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Review of Literature

REVIEW OF LITERATURE

PCOS, features and diagnosis


Polycystic

ovary

syndrome

(PCOS)

is

common

reproductive

endocrinological disorder among women of fertile age. The history of PCOS dates
back to 1721. Sclerocystic changes were pointed out in the human ovary as early as
1844. However, the disorder was first described in 1935 by Stien & Leventhal in
women who presented with amenorrhea, infertility and bilateral enlarged polycystic
ovaries11. Based on the work of these two scientists, a primary defect of the ovary was
considered to be responsible for this condition and was referred to as Polycystic
Ovarian Disease (PCOD). Subsequently, extensive work has thrown light on the fact
that PCOD is no longer a disorder confined to the ovaries, but involves a complex
pathophysiology of the various organ systems. Hence, PCOD is now referred to as
Polycystic Ovarian Syndrome.

In the clinical scenario, PCOS is conventionally viewed as "a young lady,


probably obese, presenting with features of hirsutism, oligomenorrhea and infertility".
But increased interest in PCOS has led to the realization that it involves far more than
just the reproductive system. PCOS presents an early manifestation of the metabolic
syndrome with a cluster of abnormalities where the combination of insulin resistance
and compensatory hyperinsulinemia predisposes individuals to develop a high plasma
triglyceride and a low high-density lipoprotein cholesterol concentration, high blood
pressure and coronary heart disease12.Therefore PCOS is sometimes defined as a
Metabolic Syndrome (MetS) that includes obesity, dyslipidemia, insulin resistance,
diabetes mellitus, hypertension and cardiac diseases13. Furthermore, recent studies
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have focused on association of PCOS with malignancies like cancerous conditions of
the Endometrium, Breast and Ovary14,15. Though, many theories have been proposed
in this regard, a definite association is yet to be established.

There is no consensus as to the clinical definition of PCOS. However, criteria


based on the 1990 National Institute of Health-National Institute for Child
Development an Human Disease (NIH-NICHD) conference on PCOS includes
hyperandrogenism and/or hyperandrogenemia, (testosterone or unbound testosterone
more than two standard deviations above a control group of cycling reproductive-age
women), oligo-ovulation, (six or fewer episodes of vaginal bleeding a year) and
exclusion of other known disorders such as congenital adrenal hyperplasia,
hyperprolactinemia, or Cushing's syndrome16. However, there is no consistent clinical
marker or phenotype that is unique to PCOS distinguishing it from other forms of
hyperandrogenism.

The heterogenous clinical presentation as observed above thus is a matter of


debate as to how best PCOS can be defined. A joint meeting of the AMERICAN
SOCEITY OF REPRODUCTIVE MEDICINE (ASRM) and EUROPEAN SOCEITY
OF HUMAN REPRODUCTION (ESHRE) at ROTTERDAM in 2003 has come up
with a consensus on an accepted definition of PCOS. To make a diagnosis of PCOS at
least two of the following criteria must be met17.
1. Oligo/anovulation
2. Hyperandrogenism (clinical / biochemical) after excluding other causes of
androgen excess.

Review of Literature
3. Polycystic ovaries as seen on ultrasonography (USG) - presence of 12 or more
follicles measuring 2-9 mm and an increased ovarian volume of > 10 cm cube.

Epidemiology
Data on the prevalence of PCOS are variable. This may be due, in part, to the
lack of well accepted criteria for diagnosis. The prevalence of PCOS varies between
2.5 and 11 %. More recent European and American studies using NIH criteria are in
agreement that PCOS is a common endocrine disorder, affecting women of
reproductive age up to 6.8%18,19.

On the basis of histology, the major diagnostic macroscopic features of PCO


are bilateral enlargement, thickened ovarian capsule, multiple follicular cysts (usually
ranging between 2-8 mm in diameter) and an increased amount of stroma20. If PCOS
is defined histopathologically (i.e. by the presence of polycystic ovaries upon
oophorectomy or wedge resection), between 1.4-3.5 of unselected women and 0.64.3% of infertile women suffer from this syndrome.

Histological features of polycystic ovary


It includes whole ovarian hypertrophy, Thickened capsule, Increased number
of subcapsular follicle cysts, Scarcity of corporea lutea or albicantia, Hyperplasia and
fibrosis of the ovarian stroma, Decreased thickness of the granulosa layer, Atretic
pattern of the granulosa layer, Increased thickness of the theca interna, Premature
luteinization of theca cells.

Review of Literature
If PCOS is defined by the ultrasonographic appearance of PCO, the prevalence
varies. Polycystic ovaries are seen in 92% of women with idiopathic hirsutism, 87%
of women with oligomenorrhea, 21-23% of randomly selected women, 23 % of
women who consider themselves normal and who report regular menstrual cycles and
in 17% of women participating in routine PAP smear21. However, nor do all patients
with hyperandrogenism demonstrate PCO22. It is also true that PCOS is a very
heterogeneous and complex syndrome and cannot be diagnosed on one imaging
technique. In clinical practice, ultrasonography has replaced the histologic evaluation
of PCO and numerous parameters have been used for definition.

Ultrasonographic criteria used for the diagnosis of PCO


External morphological signs

Internal morphological signs

Increased ovarian area or volume

Number of small, echoless regions


< 10 mm in size per ovary

Increased roundness index (ovarian

Peripheral position of microcysts

width/ovarian length ratio)


Reduced uterine width/ovarian length

Increased echogenity of ovarian

ratio(U/O)

stroma Increased surface of ovarian


stroma on a cross-sectional cut,
(computerized measure)

When Poison and colleagues23 examined a large group of volunteers from the
general population in England, they found that 22% of 257 women had polycystic
ovaries by ultrasound examination; however, one third of these had regular menstrual
cycles. A similar prevalence of polycystic ovary morphology detected by ultrasound

Review of Literature
was found in a New Zealand population. Other studies have confirmed that about 25%
of normal, cycling women have polycystic ovaries on ultrasound examination. When
a subset of women with polycystic ovaries was evaluated endocrinologically, fewer
than half had an abnormally elevated testosterone level. However, as the criteria for
diagnosis of the endocrine syndrome were expanded to include symptoms (irregular
menses and/or hirsutism) or a biochemical abnormality (elevated testosterone and/or
LH level), eventually 92% of these women with polycystic ovaries had another
abnormality. Of course, it is tempting to postulate what percentage of women with
normal ovaries on ultrasound would also have one of these abnormalities.
Extrapolating from the menstrual disorder prevalence data and the ovarian
morphology data, it has been estimated that 5% to 10% of the female population may
be affected.

