistance is higher in obese women. In fact, obesity itself is associated with insulin
resistance, hyperinsulinemia, longer follicular phases, longer menstrual cycles, reduced levels of circulating
sex hormone-binding globulins (SHBG) and hyperandrogenemia.
5. Early in the course of the disease, the pancreatic beta cells produce excess insulin, leading to fasting and
postprandial hyperinsulinemia. But the response to insulin is inadequate and postprandial hyperglycemia
is observed. However, fasting hyperglycaemia develops later.
6. Effects of hyperinsulinemia and insulin resistance:
Hyperinsulinemia and insulin resistance leads to hyperandrogenism and stigmata of insulin resistance
syndrome through:
a) Increased production of gonadotropins and consequently, androgen production in the
ovaries/adrenal glands.
b) Reduced hepatic production and circulating levels of SHBG
c) Enhancement of physiological effects of LH. (Figure 2).

Peripheral
Insulin resistance

Increased Free
Increased
androgen
blood glucose

Decreased
Pancreas Insulin Resistance in Polycystic Ovary Syndrome SHBG

Liver
Increased
Insulin secretion
Increased
androgen

Ovarian theca cells

produce
excessive androgen

Figure.2 Insulin resistance in PCOS

C. Hyperandrogenism and hyperandrogenemia:

Majority of androgens in an adult female are derived from the ovaries followed by the adrenals and adipose
tissue.
• Ovarian hyperandrogenemia in PCOS is characterized by an elevated intrafollicular (antral follicles)
androgen levels due to the lack of granulosa cell aromatase activity and theca cell hyperplasia.
• Adrenal hyperandrogenemia is seen only in about 20-30% of PCOS cases. It has mostly a genetic origin.
These women have raised serum DHEA-S levels.

D. Genetic predisposition, environmental and intraovarian factors:

Genetic factors: PCOS may have an autosomal dominant inheritance. It may be linked to a single or multiple
gene defect. Some proposed genes are:
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a) Genes associated with anovulation- CYP encoding the P450c17 enzymes, SHBG and FSH receptors.
b) Genes coding for the synthesis, transport and regulation of androgens. Gene DENND 1A, in the
ovarian theca cells is associated with excessive androgen production.
c) Genes involved in folliculogenesis
d) Genes regulating insulin metabolism.
e) Gene polymorphism for TNF-alpha, IL-6 and IL-6 receptors
f) Allelic variants of fibrillin-3 (FBN3) and variants of LH receptors (LHR) in women of European and
Chinese descent.

Intraovarian factors: Factors affecting intraovarian folliculogenesis (growth factors, cytokines, homocysteine,
leptins, and oxidative stress to the growing follicles) also play an important role in the development of PCOS.

Environmental and other factors: Diet, sedentary lifestyle, valproate (associated with hyperandrogenemia), and
lifestyle patterns are associated with the development of PCOS. Environmental disrupting chemicals (EDCs) such
as Bisphenol A (BPA) are linked to PCOS development

Clinical manifestations and health risks with PCOS b,f

A. Biochemical hyperandrogenism/ Hyperandrogenaemiah

Androgens in PCOS
• The five major androgens of importance are testosterone, dehydroepiandrosterone (DHEA)
dehydroepiandrosterone sulfate (DHEA-S), androstenedione and androstenediol.
• Testosterone: 25% of secretion by ovaries and adrenals, each; rest by peripheral conversion in adipose
tissue. The metabolism of testosterone occurs in liver by glucuronidation or sulphuration. The
biologically active metabolite of testosterone is known as dihydrotestosterone.
• Testosterone and dihydrotestosterone act on the androgen receptors and have direct androgenic
effect.
• Dihydrotestosterone is the most potent form of androgen, but it circulates in negligible amounts. It is
of negligible value in diagnosing hyperandrogenemia. However, it is useful for detecting androgen-
producing adrenal tumors.g
• Eighty percent of DHEA and 100% of DHEA-S is secreted by adrenals. The rest 20% of DHEA and 50% of
androstenedione are secreted by ovaries.
• DHEA, DHEA-S and androstenedione are precursors to testosterone and do not have a direct
androgenic action. The peripheral conversion of androstenedione and DHEA to testosterone occurs
in skin, fat, liver and urogenital systems.
• Androstenedione is higher in premenopausal women than men, but only 10% as potent as
testosterone.
• Ninety-nine percent of testosterone circulates bound to SHBG (80%) and albumin (19%). Only 1%
circulates free. All other androgens are mostly solely bound to albumin.

