Polycystic ovarian syndrome

Abstract

Polycystic ovarian syndrome (PCOS) is a "multispeciality" disorder suspected in patients with irregular menses and clinical signs of hyperandrogenism such as acne, seborrhoea, hirsutism, irregular menses, infertility, and alopecia. Recently, PCOS has been associated with the metabolic syndrome. Patients may develop obesity, insulin resistance, acanthosis nigricans, Type 2 diabetes, dyslipidemias, hypertension, non-alcoholic liver disease, and obstructive sleep apnoea. Good clinical examination with hematological and radiological investigations is required for clinical evaluation. Management is a combined effort involving a dermatologist, endocrinologist, gynecologist, and nutritionist. Morbidity in addition includes a low "self image" and poor quality of life. Long term medications and lifestyle changes are essential for a successful outcome. This article focuses on understanding the normal and abnormal endocrine functions involved in the pathogenesis of PCOS. Proper diagnosis and management of the patient is discussed.

Full text

Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3310
Polycystic ovarian syndrome
Nina Madnani, Kaleem Khan, Phulrenu Chauhan
1
, Girish Parmar
1
ABSTRACT
Polycystic ovarian syndrome (PCOS) is a “multispeciality” disorder suspected in patients
with irregular menses and clinical signs of hyperandrogenism such as acne, seborrhoea,
hirsutism, irregular menses, infertility, and alopecia. Recently, PCOS has been associated
with the metabolic syndrome. Patients may develop obesity, insulin resistance, acanthosis
nigricans, Type 2 diabetes, dyslipidemias, hypertension, non‑alcoholic liver disease, and
obstructive sleep apnoea. Good clinical examination with hematological and radiological
investigations is required for clinical evaluation. Management is a combined effort involving
a dermatologist, endocrinologist, gynecologist, and nutritionist. Morbidity in addition includes
a low “self image” and poor quality of life. Long term medications and lifestyle changes are
essential for a successful outcome. This article focuses on understanding the normal and
abnormal endocrine functions involved in the pathogenesis of PCOS. Proper diagnosis and
management of the patient is discussed.
Key words: Hyperandrogenemia, hyperandrogenism, insulin resistance, metabolic syndrome,
polycystic ovary
Departments of Dermatology,
and 1Endocrinology,
P. D. Hinduja National
Hospital, Mahim, Mumbai,
India
Address for correspondence:
Dr. Nina Madnani,
Department of Dermatology,
P. D. Hinduja National
Hospital, Veer Savarkar
Marg, Mahim,
Mumbai ‑ 400 016, India.
E‑mail:
ninamadnani@gmail.com
How to cite this article: Madnani N, Khan K, Chauhan P, Parmar G. Polycystic ovarian syndrome. Indian J Dermatol Venereol Leprol
2013;79:310‑21.
Received: October, 2012. Accepted: December, 2012. Source of Support: Nil. Conict of Interest: None declared.
INTRODUCTION
In 1935, Stein and Leventhal reported a series of 7
women who presented with oligo/amenorrhoea,
hirsutism, obesity, infertility, and bilateral polycystic
ovaries (Stein‑Leventhal syndrome).[1] Bilateral
wedge resection of the enlarged ovaries was
therapeutic in normalizing the menses and fertility
of the women studied. They concluded that there
was a primary ovarian defect, and the disorder was
known as polycystic ovarian disease (PCOD). Today,
PCOD has been associated with various metabolic
disorders, and is now known as polycystic ovarian
syndrome (PCOS). Following terminologies are
important for better understanding of the clinical
syndrome:
• Hyperandrogenemia is the presence of
abnormally high amounts of androgens
detectable in the blood circulation.
• Hyperandrogenism is the clinical manifestation
of excessive androgen production/secretion,
characterized by oligo/amenorrhoea, infertility,
acne, seborrhoea, hirsutism, and alopecia.
• Cutaneous hyperandrogenism is considered
when there is no documented evidence of
hyperandrogenemia but the clinical signs of
hyperandrogenism are present.
• Hypertrichosis is the presence of excessive hair
in non‑androgen dependent areas.
• Hirsutism is the presence of excess and coarse
terminal hairs in a male‑pattern distribution,
such as upper lip, chin, cheeks, shoulders,
abdomen, lower back and inner thighs.
• Polycysticovariandisease(PCOD)wasdescribed
by Stein and Leventhal[1] in women with oligo/
amenorrhoea, hirsutism, obesity, infertility
and bilateral polycystic ovaries, managed with
wedge ovarian resection.
• Polycystic ovarian syndrome (PCOS) is
PCOD+ metabolic disease.
PCOS is a common disorder with an
incidence varying from 5% to 10%. It is
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Madnani, et al. Polycystic ovarian syndrome
311Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
observed in women of child‑bearing age
across all cultures, and ethnicities.[2] A
prospective study of Indian adolescents
reported an incidence of 9.13%.[3]
The common features of PCOS are
irregular or anovulatory cycles with signs
of hyperandrogenism like acne, seborrhoea,
hirsutism, alopecia, frank virilization, and
with polycystic ovaries on pelvic sonography.