Mild forms of PCOS are characterized by elevated androgens but with normal
ovulation. About 16 %- 25 % of the women have polycystic appearing ovaries on
ultrasound examination but are otherwise normal. Interestingly, about 1/3 of these
patients have abnormal serum lipid profiles and increased androgen production from
the ovaries. However, the ultrasound scan findings may be present in up to 33% of
women in the general population many of whom may not have any obvious problems.

Ethnic Studies
There have been multiple case reports suggesting that PCOS exists in most
major ethnic groups, although the phenotype varies according to ethnicity. Aono and
coworkers24 identified a group of 11 Japanese women with polycystic ovaries
identified on laparoscopy or laparotomy that had a significantly elevated mean

Review of Literature
testosterone level and LH/FSH ratio compared to ethnic controls. Carmina and
associates25 studied a cohort of 75 patients with hyperandrogenic chronic anovulation
composed of 25 Japanese, 25 Italian, and 25 Hispanic Americans compared to ethnic
controls. Women from Japan were less obese and were not hirsute compared to the
other ethnic groups. All groups had similar testosterone and LH levels and a similar
incidence of polycystic ovaries on ultrasound. Adrenal androgens were elevated in
comparable numbers of patients and to a similar degree. Insulin resistance was
significantly elevated but similar in all groups. These data suggest that ethnicity may
play a significant role in the phenotype of the syndrome.

Clinical Features
Oligomenorrhea or dysfunctional bleeding is an early and dominant symptom of the
anovulatory component of PCOS. The menstrual irregularity of the PCOS is chronic
and can manifest in several different ways. Probably the most common is erratic
menstruation owing to anovulation. Some women with PCOS have prolonged
amenorrhea associated with endometrial atrophy and some will have regular cycles at
first and experience menstrual irregularity in association with weight gain. The
occurrence of oligomenorrhea may be explained by PCOS in approximately 85-90%
of women, whereas 30-40% of amenorrheic patients have been reported to have the
disorder20.

Hyperandrogenism is the second defining characteristic of PCOS. According


to a study in subjects between 14-36 years old, PCOS is a disorder with perimenarchal
onset and the clinical, endocrine and ultrasound features were not changed by the age
of 36 years, although patients were prone to gain weight26. However, it has also been

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Review of Literature
shown that hyperandrogenism partly resolves before menopause in women with
PCOS and they tend to gain more regular menstrual cycles with increasing age after
40 years27. A decline in follicle cohort has been reported to occur while aging. Several
findings have suggested, however, that the common denominator in women with
hyperandrogenic anovulation could be functional ovarian hyperandrogenism (FOH)
whether or not they have typical PCOS.

Clinically, the most common sign of hyperandrogenism in PCOS women is


hirsutism. The range of the prevalence of hirsutism in PCOS women varies between
17 and 83%28. Hirsutism may develop peripubertally or during adolescence or it may
be absent until the third decade of life. Another common sign of hyperandrogenism is
acne. Overt signs of virilization, i.e. male pattern balding, alopecia, increased muscle
mass, a deepening voice or clitoromegaly usually reflect the presence of an androgenproducing tumor or ovarian hyperthecosis. There is strong evidence of a peripubertal
onset of the PCOS the symptoms of which has been used as a diagnostic citeria29.

Infertility was included in the original description of PCOS. The prevalence of


infertility caused mainly by anovulation, in PCOS women varies between 35 and
94%28. However, women with PCOS are as likely to have children as healthy
women, although often after infertility treatment. Also, women with PCOS who
conceive are at a higher risk of Gestational Diabetes Mellitus. Some studies have also
described an increased miscarriage rate in PCOS, the mechanism of which is poorly
understood. It has been suggested that high follicular phase concentrations of LH have
a deleterious effect on rates of conception and miscarriage30.

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Review of Literature
Although the role of obesity in the development of PCOS is still not very
clear, several studies have shown a modest increase in the prevalence of PCOS with
increasing BMI. Though these studies suggest environmental factors such as eating
habits may determine the degree of obesity in PCOS, it has been suggested that PCOS
is more due to inherited than to environmental factors.

Most investigators have found that 30-50% of PCOS women are obese and
tend to have an increased waist-hip ratio, (WHR) i.e. abdominal (visceral) obesity.
Central fat excess is associated with an increase in low grade chronic inflammation
and insulin resistance (IR) and with metabolic dysfunction in women with PCOS. It
may also contribute to the development of glucose and lipid metabolism disorders. Of
course involvement of excess visceral fat is well known in cardiovascular risks since
visceral fat is a source of many cytokines31.

Obesity, in particular, central obesity, plays a key role in the development of


PCOS, and the majority of women with PCOS are overweight or obese. The
mechanisms by which obesity influences the pathophysiology and clinical expression
of PCOS are not completely understood, but obesity is, as an independent factor,
associated with IR and sex steroid disturbances, which may lead to an increased risk
of menstrual irregularities and hyperandrogenemia. Obesity makes it difficult to
interpret the role of genetic intrinsic defects in the etiology of PCOS32 and it is
possible that different pathogenic factors account for the development of the PCOSphenotype in lean and obese women. IR is associated with an increased risk of
developing impaired glucose tolerance (IGT) or manifest type 2 diabetes, lipid
disturbances and cardiovascular diseases. Accordingly, an increased prevalence of

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Review of Literature
IGT, type 2 diabetes and dyslipidemia has also been found in women with PCOS. The
well-known obesity-associated disturbances in the glucose and insulin metabolism
leading to IGT or type 2 diabetes may however be different from those in women with
PCOS, in particular, lean women with PCOS33.