Hyperandrogenemia
Conditions that lead to reduced levels of SHBG are associated with hyperandrogenaemia.
These include
I. Exogenic administration of androgen, synthetic progestins (norethindrone, norgestrel,
desogestrel, norgestimate), glucocorticoids, insulin and growth hormones.
II. Obesity
III. Hypothyroidism
IV. Hyperinsulinemia
V. Acromegaly

Investigations for suspected hyperandrogenaemiah

I. Total testosterone
II. Free testosterone (highly sensitive, however, measurement poses technical challenges. Free
testosterone should be measured during the follicular phase of menstrual cycle)
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III. DHEAS (clinical utility of routine DHEA-S testing for mild clinical hyperandrogenism is limited; AE-
PCOS 2006 criteria consider DHEA-S levels to be particularly useful in making a diagnosis of
hyperandrogenemia in PCOS. However, the Rotterdam criteria do not include it)
IV. 17-hydroxyprogesterone
V. Thyroid stimulating hormone
VI. Prolactin

Figure 4: Hirsutism workup

Hirsutism

Virilization absent Virilization present

Cycles regular Cycles irregular Full hormonal workup (DHEA-

S, 17-OH progesterone)
Imaging studies

Serum 17-OH
Surgical exploration
testosterone progesterone

≥ 200 ng/dL ≥ 200 ng/dL 17-OH TSH Prolactin

Imaging and progesterone If normal, If normal,
surgical consider consider
exploration for anovulation Congenital
ACTH adrenal
adrenal/ovarian (PCOS)
stimulation hyperplasia; if
neoplasm test raised
< 200 ng/dL consider
Anovulation imaging of
(PCOS) ≥ 1000 ng/dL pituitary
Late onset CAH and/or ovaries

< 1000 ng/dL

Heterozygote carriers of 21
hydroxylase deficiency

B. Clinical Hyperandrogenism

Hirsutism, acne and androgenic alopecia are secondary to effects of androgens on the pilosebaceous unit of the
skin.
• Hirsutism:
1. It is the growth of terminal hairs on the face or body in male pattern.
2. The modified Ferriman-Gallwey score is a recognized scoring system for assessing hirsutism. A
score from 0 to 4 is given for hair growth in each of the nine androgen sensitive areas. The score
ranges from 0 to a total of 36. A score greater than 8 indicates hirsutism.
3. Hirsutism is usually conclusive for clinical hyperandrogenism in the majority of cases.
4. However, when hirsutism has sudden onset, rapid progression, or is associated with virilisation
(clitoromegaly, deepening of voice, increase in muscle mass, rapidly progressive hirsutism, or
alopecia) the diagnosis of an androgen-producing tumor is more likely.
• Acne:
1. It is the second most common manifestation of hyperandrogenism after hirsutism.
2. Hyperandrogenic acne in PCOS in adolescents can be mistaken for normal pubertal acne, but the
latter is more common and severe in men.

ferriman gallway score: 9 sites

upper lip , chin, upper chest, upper abdomen, lower abdomen
upper arm, thigh, upper back, lower back
points 0-4
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3.Screen adolescent women with moderate to severe acne and those with progression or
development of new acne for PCOS.
• Androgenic alopecia:
1. It is an uncommon feature of hyperandrogenism in PCOS
2. High androgen levels cause pilosebaceous unit atresia and androgenic alopecia.
3. There is sparing of the front hairline and diffuse hair loss on the crown and top of the head in
addition to significant hair loss in the wider central part.
4. The Ludwig scale is recommended for grading alopecia due to hyperandrogenism in PCOS.

C. Ovulatory and menstrual dysfunction

• Around 60 to 85% of women with PCOS have menstrual irregularities

• Twenty percent women with PCOS have normal menstrual cycles.
• The most common menstrual abnormalities observed in PCOS are oligomenorrhea and amenorrhea.