Recently, PCOS has been associated
with obesity, insulin‑resistance (IR) and
a risk of developing Type 2 diabetes
mellitus (T2DM).[4] The metabolic and
reproductive abnormalities have predisposed
women to develop infertility and endometrial
cancer, necessitating early diagnosis
and appropriate treatment.[5] A better
understanding of the complexities involved
in PCOS necessitates the understanding of
what is “normal ovulation”.
• Anormalovulatorycycleismaintainedduetoa
complex interplay of hormones secreted from the
pituitary, hypothalamus, adrenals, and ovaries.
Up‑regulation or down‑regulation of these
hormones is carried out by an efficient feed‑back
mechanism to maintain equilibrium [Figure 1].
The hypothalamus secretes gonadotropin
releasing hormone (GnRH) in a fixed, pulsatile
manner. This acts upon the cells of the anterior
pituitary to secrete two important hormones,
the follicle stimulating hormone (FSH) and the
leutinising hormone (LH), both targeting the
follicles in the outer cortex of the ovary which
are in various stages of development. FSH
secretion is regulated by a negative feedback
from estradiol, inhibin and progesterone. The
inner lining of the ovarian follicles is composed
of granulosa cells and theca cells. Receptors for
FSH are exclusively present on the granulosa
cells. Under the influence of FSH, the follicles
are recruited, but only one developing follicle
undergoes maturation to become the dominant
or graffian follicle. Interestingly, early stages of
follicular development up to 2 to 5 mm seem
to be independent of the need for FSH. FSH
is also essential for induction of aromatase
activitywithinthegranulosacells.LHreceptors
are expressed by the theca cells of all follicles
and the granulosa cells of large pre‑ovulatory
follicles. It is the stimulation of the latter
receptors by the LH surge seen in mid‑cycle,
which is responsible for ovulation. Estradiol has
a positive feedback response for LH release at
thelevelof pituitary.Also, LHplaysa vitalrole
in androgen production by the theca cells.
OVARIAN STEROIDOGENESIS
Cholesterol, the precursor for steroid synthesis in the
ovaries, undergoes a series of conversions to form
androstenedione (enzymes 3β‑HSD, 17α‑hydroxylase
and 17, 20–lyase mediate this conversion).
Androstenedione gets converted to testosterone (by
17β‑HSD)andtoestrone(byaromatase)inthegranulosa
cells [Figure 2]. The ovaries produce 25% of circulating
Figure 1: Feedback mechanism for a normal menstrual cycle
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the outer layer. Granulosa cells are dependent on the diffusing
androstenedione from the theca cells for substrate as they are not
in direct connection with the circulation (Two cell hypothesis). All
steroid hormones are derived from cholesterol. Its entry into the
mitochondria is mediated by StAR (Steroidogenic acute regulatory
protein) and is the rate limiting step in ovarian steroidogenesis
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Madnani, et al. Polycystic ovarian syndrome
Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3312
testosterone,whichisdependentonLHsecretedbythe
anterior pituitary. The ovaries also secrete 50% of the
androstenedione and 20% of dehydroepiandrosterone
(DHEA)[Table1].Testosteroneisusedasamarkerof
ovarian androgen secretion.
EXTRA OVARIAN STEROIDOGENESIS
The adrenals synthesize androgens from cholesterol,
under the influence of adreno corticotropic hormone
(ACTH) (secreted by the anterior pituitary), through
multiple steps. The adrenal androgens consist of all
the dehydroepiandrosterone sulphate (DHEAS) and
80% of the DHEA. The adrenals also secrete 50% of
androstenedione and 25% of circulating testosterone.
DHEAS and 11‑androstenedione are not secreted
by the ovaries, and therefore are used as markers
of adrenal androgen secretion. Both prolactin and
estrogen can affect adrenal androgen production.
The peripheral tissues like the skin, liver, and
adipose tissue also take part in androgen synthesis by
converting the weaker androgens to the more potent
ones. Androgen receptor‑activation takes place only
withtestosteroneanddihydrotestosterone(DHT).25%
of the circulating testosterone is produced individually
by the ovaries and adrenals. The remaining 50% by
the peripheral conversion of androstenedione.[6] Only
1% of the androgens produced circulates freely. Of the
remaining 99%, 80% is bound to sex hormone binding
globulin(SHBG),and18%toalbumin.IfSHBGlevels
are reduced, the amount of free circulating testosterone
increases. DHEAS, DHEA and androstenedione are
bound to albumin and freely available to tissues.
There is no regulatory feedback mechanism in both
the adrenals and ovaries in response to androgen
production.
ROLE OF INSULIN
Insulin plays an important role in the normal ovarian
cycle in the following ways: It enhances the amplitude of
LHpulsesatthelevelofpituitary,butnottheirfrequency.
It modulates the LH‑mediated androstenedione
production in theca cells and FSH‑mediated estradiol
production in granulosa cells, probably by increasing
ovarian cytochrome P457 enzyme activity. In the liver,
increased insulin levels inhibit production of sex
hormonebindingglobulin(SHBG).It inhibits hepatic
production of IGFBP‑1 which results in increased levels
of circulating IGF‑1 (Insulin like growth factor 1) levels.
It binds to the IGF‑1 receptors on the ovary and directly
stimulates androgen production.[7]
EVOLUTION OF POLYCYSTIC OVARIAN SYNDROME
The key steps in the evolution of PCOS are enumerated
below, but not necessarily in chronological order.