Carmina et al.34 demonstrated that women with PCOS from Sicily are less
obese than women from Pennsylvania and that body mass was significantly higher in
US women with PCOS compared with Italian women. However, total calorie intake
and dietary constituents were similar, except from higher saturated fat content in diet
of US women. Therefore, it was hypothesized that diet alone does not explain
differences in body mass, since their food differed only in the quality of consumed
fats and not in quantity. From these data, it was concluded that genetic and lifestyle
factors contribute to body weight differences. Food quality seems to play more active
role in metabolic abnormalities and could interfere in reproductive dysfunction in
PCOS directly or indirectly.

It has also been suggested that global adiposity rather than abnormal regional
fat characterizes women with PCOS. However certain studies suggest that visceral fat
is directly associated with subclinical CVD in PCOS women. But some studies have
reported that PCOS cases and BMI/body fat mass matched control women are
indistinguishable with respect to distribution of fat within visceral, abdominal
subcutaneous and gluteofemoral subcutaneous depots despite significant differences
in insulin resistance between these two groups35.

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Review of Literature
Metabolic syndrome (MetS) (Syndrome X; Insulin Resistance Syndrome)
MetS is a variably expressed cluster of glucose abnormalities, central obesity,
hypertension and dyslipidemia. It results from insulin resistance interacting with
obesity and age. The fact is that MetS and.PCOS have insulin resistance and obesity
at the core of their pathophysiology and have inheritable components is very
interesting. MetS is substantially higher in PCOS women than in general population.
Prevalence of MetS in PCOS is lower in Italian women than in women from USA
suggesting that genetic factors but mostly differences mostly in life and diet
profoundly influence the prevalence of MetS in women with PCOS.

Obesity is a disease of interaction between genes and a changed environment


that underlies disturbances of lipid and glucose metabolism. Diabetes, cardiovascular
disease, cancers and anovulation are the principal manifestations. Insulin resistance
consequent upon obesity causes them and 'metabolic syndrome' is the term used to
describe them. Metabolic syndrome results from the maladaptation to over nutrition of
genes selected to survive under nutrition. Data from around the industrialized world
suggest that obesity rates have tripled in a generation, so that obesity and its likely
causes are an appropriate place to start in any consideration of the metabolic
syndrome. Different criteria for MetS classification is given in the Table below.

MetS is characterized by a cluster of cardiometabolic risks including insulin


resistance and diabetes. The recognition of the role of insulin resistance rather than
hyperandrogenemia as the main culprit in the pathogenesis of PCOS has important
therapeutic implications. With increasing recognition of the importance of its
metabolic consequences future therapeutic considerations should go beyond the target

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Review of Literature
of short term symptom control in preventing cardiometabolic risks. That includes
weight reduction, dietary modification and increased physical activity36.

Women with PCOS have been shown to have elevated prevalence of IGT,
DM2 and MetS in both BMI and non-BMI matched studies. PCOS women with
obesity, cigarette smoking, dyslipidemia, hypertension, IGT and subclinical vascular
disease are at risk, where as those with MetS and or T2DM are high risk for CVD.
The prevalence of MetS in PCOS women shows a marked variation between countries
and ethnic groups, probably due to differences in diet, lifestyle and genetic factors. On
the basis of the Adult Treatment Panel III criteria, the prevalence of MetS was
reported to be 1.6%, 8.2% and 43% in Czech, Italian and US women with PCOS,
respectively. Parental metabolic syndrome is related to the PCOS phenotype in their
offspring, indicating that familial factors seem to be fundamental to the pathogenesis
of PCOS37.

Classification of Metabolic Syndrome with different criteria


Three of the five criteria will satisfy diagnosis of Metabolic syndrome.
M:Male; F: Female
Parameter

Adult

Adolescent

ATP III - NHA -04


Waist circumference

>88/>102 (F/M) >88/>102

(cm)

C-04

>90% of 88 cm >88

(F/M)

Blood pressure (mm Hg) >130/>85 (F/M) >130/>85

HDL-C (mg%)

C- III

<50/<40 (F/M)

>90% of

>90%

(F/M)

130/85mmHg

130/85

<50/<40

<40

<40

(F/M)
Triglyceride (mg%)

>150

>150

>110

>110

Fasting Sugar (mg%)

>110

>100

>110

>100
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Etiology and its molecular basis
The etiology of PCOS is still obscure. It has been well documented that
inappropriate gonadotrophin secretion, especially high luteinizing hormone (LH)
secretion, is associated with the classic form of PCOS. Although it was suspected as
early as 1962 that there was a wide variety of clinical presentation of PCOS, the
concept of PCOS with normal LH concentrations was not conceived until 1976. The
next milestone was the discovery of the association of PCOS and insulin resistance.
The ultrasonographic finding of polycystic ovaries was described for the first time in
1981. A definition was introduced for the ultrasonographic appearance of PCO in
1985 as one diagnostic criterion of PCOS.

There have been strong indications that polycystic ovaries usually produce
excess androgen. Chronic LH stimulation in PCOS induces sustained hypersecretion
of androgens by theca compartment, probably augmented by insulin and insulin-like
growth factors (IGFs). Most data suggests that the primary dysfunction may be at the
ovarian level or all manifestations of the syndrome might be occurring due to
secondary to hyperinsulinemia. PCOS women have been shown to have an
exaggerated 17-hydroxyprogesterone (17-OHP) and androstenedione (A) response to
gonadotrophin

releasing hormone

agonist

(GnRHa)

and

human

chorionic

gonadotrophin (hCG). Based on the results of several studies it has been suggested
that women with PCOS have a primary dysregulation of ovarian P450cl7, leading to
enhanced activities of both 17a-hydroxylase and 17, 20-lyase in the ovarian theca
cells38.

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Abnormalities in ovarian steroidogenesis and folliculogenesis
Animal models like the prenatally androgenized female rhesus monkey
provide a good nonhuman primate model for PCOS and exhibit oligoovulation,
multifollicular ovaries, elevated LH and increased upper abdominal obesity
predisposing to insulin resistance39. In these experimental studies, oligoovulation and
hyperinsulinemia was more prevalent in obese animals compared to lean ones,
demonstrating a significant positive correlation between BMI and fasting insulin
levels.

The ovary remains the primary source of hyperandrogenism in PCOS. It could


be said that androgens represent the 'necessary evil' in the ovary, since from the one
hand they are the essential substrate for estrogens production but on the other hand
their excess seems to interfere in the selection process of the principle ovarian follicle.
Consequently, intraovarian androgens concentration has to remain in specific limits,
during different stages of follicular maturation.