D. Insulin resistance

• The prevalence of insulin resistance in PCOS is between 10 and 35%. It rises with obesity.
• Upper body obesity (centripetal obesity) is characteristic of insulin resistance.
• Acanthosis nigricans is another clinical marker of insulin resistance. It is characterized by a velvety, darker
skin, especially in intertriginous areas.
• Insulin Resistance Syndrome or Syndrome X or Metabolic Syndrome:
PCOS is associated with an approximately 33.4% risk of metabolic syndrome.
The diagnostic criteria for Metabolic Syndrome includes ≥3 of the following:
a. Waist circumference ≥35 inches
b. Serum triglyceride levels ≥150 mg/dL
c. HDL cholesterol levels ≤50 mg/dL
d. Blood pressure ≥130/85 mm
e. Fasting glucose level ≥100 mg/Dl

E. Infertility

• PCOS leads to subfertility by chronic anovulation and implantation failure (to a lesser extent).
• Implantation failure is usually secondary to chronic endometrial hyperplasia and other endometrial
pathology.
• These women are also often resistant or unresponsive to conventional clomiphene citrate ovulation
induction.
• They are at higher risk of ovarian hyperstimulation syndrome (OHSS).

F. Gynaecological cancers

Women with PCOS are at risk of developing endometrial (three times higher risk), ovarian and breast cancer.

G. Sleep apnoea

• Sleelp apnea is secondary to hyperinsulinemia and hyperandrogenemia.

• It leads to daytime sleepiness, fatigue and snoring. Poor sleep, in turn, triggers a vicious cycle of insulin
resistance and sleep apnea.
• Testing for sleep disorders should be recommended in obese PCOS women planning bariatric surgery.

H. Non-alcoholic fatty liver disease (NAFLD)

• NAFLD is four times more common in PCOS.

• It develops secondary to insulin resistance.
• It is characterized by fatty infiltration of the liver and elevated serum transaminases.
• Symptoms are usually absent or only mild and nonspecific.
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• Routine NAFLD screening is not recommended in women with PCOS.

I. Metabolic, cardiovascular and mood disorders

• Obese women with PCOS have a 30-40 % risk of impaired glucose tolerance and 10% risk of overt diabetes
• Women with PCOS should be rescreened for glucose intolerance every 3 to 5 years because glucose
intolerance worsens with age
• These women have higher rates of subclinical atherosclerosis and increased cholesterol efflux and are at
increased risk of ischemic heart disease and cerebrovascular disease
• Rates of anxiety and depression are relatively higher in women with PCOS. The PCOS Questionnaire
(PCOSQ) is a validated quality of life questionnaire designed to access the psychological well-being of PCOS
patients.

Differential diagnosis of PCOSc

Table.3 Differential diagnosis of PCOS

Differential diagnosis of PCOS and relevant laboratory tests
Pregnancy
Laboratory evaluation: Urine pregnancy test, serum hCG levels.
Hyperprolactinemia
Laboratory evaluation: Serum prolactin
Hypothyroidism
Laboratory evaluation: Serum TSH
Non classical (Late-onset) congenital adrenal hyperplasia
Onset is insidious; premenarchal and peri-menarchal
Autosomal recessive disorder due to the deficiency of 21- hydroxylase enzyme (most common)
It is characterized by hyperandrogenism, hyperandrogenaemia and oligo/anovulation
Laboratory evaluation: 17-hydroxyprogesterone
HAIR-AN syndrome (Hirsutism, insulin resistance, acanthosis nigricans)
Onset is gradual
It is a marker of severe insulin resistance
It is characterized by hyperandrogenism, acanthosis nigricans, signs of virilisation
Laboratory evaluation: Raised serum testosterone and fasting insulin levels
Ovarian tumours and hyperthecosis
Onset is sudden. Seen during reproductive age
Characterized by hyperandrogenism, hyperandrogenaemia and oligo/anovulation
Laboratory evaluation: Total testosterone
Adrenal tumours
Onset is sudden. Seen during reproductive age
It is characterized by hyperandrogenism, hyperandrogenaemia and oligo/anovulation
Laboratory evaluation: Raised serum testosterone (>150-200 ng/dL), DHEA, DHEA-S (> 700 µg/dL), and
Cortisol levels. However, the cut-offs set for serum testosterone and DHEA-S have poor sensitivity.
Idiopathic hirsutism
Onset is gradual
It is due to 5 alpha reductase overactivity and characterized by hyperandrogenism. Levels of serum androgens
and markers of metabolic dysfunction are normal.
Cushing’s syndrome
24-hour urinary free cortisol. Extremely rare disorder (1 in 1,000,000). Screening is recommended only in
cases where coexisting signs of Cushing’s syndrome, viz. moon facies, buffalo hump, abdominal striae,
centripetal fat distribution, and hypertension. Women with proximal limb myopathies and easy brusing
should also be screened.
Exogenous androgens
Acromegaly
Genetic defects in insulin action (Leprechaunism, Rabson Mendenhall syndrome, Lipodystrophy)
Primary hypothalamic amenorrhea
Primary ovarian failure
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Evaluation of PCOSd