Pituitary dysfunction
There is an increase in the frequency and amplitude
ofGnRHpulsewhichresultsinelevatedlevelsofLH.
However, whether this alteration in LH secretion is
due to an intrinsic defect of the hypothalamus or due
to external factors such as loss of negative feedback
mechanism from the ovary, or increase in insulin
levels, remains an unresolved debate. Excessive
secretion of LH has traditionally been considered as
ahallmarkofclassicPCOS.AnLH/FSHratioofmore
than 2 especially in obese women is significant.
Enhanced ovarian androgen production
AbnormalLHinfluenceonthethecalcellsoftheovaries
results in overproduction of androgens. However,
all patients of PCOS do not have elevated levels of
LH but still have elevated levels of androgens. This
can be explained on the findings that ovarian thecal
cells of women with PCOS have elevated CYP17 gene
expression. The encoded enzyme (P450c17) is capable of
both, 17‑hydroxylation and 17, 20‑layse functions which
is a key step in ovarian steroidogenesis.[8] Neelson et al.,
in 2001 showed that the p450c17 and 3β‑HSDenzyme
activity is disproportionately higher in the thecal cells
of PCOS women as compared to normal women. So, the
enhanced production of testosterone precursors is the
probably the cause of elevated androgen levels.
Development of insulin resistance
Women with PCOS have decreased sensitivity to
circulating insulin irrespective of weight (obesity),
thus suggesting that this insulin insensitivity is
intrinsic to PCOS.[9] This has been attributed to
a defect in phosphorylation of tyrosine kinase
in the insulin receptor. Normally, tyrosine
autophosphorylation increases the insulin ‑ mediated
Table 1: Source of circulating hormones (approximate
concentration)
Site Testosterone
(%)
DHEA
(%)
Androstenedione
(%)
DHEAS
(%)
Ovaries 20 20 50 -
Adrenals 25 80 50 100
DHEAS: Dehydroepiandrosterone sulfate, DHEA-Dehydroepiandrosterone
sulfate

Madnani, et al. Polycystic ovarian syndrome
313Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
metabolic changes within muscle and adipose cells.
Serine phosphorylation inhibits this action. Also,
serine phosphorylation has a stimulatory effect on
17,20‑lyase enzyme activity in the ovaries which is
responsible for production of androstenedione. Up
to 50% of women with PCOS have a genetic defect
coding for serine phosphorylation of insulin receptors.
The resulting increased insulin levels, directly and
indirectly, increase androgen production.[10] So
conversely, a reduction in serum insulin levels should
result in reduction in androgen levels.
ETIOPATHOGENESIS
Although the exact etiology is unknown, PCOS is a
multi‑factorial disease with a strong genetic influence.
Various animal models have been used to understand
the pathophysiology of PCOS. Each model has its own
limitation but rodents are the most widely used.[11]
Others include mice, rhesus monkeys, ewes and more
recently, sheep. These models have provided evidence
that intra‑uterine fetal exposure to androgen excess is
associated with development of PCOS in later life.[12]
Genetic basis of this disease can be seen from studies
evaluating the genetic pool of patients with PCOS.
Legro and colleagues studied the siblings of 80 patients
diagnosed with PCOS. Out of a total of 115 sisters,
46% had evidence of hyperandrogenemia and amongst
them, almost half fulfilled the criteria for PCOS. It was
also noted that brothers of the patients with PCOS had
increasedlevelsof DHEASwhencompared withage
matched controls.[13] Fathers of adolescent girls have
a very high incidence of obesity (94%) and metabolic
syndrome (79%). Also, mothers of such patients tend
to be obese (54.4%) or overweight (11.4%) with the
incidence of metabolic syndrome being 34%.[14]
CLINICAL FEATURES
The patient seeks a dermatology consultation for one
or more complaints like acne, hirsutism, alopecia,
acanthosis nigricans, skin tags and occasionally,
darkening of complexion with weight gain. If
irregular menstrual cycles or primary infertility
are the main complaints, the patient may consult a
gynaecologist. An endocrinologist may be consulted
for hirsutism and the metabolic syndrome. Very rarely
do patients present with all the clinical signs and
symptoms of PCOS and some may not be forthcoming
with information of concurrent treatment from a
gynaecologist or an endocrinologist. An alert clinician
should be able to link the symptoms together, pointing
to a possible underlying defect of hyperandrogenism.
Acne vulgaris
Patients with PCOS complain of inflammatory acne
minimally responsive to conventional line of treatment.
Even if responsive, lesions promptly recur on
stopping treatment, necessitating treatment with oral
isotretinoin and/or hormonal therapy. An important
feature seen in these patients is the development of
multiple closed comedones which rapidly transform
into tender, lumpy nodules, distributed in the lower
half of face and jaw‑line (V distribution) [Figure 3].
These tend to persist beyond the usual course of
5‑7 days. A pre‑menstrual flare is also common. Acne
lesions may not only be localized to the face, but may
also be present on the chest, shoulders and back.