Androgen biosynthesis in the human ovary takes place primarily in theca


interstitial cells (TIC), whose activity is excessive in PCOS. The ovarian
hyperandrogenism is a result of increased activity throughout the thecal cell steroid
production pathway. This increased activity of thecal cell steroid production is
intrinsic to the thecal cell because it persists after multiple passages of thecal cell
cultures in vitro. The data from several studies suggest that there are certain defects in
thecal cell steroidogenesis and it is unlikely that the hyperandrogenaemia of PCOS is
principally determined by molecular or genetic defects in a single steroidogenic
enzyme activity40.

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Although theca cell dysfunction seems to be the main defect of intraovarian
hyperandrogenism, granulosa cell (GC) deregulation may also play a role, via
regulatory factors secreted from GC. Ovarian GC produce inhibins which are thought
to modulate directly follicular steroidogenesis. The earliest follicular abnormality in
PCOS is an increased number of early-growing and selectable follicles, in which
intraovarian

hyperandrogenism is involved. Recent data have shown that

overproduction of Antimullerian hormone/factor (AMH) from GC in PCOS could be


implicated in hyperandrogenism, since a positive correlation has been found between
AMH, T and androstenedione in PCOS but not in controls. These findings could well
be linked with a paracrine action of AMH on theca cell's over activity by the
demonstration of the AMH type II receptor (AMHRII) in TIC of maturing follicles.
Another factor, although still controversial, which has also been implicated in
hyperandrogenemia, basal or LH stimulated, is the growth differentiation factor-9
(GDF-9).

Supportive data come from in vivo studies, in intact monkeys,

demonstrating that androgen treatment increases the number of pre-antral and small
antral follicles up to 1 mm in diameter, by acting through androgen receptors. The
role of androgen excess signifies their close relationship with the accumulation of 2-5
mm follicles, which gives the typical aspect of multifollicular ovaries at
ultrasonography41.

Accumulating data suggest that intraovarian androgen excess interacts with


the recruitment process of large numbers of small preovulatory follicles, which fail to
respond to normal concentrations of FSH, instead of the emergence of a single
dominant follicle.

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Pathophysiological mechanisms in the development of PCOS

The second major abnormality in the folliculogenesis which may explain the
anovulation of PCOS is the manifestation of follicular arrest in which the selection of
the dominant follicle is impaired, despite the excess in the number of selectable
follicles. Interestingly, early exposure of GC to LH inhibits their proliferation in a
way that the development of the dominant ovarian follicle is interrupted.

A common feature in PCOS is an overall increase in plasma LH


concentrations, consisting of both increased LH pulse frequency and LH pulse
amplitude. The resulting elevated serum LH concentration promotes ovarian TIC
steroidogenesis38. Recent data suggest that it results from an impaired negative
feedback on LH secretion, because of excessive androgen action on the hypothalamicpituitary axis. In addition, when patients with PCOS were given fixed dose of human
chorionic

gonadotrophin

(HCG),

they

showed

hyper

responses

of

17-

hydroxyprogesterone and androstenedione (4A). Furthermore, patients with PCOS


underwent regulation of their LH -abnormality, through a 1-month treatment with
GnRH

agonist;

they

continued

to

exhibit

17-hydroxyprogesteroos

hyperresponsiveness to HCG42.

Insulin Resistance (IR) and Abnormalities in metabolic pathways


Several steps in the glucose and insulin metabolism have been investigated
and debated to understand whether IR is caused by a defect in insulin action or a
primary defect in -cell function or decreased hepatic clearance of insulin, or a

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combination of all these factors. An intrinsic genetic defect in the post-receptor
insulin signal transduction has been found in women with PCOS43. This may lead to
decreased insulin action and a compensatory increased insulin secretion from the
pancreatic -cells. Regarding -cell function, some investigators have shown a
defective glucose-stimulated insulin secretion, indicating a primary defect in -cell
function. Others have found an increased insulin response a possible compensatory
mechanism to a peripheral defect in insulin action, and yet others have found
unaffected acute insulin secretion.

The role of hyperinsulinemia and insulin resistance was established on


reproductive and metabolic aspects of the syndrome. Pioneering studies have shown
that the classic PCOS syndrome is determined by a distinct form of insulin resistance;
however, this molecular defect is not universally present. In PCOS, increased insulin
levels are incriminated for direct stimulation of ovarian androgens' production by
means of the favourable action of this hormone to 17a-hydroxylase and to 17,20 lyase
(cytochrome P450cl 7a) and in cytochrome P450scc38,44,45.

Hyperinsulinaemia provides another determinant of hyperandrogenism by


enhancing the effects of LH on TIC steroid production. The final outcome of this
intraovarian hostile interaction, it seems to result in arresting the follicular maturation
process.

New concepts in PCOS


PCOS manifests during adolescence. But emerging data suggests that PCOS
may originate in intrauterine life (IUL). Prenatal androgenization of female fetus

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induced by genetic and environmental factors or the interaction of both may program
differentiating target tissues toward the development of PCOS phenotype in adult
life46.

A few studies have proposed that PCOS has its origin in fetal life. This has
been explained as a genetically determined hypersecretion of androgen by the fetal
ovary resulting in programming of the fetal hypothalamo-pituitary axis (HPA). This
leads to excess production of LH and physiological amplification of insulin resistance
at puberty. An association between low birth weight and PCOS is a new concept. It
has been reported that low birth weight is linked to insulin resistance and that persists
throughout life. Dehydroepiandrosterone (DHEA) is found to be at a higher level in
low birth weight individuals which is responsible for early pubarche. This elevated
androgen coupled with hyperinsulinemia and insulin resistance predisposes the young
girls to develop PCOS. Studies have shown that girls with premature puberty are at an
increased risk of developing PCOS after puberty. Post pubertal girls especially are
affected with irregular menstrual cycles. Therefore, manifestations of PCOS may be
explained on the basis of the severity of hyperandrogenism, hyperinsulinemia, insulin
resistance and other modified environmental factors.