The diagnostic approach to PCOS involves a thorough history and examination.

Table.4 Suggested evaluations for PCOS

History Physical examination Investigations Optional investigations
• Onset and duration • Blood pressure • Tests for biochemical • LH/FSH ratio
of oligo/anovulation • BMI (kg/m2): 25–30 hyperandrogenaemia • Fasting insulin
• History of sudden overweight; >30 obese (Total testosterone and • 24-hours urinary
increase or decrease • Waist circumference for SHBG or bioavailable and cortisol (in
in weight body fat distribution free testosterone) selected cases of
• Family history of (Normal ≤35 inches) • Tests to rule out other late-onset PCOS or
PCOS, premature • Skin changes of causes of signs of Cushing’s
onset of hyperandrogenaemia hyperandrogenism: TSH, syndrome)
cardiovascular and insulin resistance Prolactin, 17-
disease (males < 55 (hirsutism, acne, Hydroxyprogesterone
years and females < alopecia-male pattern, • Tests for metabolic
65 years), acanthosis nigricans, skin abnormalities: 2-hour
hypertension, tags) oral glucose tolerance
diabetes, test, Fasting lipid and
endometrial lipoprotein levels
carcinoma • Ultrasonography
• History of infertility (preferable TVS, where
• Personal history of feasible): Presence of
smoking (17-22% polycystic ovaries,
increased risk), endometrial
alcohol intake, diet abnormalities.
and exercise

Table 5 A summary of recommended investigations for establishing a diagnosis of PCOSd

Serum Thyroid Stimulating Hormone (TSH)

Serum Testosterone
Women with hyperandrogenic anovulation make up 7% of the reproductive aged women.
Total testosterone is more reliable than free testosterone
Levels of testosterone may be normal in PCOS
Normal value: 20-80 ng/dL
PCOS: ≤ 150 ng/dL
Ovarian/ adrenal tumor: ≥ 200 ng/dL
Oral contraceptives should be stopped three months prior to testing
Serum DHEA-S
DHEA-S levels may be unchanged or marginally raised in PCOS
Levels ≥ 800 µg/dL are suggestive of adrenal tumor
LH/FSH ratio
A ratio of ≥ 2 is suggestive of PCOS but not very sensitive or specific
Serum Prolactin
Mild hyperprolactinemia may be seen in 5-30% of PCOS patients
Hyperprolactinemia is usually transient and levels reach 50% above the upper limit in PCOS.
Prolactin producing tumors may be associated with PCOM by stimulating ovarian androgen production
Normal levels: 15-20 ng/dl
17 Hydroxyprogesterone
Levels < 200 ng/dL exclude non-classical/ late onset congenital adrenal hyperplasia (21-Hydroxylase deficiency).
If levels are ≥ 200 ng/dL (up to 400 ng/dL for morning or follicular phase sample), ACTH stimulation (intravenous 250 µg)
is given. 17-OH Progesterone levels ≥ 1000 ng/dL confirms 21-Hydroxylase deficiency.
Oral contraceptives and glucocorticoids can alter the values.
24-hour urine free cortisol
Mild elevations seen in PCOS
Levels ≥2 times the upper limit of normal are suggestive of Cushing’s syndrome.
Oral contraceptives should be stopped before the test
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75gm OGTT
Recommended test for screening glucose intolerance in women with PCOS
The OGTT is a better predictor of insulin resistance compared to fasting glucose
The ACOG recommends a fasting blood glucose test followed by blood glucose levels after 2 hours of 75-gram oral glucose
intake.
Fasting blood sugar levels (Normal <110 mg/dL; impaired 110-125 mg/dL; type 2 diabetes >126 mg/dL)
2-hour blood sugar levels after 75-gram oral glucose intake (Normal < 140 mg/dL; impaired glucose tolerance ≥ 140 – 199
mg/dL; type 2 diabetes ≥ 200 mg/dL)
Glycosylated hemoglobin (HbA1c)
Not recommended as a screening test for glucose intolerance due to its high false negativity.
Fasting insulin levels
May be done in young women with features of hyperandrogenaemia and insulin resistance
A fasting serum insulin of more than 20 to 30 mIU/ml indicates insulin resistance.
It is a poor marker of insulin resistance than presence of metabolic syndrome.
Lipid profile
Total cholesterol (Normal ≥ 50mg/dL)
HDL (Normal ≥ 50mg/dL)
Triglycerides levels (Normal ≤ 150mg/dL)
USG pelvis (TVS)
Either of the ovaries is polycystic (≥ 12 follicles, 2-9 mm in diameter, or raised ovarian volume >10 cm3)
Note: Polycystic ovaries may be seen in 25 to 30% of healthy reproductive aged women.
Presence of endometrial abnormalities (e.g. hyperplasia)