Prompt relapse after stopping the treatment, strongly
suggests a hormonal basis. Patients may in addition,
have a history of irregular periods, and evidence of
hirsutism, alopecia, or a positive family history of
PCOS. The severity of hirsutism may not be matching
the severity of acne, and would be dependent on the
balance of activity between the alfa‑hydroxy type 2
vis‑a‑vis type 1.[15]
Hirsutism
Excessive facial hair is a racial trait for the Indian
sub‑continent, running within families and especially
strong in certain ethnic groups. This should be kept
in mind while evaluating patients complaining of
excessive facial/body hair. Androgens affect various
aspects of follicular activity. Acting via androgen
receptors and secretory factors, they increase the
growth rate, diameter and melanization of hair in
androgen‑sensitive areas. It is these thick, coarse,
terminal hair, in androgen‑dependent areas which are
unsightly on a female[16] and point to an underlying
hyper‑androgenic state [Figure 4]. Evaluation of the
degree of hirsutism is done by adopting a modified
Ferriman‑Galway score which evaluates 9 body areas
on a scale of 1 to 4. The total scores are significant if
more than 6 to 8.[15,17]
Alopecia
Notallcases of femalepatternhair loss (FPHL)may
be of androgenic origin.[18] Patterned hair loss in PCOS
may be difficult to distinguish from those secondary
to other hyperandrogenic states [Figure 5]. Various
clinical presentations include those described by
Ludwig (diffuse), Hamilton (male pattern), and
Olsen (frontal accentuation).[18] Women with early

Madnani, et al. Polycystic ovarian syndrome
Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3314
onsetFPHLaremuchmorelikelytohaveanassociated
hyperandrogenism. Hormonal influences convert
terminal to vellus hair, making the scalp appear bald.
Acanthosis nigricans
Typically thick dark velvety skin situated on the
nape of the neck, axillae, groins and other frictional
areas may often be the first clue of insulin resistance
[Figure 6]. The thickening occurs due to the
stimulation of tyrosine kinase growth factor ‑
signaling pathways in the epidermis. Insulin ‑ like
growth factor receptor 1 (IGF1R) is present in many
tissues including the epidermis and ovary. High
levels of insulin directly or indirectly stimulate the
IGF1R resulting in the skin changes. Skin tags in the
frictional areas like the neck, axillae, groins, infra
mammary or even under a pendulous abdominal
fold are common, especially in obese individuals.
Irregular menses and infertility
PCOS is characterised by chronic menstrual
irregularities or changes in menstrual pattern with
reduced fertility. The anovulatory or oligoovulatory
cycles result in continuous endometrial stimulation
with estrogens, resulting in endometrial hyperplasia,
thus increasing the risk of endometrial cancers.[19]
Metabolic complications
The incidence of type 2 Diabetes and gestational
diabetes is markedly increased in both lean and obese
women with PCOS.[4] Other morbidities include sleep
apnoea, non‑alcoholic liver disease, hypertension
and dyslipidemia. The increased incidence of
cardiovascular disease although probable, is still not
supported in controlled studies.
QUALITY OF LIFE ISSUES
Dokras et al. did a meta‑analysis and systematic review
of studies comparing anxiety symptoms in women
with PCOS compared to normal, and concluded that
all women with PCOS should be screened for anxiety
symptoms.[20]
Figure 4: Hirsutism in a patient with PCOS
Figure 6: Acanthosis nigricans and hirsutism in an obese girl
with PCOS
Figure 5: Patterned hair loss with bi‑temporal recession in a
patient with PCOS
Figure 3: Acne with hirsutism in a patient with PCOS

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DIAGNOSTIC CRITERIA
Since 1990, various bodies have laid down criteria for the
diagnosis of PCOS, based on oligo or anovulation, signs
of hyperandrogenism, and ovarian sonography [Table 2].
As mentioned in the Rotterdam diagnostic criteria,
important causes of androgen excess must be ruled
out before diagnosing PCOS and investigations
should be directed towards detecting these conditions
like late‑onset congenital adrenal hyperplasia,
hyperprolactinemia, pituitary tumors, ovarian tumors,
etc., [Table 3]. When a diagnosis of PCOS is made, it is
almost one of exclusion.
Hormonalevaluationshouldbedoneinthepre‑ovulatory
phase. Since the levels of various hormones fluctuate
considerably with a single menstrual cycle, it is best to
carry out investigations in a fixed time within the cycle.
The fourteenth day seems ideal, but since most patients
have anovulatory or irregular cycles, the only fixed
window for investigation would be immediately after
the menstrual bleeding begins i.e. between the second
tofourthdayofthecycle.Normally,inthisphase,FSH
levelsare3to4timeshigherthanLH, butin patients
withPCOS,thisisreversedandaLH/FSHratiogreater
than 2 is very suggestive of pituitary dysfunction.
A highly raised serum testosterone level (more than
3 times the upper normal range) is very suggestive of a
neoplasm. If level of androstenedione is concomitantly
elevated, it is almost diagnostic of an ovarian or
adrenal malignancy, the former being much more
frequent than the latter. Hence all patients with
severely raised testosterone levels must undergo a
trans‑vaginal ultrasound to rule out any ovarian tumor.
Adrenal tumors are more virilising and are associated
with increased levels of DHEAS (>8 mmol/ml). The
raised testosterone levels in such cases is secondary
to increased peripheral conversion. A CT scan of the
abdomen is the investigation of choice to rule out
adrenal tumors.