PCOS subjects are predisposed to abdominal fat accretion (androgen


phenotype adiposity) and insulin resistance is a characteristic feature of obese and
normal weight patients with PCOS. The MetS is associated with accelerated
atherosclerosis and characterized by metabolic and non metabolic cardiovascular
risks. Six components of MetS may predispose to CVD are abdominal obesity,
atherogenic dyslipidemia, elevated blood pressure, IR and or glucose intolerance,

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proinflammatory and prothrombotic state. There have been multiple inflammatory
markers in PCOS such as C-reactive protein, classical proinflammatory cytokines
(TNFalpha, ILlbeta, and IL6) intracellular adhesion molecule, vascular adhesion
molecule 1 as well as adinopectin, visfatin and resistin as prothrombotic and
proatherogenic factor.

PCOS clinical signs often emerge during peripubertal years with premature
pubarche being the earliest manifestations in some girls. In most girls PCOS
manifests

after adolescence with

weight

gain,

clinical

hyperandrogenism,

oligomenorrhea and IR. It is suggested that the metabolic abnormalities described in


PCOS are present before the onset of hyperandrogenism. This has been supported by
adinopectin level measurements which is a good marker of metabolic derangement in
PCOS obese women. Adinopectin is involved in the regulation of insulin action and
glucose metabolism. Serum levels of adinopectin are inversely correlated with BMI37.
This study confirms the existence of low grade chronic inflammation in early stages
of visceral obesity and in lean PCOS patients and IR through ghrelin and PYY
profiles.

Ghrelin is not only in stomach but also in abundance in cardiovascular system


and in peripheral blood mononuclear cells. Low levels of ghrelin have been associated
with chronic conditions such as obesity, IR, T2D and hypertension47,48.

Antimullerian hormone (AMH) is a growth factor found to play an important


role in the growth and selection of the follicle. AMH level is increased in women with
PCOS while its expression is paradoxically reduced during the initial stage of

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follicular recruitment. AMH also called as Mullerian inhibiting substance produced
exclusively in the gonads by Sertoli cells and granulose cells. It is important for the
normal differentiation of reproductive structures. The main role of AMH is to cause
Mullerain ducts to regress. It is also important for the development of testis. During
postnatal life AMH levels are decreased in females. AMH levels are increased in
daughters of PCOS mothers at the time of prepuberty. This may suggest that may
have an altered follicular development leading to increased follicular mass that
persists during puberty. AMH levels reflect severity of PCOS41,49.

Obstructive sleep apnoea (OSA) is characterized by frequent microarousals


and reductions in slow wave sleep. Ermann has shown that OSA is associated with 7fold increase women with PCOS than in control subjects. Since OSA causes increased
sympathetic activity which is presumed to be the cause of microarousals in OSA.
Mood disorders are common in PCOS women45.

Remedy for PCOS: Exercise/Life Style Modification


Goals of therapy for PCOS patients should include decreasing levels of free
androgens in the blood, blocking androgen activity in target tissues, stabilizing the
endometrium, and reducing insulin resistance. However, by decreasing testosterone, it
may reduce ovarian cysts and help re-establish the delicate balance of hormones,
thereby enhancing the likelihood of ovulation, without which there is no chance of
becoming pregnant. At the present time there are no pharmaceutical drugs that will
heal PCOS or no single pill that will cure Metabolic Syndrome. But there are ways to
address Insulin Resistance, an underlying cause of these conditions as well as PCOS
symptoms. It is suggested that a system that combines a realistic exercise program,

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nutritional guidance and a support system may help to change unhealthy lifestyle
choices and lose weight.

It is suggested that life style modification should be greater than or equal to


7% loss in weight and maintenance with <25% of calories from fat and a total caloric
intake of 1200 to 1800 calories per day. It is recommended that the patient should
have more than 2 hours of moderate physical activity per week and be on a low
glycemic index diet to improve insulin resistance. It is suggested that PCOS patients
can consider brisk walking 3-5 times a week. Weight loss and exercise have been
shown to improve fertility and lowering of androgen levels. Thus, life style
modification in the treatment for PCOS might reduce the long term risk of diabetes,
heart disease and possibly endometrial cancer50,51. For treating acne and hirsutism,
both medical and surgical approaches can be considered.

Studies have shown that long term use of hypocaloric diets will improve the
metabolic derangements in patients with PCOS. Some have concerns about a low
carbohydrate and high fat diet in PCOS due to the already abnormal lipid profiles seen
in patients with PCOS. In a study published by in 1992, twenty-four obese PCOS
spent 6 months on a low calorie (1000 kcal), low fat diet. There was a marked
improvement in their clinical parameters and lowered insulin levels. A report by
Jakubowicz and Nestter52 showed, a reduction in serum testosterone levels using a
similar dietary regimen. A very well designed study from Italy examined the long
term effects of metformin and hypocaloric diet on PCOS. Metformin improved the
hirsutism, menstrual function, visceral adipose tissue, and glucose stimulated insulin
secretion. In a study of 128 nonobese women with PCOS, with fasting insulin <15

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IU/ml, metformin did induce ovulation although requiring ~6 months to show effect.
Nestler suggested that the finding could be interpreted to show that these women did
actually have IR or that metformin directly inhibited ovarian androgen biosynthesis.
There is some evidence that "life style" modification may be an effective adjunct to
our treatment of PCOS. Many patients have attempted to diet all their life with limited
success. Some have even attempted gastric bypass surgery to effectively starve
themselves. A very interesting study from Sweden by Ek et al.53 showed that PCOS
patients had a marked reduction in the lipolytic (i.e. fat breakdown) effects of
noradrenalin due to a decreased number of noradrenalin receptors on fat cells. Weight
reduction has been shown to increase noradrenalin sensitivity in PCOS patients. Thus,
there may be a link between the sympathetic nervous system and PCOS where
exercise may help.

25

Review of Literature
PCOS in India and the subcontinent

Rapid urbanization and changes in life style in many developing countries is


causing an increase in many complex diseases like PCOS, cardiovascular diseases and
diabetes. On an average PCOS affects 5-10 % of the women in reproductive age
group worldwide. Prevalence of PCOS is rapidly rising among Indians also. Estimates
of PCOS in migrant Indians have been estimated at 52% level. And about 37% among
the north Indian women have been estimated to suffer from PCOS54'55. According to a
newspaper report (Times of India, 2007/12/01), gynecologists believe that 25% of the
women visiting them in Hyderabad (South India) are suffering from PCOS that has
jumped manifold over the last couple of years. Such large variation in the prevalence
rate is because of the lack of a universal definition for PCOS.