Management of PCOSe

The management of PCOS is based on the presenting complaints.

A. Treatment of anovulatory infertility:

1. Preconception counseling should focus on lifestyle modifications, weight reduction, exercise, smoking
and alcohol cessation. (Figure 3)

2. First line treatment: Letrozole is the recommended first line drug for ovulation induction in PCOS.
Clomiphene citrate is also used for ovulation induction.
3. Second line treatment: Either exogenous gonadotropins or laparoscopic ovarian surgery can be used
as second line treatment.

Table 6 Pharmacological treatments of PCOS patients willing to conceive

Drugs Dosage Side effects
Letrozole- Aromatase inhibitor Starting dose: 2.5 mg/day Contraindicated for use during
Not approved by FDA. (maximum 7.5 mg/d) for 5 days pregnancy
First line agent of choice for ovulation on day 3, 4, or 5 of cycle.
induction in PCOS. Dose >7.5 mg/day not
Increased ovulation rates, clinical pregnancy recommended as associated
rates and live birth rates compared to with endometrial thinning.
clomiphene citrate.
Causes monofollicular development but rates
of twin gestation comparable to clomiphene
citrate.
Clomiphene citrate Starting dose: 50 mg once a day Contraindicated for use in pregnancy.
Earlier used as first line ovulation induction for 5 days on day 3, 4, or 5 or 6 Associated with multiple follicle
drug. of cycle. development.
FDA approved for ovulation induction. Maximum dose: 150mg Endometrial thinning and difficult
Dexamethasone when given with clomiphene implantation
citrate increases pregnancy and live birth Risk of multiple pregnancy
rates. comparable to letrozole
Induces ovulation in 80% women with a Live birth rates are lower than
pregnancy rate of 40%. letrozole
Gonadotrophins Low-dose therapy Higher risk of ovarian hyper
recommended stimulation syndrome and multiple
pregnancy
 11

Second line ovulation induction agents.

Used when letrozole or clomiphene citrate
fails
Ovarian drilling
Laparoscopic ovarian drilling may be done with laser or diathermy.
Low risk of multiple pregnancy
Effects may be temporary.
Long term effects on fertility unknown.
Does not improve metabolic dysfunction associated with PCOS
Metformin
Live birth rates rise when used in combination with clomiphene citrate
Role in preventing early pregnancy loss is unknown
Dose: 1500-2000 mg per day in divided doses
In vitro fertilization
Usually reserved for cases where other methods fail to achieve a pregnancy