Non‑classical adrenal hyperplasia (NCAH) is a very
close mimic to the PCOS and an 8:00 am serum
17‑hydroxyprogesterone level should be done in
suspected cases (normal is<2 ug/ml). While a level of
more than 8 ug/ml is diagnostic, it is the range in between
(2‑8 ug/ml) which requires further investigation.[21]
Prolactinoma may be an important cause for androgen
excess. Although elevated plasma prolactin levels
are highly suggestive of a prolactinoma, other causes
of hyperprolactemia like hypothyroisim, Cushing’s
disease, medications, etc., should be ruled out. Isolated
increase in prolactin level is not uncommon in today’s
stressful life, and its significance should be in context
with the clinical presentation.
Insulin levels may be increased in a majority of patients
with PCOS. The hyperinsulinemic‑euglycemic clamp
technique is gold standard for assessing insulin sensitivity,
but is impractical in everyday practice. Rather, a ratio of
fasting glucose to fasting insulin is a simple and effective
alternative. A ratio of less than 7 is highly suggestive of
a hyperinsulenemic state. In the authors’ experience,
a fasting serum insulin level more than 15, and serum
insulin level post 75gm glucose of more than 25 can also
serve as a rough guide to a hyperinsulinemic status.
In 2003, Rotterdam criteria was the first to introduced
the role of ultrasound examination of the ovaries as a
diagnostic criteria. Although ovarian morphology is
better depicted on trans‑vaginal ultrasound examination,
trans‑abdominal ultrasound examination is preferred in
adolescents and mandatory in unmarried women. Unlike
blood investigations, the ultrasonography (USG) may be
performed during any phase of the menstrual cycle but
to avoid any confusion with a dominant follicle, it is
best performed within few days of menstrual bleeding.
Table 2: Various diagnostic criteria dened for PCOS
Criteria NIH 1990 Rotterdam 2003 Androgen Excess Society 2006
Diagnostic criteria Must include Two of following three Must include
Chronic anovulation 1. Oligo/anovulation Ovarian dysfunction
Oligo/anovulation
Polycystic ovaries on USG
Clinical and/or biochemical
signs of hyperandrogenism
2. Clinical and/or biochemical
signs of hyperandrogenism
Androgen Excess
Hirsutism
hyperandrogenemia
3. Polycystic ovaries on USG
All criteria assume that other causes of androgen excess have been ruled out, PCOS: Polycystic ovarian syndrome

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Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3316
The USG classically shows multiple subcentimeter
cysts (>12, 2‑9 mm) within the ovaries [Figure 7]. The
“string of pearls” appearance (peripheral arrangement
of the follicles surrounding a central echogenic stroma),
though characteristic, is not a requirement for diagnosis.
The other ultrasonographic feature is that the volume
of the ovaries should be each more than 10cc. These
changes need not be seen in both ovaries to make a
diagnosis of polycystic ovaries.
Investigations must be done to rule out underlying
metabolic abnormality and include blood sugars
and lipid profile. Physical evaluation must include
BMI (wt/ht2) calculation and whether patient has
central obesity (waist: hip ratio), as these patients are
at a higher risk of developing metabolic syndrome.[22]
PCOS MANAGEMENT
PCOS is a highly prevalent heterogeneous syndrome
of clinical and/or biochemical androgen excess,
ovulatory dysfunction and polycystic ovaries (PCO).
Despite it being one of the most common reproductive
health problems of women, its effective treatment
remains a significant challenge to medical profession.
Treatment of women with PCOS tends to be symptom
based. It is often difficult to treat all complaints at
the same time. The most difficult one is the desire
to treat both anovulatory infertility and hirsutism
concurrently. Oral contraceptives are contra‑indicated
in infertility treatments because they block ovulation
and anti‑androgens in view of their potential
teratogenic effects in a male fetus. Because of these
conundrums in clinical care, treatment tends to fall
into two categories, either the treatment of anovulatory
infertility or the long term maintenance treatment for
PCOS related symptoms (i.e., hirsutism, menstrual
disorders, obesity, etc.).
LONG TERM MAINTENANCE OF PCOS
The term maintenance acknowledges the fact that
there is no known cure for PCOS. Often the triad of
hirsutism, oligomenorrhea, and obesity forms the key
presenting symptoms. It may make sense to choose
a primary metabolic parameter upon which to base
initial treatment. Glucose intolerance is the strongest
risk factor for diabetes and is also an independent
risk factor for cardiovascular events in these women.
Additional targeted therapies for hirsutism and/
or oligomenorrhea could be added depending on
response to the initial therapy. Contraception should be
considered if the patient is trying to avoid pregnancy.
THERAPIES AIMED AT IMPROVING INSULIN SENSITIVITY
TO TREAT ANOVULATION AND ANDROGEN EXCESS
A logical approach to the management of PCOS
includes using life style measures and medications that
improve insulin sensitivity in target tissues, achieving
reductions in insulin secretion, and stabilizing glucose
tolerance.