Some studies conducted in India have been confined to clinical dimensions of


PCOS. Other studies on Indians are from South Asia and emigrant Indians. Except a
couple of genetic association studies, no family studies have been reported so far.
Maitra et al56 conducted mutational analysis of CPY1A1 and leptin as genetic
determinants of hyperandrogenicity and obesity in PCOS. The same group has shown
the existence of dyslipidemia associated with cardiovascular risks and obesity in
PCOS. Kalra57 and his coworkers have shown that insulin resistance is associated
with dyslipidemia in women with PCOS independent of obesity. Zagar et al58 have
shown a higher prevalence of PCOS associated with type 2 diabetes. Another study
has shown that South Indian women with reproductive abnormalities of PCOS have
greater insulin resistance and intima media thickness that would lead to risks of
vascular diseases59. A summary of the important studies and the outcome are given in

26

Review of Literature
Table and the references are quoted as reference number cited in the original
article54,55. Type 2 diabetes is common among South Asians and insulin resistance is
central to the pathogenesis of PCOS. Asian Indians being more resistant to insulin
may exhibit higher predisposition to metabolic syndrome also at an early stage.
Although, Indian population contributes greatly to the worlds total population genetic
studies related to PCOS is scanty and therefore it has become imperative to explore
the etiology (both environmental and genetic) in the manifestation of PCOS.

Summary of Studies on PCOS from India and the subcontinent54-56,60,61


Authors/s

&

Study

Outcome

Year

Reference
number in
original
article54

Rodin DA et al.

PCOS

& metabolic

PCOS in immigrant Asian

1998

abnormalities

women is 52%

Zagar et al 2005

PCOS on USG in north

PCOS at 61% level

Indian women
3

Wijeyaratne et al

PCOS in South Asians and Higher prevalence of

2002

Caucasians

hirsutism, acne, etc.

Zagar et al 2002

Hisutism in Kashmiri

10.5 had hirsutism and 37%

women

by F-G scoring

Jialal et al 1987

Sundaram et al

PCOD

and

insulin

resistance in non-obese

correlated

PCOS & atherosclerosis

Hyperinsulinemia, & intima

2003
7

Kaushal et al

PCOS & Family studies on Insulin resistance and

2004

insulin resistance

metabolic syndrome +

Management of metabolic

Insulin resistance and

syndrome

metabolic syndrome +

Deedwania

12

15

16

media thickness+

&

Gupta 2006
9

Hyperandrogeneism and IR

Wijeyaratne et al PCOS & metabolic

Dyslipidemia, obesity &

2006

hypertension +

syndrome in South Asian

17

18

29

women
10. Babu et al 2004

Genetic polymorphism in

Imbalance in

south Indian women

enzyme activities & PCOS +

35

27

Review of Literature
11

Kriplani &

Metformin & PCOS

Agarwal, 2004
12

13

Dasgupta

&

Reddy, 2008.

45

Dasgupta et al
2010.

50

Improvement in menstrual

55

cyclicity
Genetic etiology of PCOS

Lack of genetic studies on


Indian population

Androgen receptor in
PCOS of south Indian
women

14

Aruna et al.

Metformin therapy in

Improve menstrual

PCOS

cyclicity.& fertility

Maitra et al.

Mutational analysis of

No variation with the exons

46

CYP11A1 & Leptin in

of the gene

2004.
15

2004.

51

PCOS

28

Review of Literature
Genetics of PCOS - 'A family affair'

Genetic studies of women with PCOS and their families may provide major
insight into this common endocrine abnormality and also into many of its metabolic
sequelae. Susceptibility to inheritance of PCOS seems to be equally probable from the
maternal and paternal side of the family. It is estimated that a woman's risk for
developing PCOS is higher if she has an affected sister, but at a lower risk if other
family members are affected. Though the genetic studies have not yet determined the
pattern of heredity, most of the family studies have shown a simple Mendelian pattern
of inheritance consistent with an autosomal dominant or X-linked partem of
inheritance62. Positive findings have been reported with candidate genes involved in
both association and linkage studies63.

However, the problems in genetic studies are the lack of uniform criteria for
diagnosis, heterogeneity of phenotypic features even within affected families and
between sisters and moreover, the disorder is expressed clinically only in women
during their reproductive years64. Furthermore, genetic investigation of PCOS is
hampered by several other factors such as small sample sizes, errors in statistical
analysis, use of ultrasound scan for the diagnosis of PCOS, a method not universally
accepted65,66.

29

Review of Literature
Summary of limitations in the susceptibility studies of PCOS
Lack of universally accepted

NICHD criteria, Ultrasonographic criteria,

diagnostic criteria and definition

Rotterdam criteria

Heterogeneity of male phenotype

Premature baldness, Increased pilosity, DHEAS


levels, and responses to GnRH and ACTH,
Insulin resistance, Glucose tolerance

Relatively small sample size of

Potential statistical erroe

the study population


Affected reproduction

Difficulty in studying more than one generation

Non-random ascertainment of

Acertainment bias

famlilies
Obscurity in the mode of

Autosomal dominant, Monogenic, X-linked

inheritance
Variable penetrance and

Difficulty in assignment of the phenotype

expressivity

(affected versus unaffected)

Locus heterogeneity

Involvement of multiple genes

Environmental interactions

Compensatory adaptation; through


hormonal treatment, nutritional control

A small number of clinical studies have been performed over the last 20 years
which have drawn attention to the phenomenon of familial clustering of cases of
polycystic ovary syndrome (Cooper et al., 1968; Ferriman and Purdie, 1979; Givens
et al., 1988; Hague et al., 1988; Lunde et al., 1989; Carey et al., 1993).

30

Review of Literature
The first genetic study was by Cooper et al.67, which showed oligomenorrhea,
hirsutism and enlarged ovaries were much more common in sisters of PCOS cases
than in sisters of controls.