1st line non-pharmacological treatment Lifestyle interventions

1st line pharmacological management for infertility

Letrozole
1st line therapy for ovulation induction

Clomiphene
citrate Clomiphene citrate
+ Metformin Metformin Gonadotrophins

2nd line pharmacological/ Surgical management

Gonadotrophins Laparoscopic Ovarian Surgery

3rd line management could be other appropriate interventions including IVF

Figure 3 Assessment and treatment of infertility

B. Therapy for menstrual disorders:

1. Combined hormonal contraceptives (CHC):

• Low-dose estrogen-progesterone CHC, are the recommended primary or first-line treatment for
menstrual irregularities associated with PCOS in women who are not considering pregnancy.
• CHC drugs work by suppressing LH and androgen secretion and increasing SHBG levels.
• The women with hyperandrogenism, CHC with antiandrogenic property are preferred. (
Cyproterone acetate, Drospirenon )
2. Insulin sensitizing agents (biguanides- metformin; thiazolidinediones- pioglitazone and rosiglitazone:
• Improved insulin sensitivity leads to a reduction in serum androgen levels, improved ovulation and
cycle regularity, and improved glucose tolerance.
• None of the antidiabetic drugs are approved by FDA for the treatment of menstrual irregularities
in PCOS.
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• Metformin is the preferred antidiabetic drug in PCOS.

Table 7 Mechanism of action of CHCs for their use in menstrual dysfunction in PCOS
Estrogen component of CHCs Progesterone component of CHCs
Increased hepatic SHBG production Supresses pituitary LH synthesis
Supresses androgen production
Decreases adrenal DHEA-S secretion
19-Nortestosterone derivatives reduce DHT
production
Fourth generation progesterone act as antiandrogens

Table 8 Various CHC, their compositions and dosing regimen.

Brand names Composition Regimen
MALA N (Supplied free of 21 white tablets of EE (30mcg) + LNG One tablet per day for 28 days.
cost at government hospitals (150mcg) + 7 brown tablets of ferrous Second pack to be restarted as
and dispensaries) fumarate (60 mg of elemental iron). soon as one pack is finished.
MALA D (INR 3/pack)
NOVELON EE (30mcg) + Desogestrel (150mcg)
FEMILON EE (20mcg) +Desogestrel (150mcg)
LOETTE EE (20mcg) + LNG (100mcg)
DIANETTE EE (35mcg) + Cyproterone acetate (2mg) One tablet per day for 21 days.
Fresh pack to be started after a
KRIMSON 35 EE (35mcg) + Cyproterone acetate (2mg) gap of one pill free week.

YASMIN EE (30mcg) + Drosperinone (3mg)

YAMINI EE (30mcg) + Drosperinone (3mg)
FREEDASE 30 EE (30mcg) + Dienogest (2mg)
*EE Ethinyl Estradiol, LNG Levonorgestrel

C. Therapy for reducing cardiovascular diseases and diabetes risk in women with PCOS:

1. Lifestyle modification:
• Regular exercise combined with dietary calorie restriction is the best approach to reducing the
metabolic risks through reducing central obesity, and improving insulin sensitivity.
• Weight loss of 5% to 10% over six months in overweight and obese individuals results in significant
clinical improvements
2. Insulin sensitizing agents:
• Metformin delays the development of diabetes in PCOS women with impaired glucose tolerance.
• It is recommended along with lifestyle modification in divided doses of 1500-2000 mg per day
• It can cause lactic acidosis with poorly controlled diabetes and renal dysfunction.
• The main side effects are diarrhoea, nausea, flatulence, bloating, and anorexia
3. Statins:
Beneficial in preventing long term metabolic complications of PCOS. Role in adolescent women with
PCOS is not well known
4. CHCs:
Low-dose CHCs are recommended

D. Therapy for hirsutism and hyperandrogenismi:

Treatment is palliative rather than curative

Combination therapy produces better results compared to single agent therapies
There is no clear primary treatment for hirsutism in PCOS. (Figure 4)
1. CHC:
• No CHC is FDA approved for hirsutism in PCOS
 13