Figure 7: Ultrasound image of both ovaries showing multiple
follicles arranged peripherally, giving a “string of pearls”
appearance
Table 3: Important investigations to be done in suspect
cases of PCOS
Name of Investigation Signicance
Lipid prole May be deranged in metabolic syndrome
Blood sugar (fasting) May be deranged in metabolic syndrome
Blood sugar (post
75 gm glucose)
May be deranged in metabolic syndrome
Insulin (fasting) >12 mIU/ml suggestive of insulin
resistance
Insulin (Post 75 gm
glucose)
>25 mIU/ml suggestive of insulin
resistance
TSH Hypothyroidism may cause oligo/
amenorrhoea
FSH/LH ratio Normally FSH> 3-4 LH
Reversal of ratio signicant
Total testosterone >3.6 ng/ml signicant
Androstenedione Elevated in ovarian pathology
Prolactin May be raised in PCOS but very high
levels indicate a pituitary tumor
17 hydroxy progesterone Elevated in late-onset CAH
DHEAS Elevated in adrenal pathology
DHT Indicative of peripheral conversion of
testosterone
Ultrasonography of
pelvis
Volume of atleast 1 ovary more than
10 cc with “string of pearl“ appearance
PCOS: Polycystic ovarian syndrome

Madnani, et al. Polycystic ovarian syndrome
317Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
Lifestyle modication
The gold standard for improving insulin sensitivity
in obese PCOS women should be weight loss, diet,
and exercise. It is recommended as the first line of
treatment in obese women who present with infertility.
Hypo‑caloricdietsresultinappropriateweightlossin
women with PCOS. Unfortunately, there have been few
studies on the effect of exercise alone on symptoms in
PCOS women,[23] although it is reasonable to assume
that exercise would have the same beneficial effects
in women with PCOS as it does in women with type 2
DM.Howevertheexerciseprogrammustbetailoredto
the degree of obesity, and the patient’s baseline fitness.
Biguanide
Metformin may be most useful in the long term
maintenance of PCOS. Metformin does lower serum
androgens, and improves ovulatory and menstrual
frequency.[24] One study estimated that menstrual
frequency improved by roughly a third from baseline.
Metformin is the drug of choice to treat glucose
intolerance and elevated diabetes risk in women with
PCOS. Its use throughout pregnancy has shown to have
beneficial effects in reducing early pregnancy loss and
have a favorable effect on plasma glucose levels and
other metabolic aspects.[25] Metformin is also associated
with weight loss in women with PCOS, although the
results in other populations are inconsistent. Metformin
is often used in conjunction with lifestyle therapy to treat
PCOS. Gastrointestinal symptoms (diarrhea, nausea,
vomiting, abdominal bloating, flatulence, and anorexia)
are the most common adverse reactions and may be
ameliorated by starting at a small dose and gradually
increasing the dose or by using the sustained‑release
versions. The dose is usually 1500‑2000 mg/day given
in divided doses. Metformin carries a small risk of lactic
acidosis, most commonly among women with poorly
controlled diabetes and impaired renal function. Other
reported side effects include vitamin B12 deficiency,[26]
peripheral neuropathy,[27] and even hepatotoxicity.[28]
Thiazolidinediones
Pioglitazone and rosiglitazone are pharmacological
ligands for the nuclear receptor peroxisome proliferator
activated receptor γ (PPARγ). They improve the action
of insulin in the liver, skeletal muscles, adipose
tissue and have only modest effect on hepatic glucose
output. Improving insulin sensitivity with these drugs
is associated with a decrease in circulating androgen
levels, improved ovulation rate, and improved
glucose tolerance.[29‑32] However the concern about
hepatotoxicity, cardiovascular risk, weight gain, and
the pregnancy category C have limited the use of these
drugs in women with PCOS.
THERAPIES AIMED AT TREATING OLIGOMENORRHEA
If the patient does not wish to conceive, medical
therapy is directed towards interruption of the
effect of unopposed estrogen on the endometrium.
Nonfluctuating levels of unopposed estradiol in
the absence of progesterone cause irregular uterine
bleeding, amenorrhea, infertility and increased risk of
endometrial cancer.
Combination of oral contraceptives
Oral contraceptives have been the mainstay of long‑term
management of PCO. They offer benefit through a variety
ofmechanisms,includingsuppressionofpituitaryLH
secretion, suppression of ovarian androgen secretion,
and increased circulating SHBG levels. Individual
OC preparations may have different doses and drug
combinations and thus have varying risk–benefit ratios.
Most oral contraceptives (OC) preperations contain
estrogen (ethiny lestradiol 0.030 mg) in combination
with anti‑androgens. Anti‑androgens include
cyproterone acetate, drosperinone, levonorgestril,
norgestimate and desogestril. The “best” oral
contraceptive for women with PCOS is unknown.
Because women with PCOS may have multiple
risk factors for serious adverse events on oral
contraceptives, they must be screened carefully
for risk factors for these events including smoking
history, presence of obesity and hypertension, and
history of clotting diathesis to mention some of the
important factors. There is no convincing evidence
that use of oral contraceptives contributes to the risk
of diabetes in women with PCOS, although there are
often adverse effects on insulin sensitivity that may
be dose dependent.[33] A low dose oral contraceptive
pill is therefore recommended. Oral contraceptives
may also be associated with a significant elevation
in circulating triglycerides as well as in high density
lipoprotein(HDL)levels,thoughthesedonotappearto
progress over time. There is no evidence to suggest that
women with PCOS experience more cardiovascular
events than the general population when they use
oral contraceptives. If a woman is taking an oral
contraceptive that contains drospirenone, a progestin
with anti‑mineralocorticoid properties, it may be
necessary to reduce her dose of spironolactone if used
concomitantly. Regular evaluation of potassium levels
are necessary.