Wilroy et al.68 showed that 47% of female offspring of PCOS affected females
were affected. Among the offspring of males with an elevated LH/FSH ratio, 89% of
daughters were affected. The finding is consistent with X-linked dominant
inheritance.

Legro et al.69 studied 80 probands diagnosed on the basis of elevated


testosterone (T) associated with oligomenorrhea (<6 menses/year). They found 36 of
80 (45%) sisters were affected on the basis of hyperandrogenemia. The proposed male
phenotypes in PCOS family studies as suggested by many authors include increased
"pilosity", abnormal gonadotropin secretion and testicular function, "premature"
balding in third and fourth decades, "early baldness or excessive hairiness", and
insulin resistance70.

In one of the six largest studies (Hague et al, 1988) no attempt was made to
identify a male phenotype. In three others,' premature balding was suggested as the
likely manifestation of affected status in men but this was based, in two of the three,
on evidence from questionnaires (Ferriman and Purdie, 1979; Lunde et al, 1989) and,
in the other, on a combination of data from direct observation, telephone interview
and questionnaires (Carey et al, 1993).

31

Review of Literature
In four of six studies, segregation analysis gave results that were consistent
with autosomal dominant inheritance (Cooper et al, 1968; Ferriman and Purdie, 1979;
Lunde et al, 1989; Carey et al, 1993) whilst one study suggested an X-linked mode
(Givens et al, 1988). In the other, the prevalence of polycystic ovaries among siblings
was too high to be explained by a simple dominant model (Hague et al, 1988). None
of the six studies has satisfactorily addressed this issue.

Of the St Marys family studies one of the large family study concluded an
oligogenic basis for the disease.

In another study on the inheritance of PCOS by A Govind et al, 29 families of


pco probands were analysed. The results of the study was consistent with an
autosomal dominant inheritance pattern of PCOS in families, perhaps caused by the
same gene. Given that both PCOS and the metabolic syndrome have insulin resistance
and obesity at the core of their pathophysiology and have heritable components,

Natasha I. Leibel et al tested the hypotheses that parental metabolic syndrome


would be related to the PCOS phenotype in their offspring and that metabolic
syndrome prevalence would be increased in adolescents with PCOS. Thirty-six
adolescent girls with PCOS and their first degree relatives were evaluated for
metabolic syndrome characteristics. The study concluded that familial factors related
to paternal metabolic syndrome seem to be fundamental to the pathogenesis of PCOS.

The following tables summarise the familial studies.

32

Review of Literature
Table 1. Summary of Diagnostic Criteria for the proband in familial studies
proposed Mode on Inheritance70.
Author

Diagnostic Criteria for I Number Studied


PCOS

Cooper et al, 1968

Mode of
Inheritance

Oligomenorrhea,

18 PCOS women

Autosomal

hirsutism, polycystic

and their first-

dominant with

ovaries (by culdoscopy,

degree relatives and reduced

gynecography, or wedge

a control group

penetrance

3 multigeneration

(?X-linked)

kindreds

dominant

resection)
Givens et al, 1971,

Oligomenorrhea,

1975, 1988; Cohen et hirsutism, and polycystic


al, 1975

ovaries (exam and surgery)

Ferriman and Purdie, Hirsutism and/or

381 PCOS women, Modified

1979

oligomenorrhea, 60% with

and relatives and a

polycystic ovaries (by air-

control group

dominant

contrast gynecography)
Lunde et al, 1989

Hague et al, 1988

Clinical symptoms

132 PCOS women

Unclear, most

(menstrual irregularities,

and first- and

consistent with

hirsutism, infertility, and

second-degree

autosomal

obesity) and multicystic

relatives and a

dominant

ovaries on wedge resection

control group

Clinical symptoms

50 PCOS women

(menstrual dysfunction,

and 17 women with exceeded

hyperandrogenism,

CAH and a control

autosomal

obesity, and infertility) and

group

dominant pattern

Segregation ratios

polycystic ovaries by
transabdominal ultrasound
Carey et al, 1993

Polycystic

ovaries

(by 10 kindreds and 62 Autosomal

transabdominal ultrasound)

relatives

dominant with
90% penetrance

Norman et al, 1996

Elevated androgens,

5 families with 24

decreased SHBG, and

females and 8 males

Not stated

polycystic ovaries on
ultrasound

33

Review of Literature
Table 2. Summary of Female Relative Affected by trait in Families of proband of PCOS 70.

Sisters

Mothers

Author

Trait

Cooper et al, 1968 History of

Female Relatives
Affected

Affected

Affected

(%)

(%)

(%)

9/19(47%)

4/13(31%)

14/24(58%)

4/13(31%)

oligomenorrhea
Hirsutism

Elevated 24-hr urinary 12/19(63%)

2/7(29%)

17-ketosteroids
Enlarged ovaries
Givens, 1988

10/19(53%)

Oligomenorrhea

0/7(0%)
16/67(24%)

Hirsutism
Ferriman and

28/54(52%)

Hirsutism

30/337(9%)

32/284(5%)

1979

Oligomenorrhea

32/337(9%)

24/284(8%)

Lunde et al, 1989

Hirsutism

8/129(6%)

17/132(13%)

Oligomenorrhea

19/129(15%) 16/132(12%)

Purdie,

Hague et al, 1988

Carey et al, 1993

Hirsutism

(28/107(26%)

Oligomenorrhea

19/107(18%)

Polycystic ovary

37/50(74%)

morphology on
ultrasound
(Elevated

16/50(32%)

testosterone
Norman et al

Polycystic ovary

1996

morphology on

111/15(73%) 77T

ultrasound
Increased testosterone 113/15(87%) 1/5(20%)
or landrostenedione
Hyperinsulinemia

10/15(66%)

5/5(100%) )

34

Review of Literature
Different approaches have been employed to elucidate the complex polygenic
origin of PCOS. They are considered in brief in the following paragraphs along with
some relevant studies.
1.

Karyotyping:
Karyotypes were the first genetic tools used in the study of PCOS. There have

been isolated case reports or small series reporting polyploidies and aneuploidies, that
include XX/XXX and XX/XO mosaics71,72. Larger cytogenetic studies on PCOS
patients, however, have found normal karyotypes73.

2.