• Oral CHCs combined with spironolactone may be beneficial

• Reduce the dose of spironolactone and monitor serum potassium levels in patients receiving CHCs
containing drospirenone, a progesterone with mineralocorticoid properties
2. Anti-androgens:
• Considered as second-line therapy of choice after CHCs for women with hyperandrogenism and
menstrual disorders
• None of the androgens have been approved by the FDA for hirsutism in PCOS
• Often used empirically
• Antagonize the binding of androgens to their receptors, or inhibit enzymes that convert less potent
forms of androgens into more potent ones.
3. Adjuvant cosmetic management of hirsutism:
These include mechanical methods of hair removal, electrolysis and laser therapy.
• Electrolysis involves cchemical destruction of the dermal papilla. It is not well studied and not
preferred.
• Laser and pulsed Light Therapies
❖ Uses laser or intense pulsed light to destroy hair follicles
❖ Selectively targets the hair bulb as the follicle melanin absorbs laser wavelength of light
❖ Darker hair and lighter skinned women show better results
❖ Therapy is planned during anagen phase of hair cycle
❖ Repeat treatment is usually required
❖ Concurrent antiandrogen treatment should be started to halt the conversion of vellus hair into
terminal hair and to prevent recurrence.
❖ Addition of eflornithine to laser therapy gives better outcomes over laser alone.
• Mechanical methods of hair removal
❖ No evidence to support that shaving increases hair density of thickness of hair shaft
❖ Plucking may be tried but there are associated risks of folliculitis, pigmentation and scarring.
4. Management of severe cases of hyperandrogenism should include appropriate referrals to a
dermatologist, medical endocrinologist, surgeons, reproductive endocrinologist or a gynecologic
oncologist.
5. Role of surgery
The role of surgery is not well defined for hyperandrogenism in PCOS
 14

Table 9 Treatment options for hirsutism

Methods of hair removal
A. Antiandrogens
Antiandrogens and their mechanism of action Dose Side effects
Spironolactone 25 to 100 mg Orthostatic hypotension
Competitive antagonism of androgen receptors in hair twice daily Increased menstrual frequency
follicles Full effect takes 6 months or more for the
Inhibits ovarian and adrenal steroidogenesis effect
Inhibition of 5-α-reductase activity Aldosterone Hyperkalemia
antagonist Teratogenic (feminization of the external
genitalia/ambiguous genitalia in male
fetuses)
Cyproterone acetate One tablet per
It is a derivative of 17α-hydroxyprogesterone (17OHP) day for 21
Has potent progestogenic activity that inhibits days. Restart
gonadotropin secretion. fresh pack
It is the progestin component of CHC ‘DIANTTEE/ after a gap of
KRIMSON 35MG 21S/ CARPELA 21S/ DIANE 35’ 7 pill free day.
containing 35 mcg EE and 2 mg CPA (in blister packs of
21 tablets).
Finasteride 5mg tablet for Better tolerated than other antiandrogens
Inhibits both type 1 (found in the skin) and type 2 prostate Minimal hepatotoxicity and renal toxicity
(found in the prostate and reproductive tissues, 5-α- cancer Teratogenic
reductase enzymes, hence blocks conversion of 1 mg tablet for
testosterone to more potent Dihydrotestosterone. male alopecia
Flutamide 125 to 250 mg Dry skin (most common)
Nonsteroidal androgen-receptor agonist per day Significant risk of teratogenicity
Antiandrogenic action Hepatitis (rare)
Used primarily in males for prostate cancer
May have additive effect when combined with life style
changes and metformin therapy in treatment of PCOS
Eflornithine hydrochloride cream, 13.9% (VANIQA) Local Local side effects- Stinging, burning,
Inhibits the enzyme ornithine decarboxylase application erythema, and rarely rash
FDA approved for the treatment of hirsutism twice a day
Addition to laser therapy improves success rates
B. Insulin sensitizing agents
No or little benefit of metformin or thiazolidinediones in treatment of hirsutism
C. Adjuvant cosmetic management of hirsutism
Mechanical hair removal (shaving, plucking, waxing, depilatory cream)- the first line treatment used by women
Electrolysis
Laser vaporisation
*EE Ethinyl oestradiol, CPA Cyproterone acetate

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ovary syndrome (PCOS) among infertile Sudanese women: a cross-sectional study. BMC Women's Health.
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international evidence-based guideline for the assessment and management of polycystic ovary
syndrome. Hum Reprod. 2018;33:1602–18.
6. Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to
polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.
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