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Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3318
Progestin
Both depot and intermittent oral medroxyprogesterone
acetate (10 mg for 10 days) have been shown to suppress
pituitary gonadotropins and circulating androgens in
women with PCOS.[34] No studies have addressed the
long‑term use of these compounds to treat hirsutism.
There is also a paucity of data to address the varying
risk benefit ratios of varying classes of progestins.
Progestin‑only oral contraceptives are an alternative
for endometrial protection, but they are associated
with a high incidence of breakthrough bleeding.
THERAPIES AIMED AT TREATING HIRSUITISM
No oral contraceptive has been approved by the
FDA for the treatment of hirsutism. A number of
observational or non‑randomized studies have noted
improvement in hirsutism in women with PCOS who
use oral contraceptives, but no studies of adequate
power confirm their benefit in improving hirsutism in
PCOS.[35]
Spironolactone
It is primarily used to treat hirsutism and appears
effective, though the evidence is weak. It is a diuretic
and aldosterone antagonist, also binds to the androgen
receptor as an antagonist. It has other mechanisms of
action, including inhibition of ovarian and adrenal
steroidogenesis, competition for androgen receptors in
hair follicles, and direct inhibition of 5 alpha reductase
activity. The usual dose is 25–100 mg twice a day, and
is titrated to balance efficacy while avoiding side effects
such as orthostatic hypotension. A full clinical effect
may take 6 months or more. About 20% of women using
spironolactone will experience increased menstrual
frequency.[36] Because it can cause and exacerbate
hyperkalemia, spironolactone should be used cautiously
in women with renal impairment. Rarely, exposure has
resulted in ambiguous genitalia in male infants.
Cyproterone acetate
It is a progestogen with anti‑androgen properties. It is
frequently combined in an oral contraceptive tablets and
is popular in the treatment of PCOS. A newer progestin
from the same class, drospirenone has been marketed
in the U.S. as especially effective for the treatment of
female hyperandrogenism, although the data suggesting
this is superior to other formulations is not based on
head to head randomized trials.[37] When given as
100mg/day, it inhibits testosterone production resulting
in upto 75% decrease in circulating testosterone levels.
Flutamide
It is an androgen‑receptor antagonist, and is another
non steroidal anti‑androgen that has been shown to be
effective against hirsutism in smaller trials The most
common side effect is dry skin, but its use has been
associated with hepatitis in rare cases. The common
dosage is 250 mg/day. The risk of teratogenicity with
this compound is significant, and contraception
should be used. Flutamide has also been combined
with lifestyle and metformin therapy for treatment of
PCOS and may have additive effects.[38]
Finasteride
It is a specific inhibitor of type II 5α reductase enzyme
found in the hair follicles on the top of the scalp and
in the sebaceous gland ducts. Its use is restricted to
women in the post‑menopausal group or women with
documented hyperandrogenic state in the dosage of
5 mg/day. Finasteride is better tolerated than other
anti‑androgens, with minimal hepatic and renal
toxicity; however, it has well‑documented risk for
teratogenicity and feminising in a male fetuses, and
adequate contraception should be used. Overall,
randomized trials have found that spironolactone,
flutamide and finasteride to have similar efficacy in
improving hirsutism.
Ornithine decarboxylase inhibitors
These have been developed for the treatment of female
hirsutism. Ornithine decarboxylase is necessary
for the production of polyamines, and inhibition of
this enzyme limits cell division and function in the
pilosebaceous unit. Recently a potent inhibitor of this
enzyme, eflornithine, has been found to be effective
as a facial cream for the treatment of unwanted facial
hair.[39] It is available as a 13.9% cream of eflornithine
hydrochloride, and is applied to affected areas twice
daily. In clinical trials, 32% of patients had marked
improvement after 24 weeks compared to 8% of
placebo treated women, and the benefit was first
noted at eight weeks. It is pregnancy category C drug.
It appears to be well tolerated, with only about 2% of
patients developing skin irritation or other adverse
reactions. Relapse is common after stopping.
Mechanical and cosmetic means of hair reduction and
destruction
Mechanical hair removal techniques like shaving,
plucking, waxing, depilatory creams, electrolysis, and
laser hair reduction (LHR) offer good cosmetic relief
and often are the front line of treatment used by women.
A word of caution regarding facial waxing as it can

Madnani, et al. Polycystic ovarian syndrome
319Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3
precipitate folliculitis. Various lasers are used for hair
reduction and include the Diode (800nm), Alexandrite
(755 nm), Long pulsed Nd‑YAG (neodymium‑doped
yttrium aluminium garnet; Nd: Y3Al5O12) (1064nm)
andIPLdevices.Thereis no“goldstandard”forLHR
but the long pulsed Nd‑YAG is the safest in pigmented
skins. It must be emphasized that LHR would be
effective only after anti‑androgen therapy has been
initiated at least 2 to 3 months prior. It results in
reduction in density and thickness of hair but if at any
point in time, there is uncontrolled androgen excess,
there will be a relapse in hirsutism.
THERAPIES AIMED AT TREATING ANOVULATORY
INFERTILITY
The recommended first‑line treatment for ovulation
induction remains the anti‑estrogen clomiphene
citrate (CC). Recommended second‑line intervention
is either exogenous gonadotropins or laparoscopic
ovarian surgery.[40] There appears to be some benefit
of addition of metformin to clomiphene, especially in
obese subjects (modified first line treatment).
Clomiphene citrate
It is a triphenylethylene derived nonsteroidal
agent that is theorized to function at the level of
the hypothalamus as an anti‑estrogen to improve
gonadotropin secretion. An important concern is the
relatively high rate of multiple pregnancies (7.8%)
after conception, majority being twins.[41]
Gonadotropins
These are frequently used to induce ovulation in
women with PCOS for whom clomiphene treatment
has failed. Low‑dose therapy with gonadotropins
offers a higher rate of ovulation, monofollicular
development, with a significantly lower risk of ovarian
hyperstimulation syndrome.[42] Pregnancy rates are
comparable with other regimens, but there have been
no adequately powered trials to answer this question.
Ovarian surgery
This is primarily recommended as second line infertility
therapy. Multiple pregnancy rates are reduced in those
women who conceive following laparoscopic drilling.
In some cases, the fertility benefits of ovarian drilling
may be temporary and adjuvant therapy after drilling
with clomiphene may be necessary.[43] Ovarian drilling
does not appear to improve metabolic abnormalities in
women with PCOS.[44]
Aromatase inhibitors
Aromatase inhibitors such as letrozole and anastrazole
have been proposed as both first and secondary
treatment for ovulation induction (in women with
PCOS and also for unexplained infertility).[45] Results in
women with PCOS appear comparable to clomiphene
from small trials. Proposed benefits include oral
administration, a shorter half life than clomiphene,
more favorable effects on the endometrium, potentially
higher implantation rates, and lower multiple
pregnancy rates due to monofollicular ovulation.
Their use is still experimental at this point.
Thiazolidinediones
Smaller trials have shown some benefit to this class
of drugs for the treatment of infertility usually in
conjunction with clomiphene.[46,47] However the
concern about hepatotoxicity, cardiovascular risk,
weight gain, and the pregnancy Category C have
limited the use of these drugs in women with PCOS.
RESEARCH ONGOING
Statins
Another area where there is emerging support in the
literature for a cardiovascular and endocrine benefit
in women with PCOS is the use of statins. They have
been shown to improve hyperandrogenemia, lipid
levels, and reduce inflammation.[48] However, their
long term effects in preventing cardiovascular disease
in young women with PCOS is unknown. There are
concerns about teratogenecity with the use of this drug
in reproductive age women, as it is FDA pregnancy
category X. The use of these drugs is still experimental
in women with PCOS.
APPROACH TO A PATIENT WITH PCOS
Suspect PCOS in women (obese/lean) with/without
a history of irregular periods with one or more of
the following complaints, namely, acne, hirsutism,
alopecia, acanthosis nigricans and metabolic
syndrome. Investigations both, hematological and
imaging are geared to rule out other hyperandrogenic
states as there is no single investigation to diagnose
PCOS. Patients must be counseled about the long
duration of treatment which includes life‑style
modifications along with the systemic treatment.
Success in effective management of a woman with
PCOS is through a synchronized effort between
the dermatologist, endocrinologist, gynecologist,
nutritionist and physical trainer.

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Indian Journal of Dermatology, Venereology, and Leprology | May-June 2013 | Vol 79 | Issue 3320
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Multiple Choice Questions
1. Ovaries are responsible for ___% of circulating testosterone
a. 20% b. 30%
c. 40% d. 50%
2. Development of insulin resistance in patients with PCOS is
a. Independent of weight b. Directly proportional to weight
c. Very rare d. Genetically determined
3. PCOS is associated with increased incidence of
a. Type 2 Diabetes Meliitus b. Gestational diabetes
c. Deranged lipid profile d. All of the above
4. All are true about metformin except
a. Lowers serum androgens b. Improves ovulatory cycles
 c. Unsafeinpregnancy d. Helpstoreduceweight
5. Treatment for hirsutism includes all except
a. Spiranolactone b. Medroxyprogesterone acetate
c. Flutamide d. Finasteride
6. Ultrasound diagnostic criteria for PCOS includes
a. Volume of each ovary more than 5 cc b. Total volume of both ovaries equal to 8 cc
c. Volume of at least one ovary larger than 10 cc d. Volume of at least one ovary more than 7.5 cc
7. Hyperinsulinemialeadsto
 a. IncreasedfrequencybutnottheamplitudeofLHsecretion b. IncreasedfrequencyandamplitudeofLHsecretion
 c. IncreasedamplitudebutnotthefrequencyofLHproduction d. Noneoftheabove
8. The progesterones which are not androgenetic are
a. Desogestrel b. Levonorgestrel
c. Norgestrel d. All of the above
9. Adverse effects of thiazolidinediones include
 a. Hepatotoxicity b. Cardiovascularrisk
c. Weight gain d. All of the above
10. Percentage of women experiencing menstrual irregularities with spirinolactone
a. 25% b. 30%
c. 20% d. 40%
Answers:
1. a, 2. a, 3. d, 4. c, 5. b, 6. c, 7. c, 8. a, 9. d, 10. c