Chromosomal/human leukocyte antigen (HLA") studies:


HLA association studies of PCOS have shown conflicting results. Mandel and

coworkers74 studied four families with two affected siblings and found no linkage. On
the other hand Hague and associates and other researchers have reported an
association in their study75.

3.

Direct sequencing of candidate gene regions:


Multiple genetic causes of adult-onset hyperandrogenism and chronic

anovulation have been identified. The prevalence of many of the mutations among
hyperandrogenic women is still being established, although they tend to be rare.
Mutations in steroidogenic enzymes gene and insulin receptor gene have been
identified76,77. Positive association and linkage have been reported with an insulin
gene variable number of tandem repeats (VNTR) locus63.

A number of linkage and association studies of candidate genes in PCOS have


yielded positive and/or mixed results, which are summarized in Table 3.

35

Review of Literature
4.

Association Studies:
Association studies are useful as preliminary tests for an association between

candidate genes and the disease phenotype. Large family clusterings of PCOS offer
the best opportunity for identifying unique strains of PCOS as they may represent a
homogeneous etiology of the syndrome, despite significant phenotypic heterogeneity
within a given pedigree. Association studies offer the advantage of studying diseases
in the following conditions; (i) whose mode of inheritance is uncertain (ii) whose
presentation is poorly defined (iii) subject to late onset and (iv) variable penetrance.

Association studies involve the case-control approach, or family-based


methods. The case control approach addresses whether the variant allele occurs more
frequently in a series of women with PCOS than in an appropriate control population.
Several case-control studies have found a positive association between PCOS and
alleles of candidate genes. In the family based methods, the focus of analysis is the
transmissions from parents to their affected offspring. However, there are many
potential areas of criticism for these types of association studies. For example,
association studies may be weakened by the heterogeneity of the syndrome, both
genetic and non-genetic.
Some of the reports on positive association studies are shown in the Table 4.

5.

Linkage studies.
Linkage analysis aims to demonstrate co-segregation of a particular genetic

variant or locus with a disease or trait, within families with affected and unaffected
members. The performance of linkage analysis depends heavily on the availability of
relatively large, informative families.

36

Review of Literature
Linkage analysis can be performed between polymorphic markers spaced at
regular genetic intervals, and these familial traits may identify critical regions for
further investigation.

6.

DNA microarravs:
This is a relatively new technique that may help to identify therapeutic targets.

DNA microarrays is useful for comparing genomic DNA variation or gene expression
profiles in different target tissues of affected and unaffected individuals.

Table 3. Candidate genes for their possible association with PCOS78.


Pathophyisology
Biosynthesis and

Candidate gene
LH and its receptor

Comment
Multicentric study, mutation of

metabolism of

LH receptor, no linkage or

androgens

association
CYP11 -cytochrome

Randomized clinical study,

P450

partial association

side chain

cleavage enzyme
CYP 17-cytochrome

No association or linkage

P450 17
hydroxylase/17,20 lyase
CYP21-cytochrome

Mutation, no association

P450 21-hydroxylase
Androgen receptor

Family studies, no association

Sex hormone binding

Polymorphism, no association

globulin (SHBG)
Other steroidogenic

Family study, no association

genes

37

Review of Literature
Genes involved in

Insulin gene VNTR

One study showed linkage and

the secretion and

association of VNTR with

action of insulin

PCOS. Further family studies


showed no association.
Insulin receptor gene

Polymorphism in the tyrosine


kinase domain of INSR
showed association with
PCOS. Caucasian family
studies, D19S884 marker
near insulin receptor gene,
chromosome 19pl3.3 showed
linkage and association

Insulin receptor substrate Polymorphisms in IRS1 and


(IRS) proteins

IRS2, no association

Insulin-like growth

Association with IGF2 and

factors (IGF)

PCOS in Spain, no linkage

Calpain-10

Contradictory data, association


in Spanish population

Genes involved

Dopamine receptor'

in gonadotrophin

genes

action and

Follistatin gene

regulation

Polymorphisms, no association

Family studies, no clear


association or linkage

Genes involved

Peroxisome proliferator- Polymorphism, prevalence in

in obesity and

activated receptor- gene finish population, no

insulin resistance

(PPAR)

association in US and Spain

Human sorbin and SH3

Multicentric european study,

domain-containing 1

no association

gene (SORBS 1)
Paraoxonase (PON1)

Polymorphism, no association

Genes encoding other

No association or linkage

molecules related to
insulin resistance

38

Review of Literature
Genes involved

Plasminogen activator

Association of 4G5G

in chronic

inhibitor-1 (PAI-1)

polymorphism in Greek

inflammation

population of PCOS women


Tumour Necrosis Factor- No association
(TNF)
Type 2 TNF Receptor

No association

gene
Interleukin-6 gene (IL-6) No linkage, or association
IL-6 signal transducer

No association

gpl30(IL-6ST)

INSR, insulin receptor; VNTR, variable number tandem repeats.


Table 4. Positive Associations with Candidate Alleles Reported in PCOS70.
Cases/
Author

PCOS Dx Criteria

Controls

Ethnicity

Candidate

Significance

Allele
Carey et

Anovulation and/or

al, 1994*

71/24

Not stated

A2 allele of

OR of 3.57 of being

hirsutism and PCO

CYP17 (17-

affected with one allele

on ultrasound

alpha

(confidence intervals not

hydroxylase)

stated)

Legro et

Elevated testosterone 47/42

Hispanic

2 allele of

OR of 3.72 (95% CI

al, 1995

and

only

DRD3

1.2-12.8) of being

chronic

anovulation

Gharani

Menstrual

(dopamine D3 affected if homozygous

97/110

Not stated

et al, 1997 disturbances


and/or hirsutism and

receptor)

for the 22 allele

216 allele of

p value <0.03 for PCOS

CYPlla

with 216 allele

(aromatase)

compared to combined

PCO on ultrasound

control group of cycling


women without PCO on
ultrasound and
asymptomatic PCO
women

Waterwort Menstrual

25/54

Not stated

III allele of

OR of 8.20(1.83-50) for

h etal,

disturbances

INS VNTR

anovulatory PCOS

1997

and/or hirsutism and

(insuline)

compared to cycling

PCO on ultrasound

women

39

Review of Literature
A genetic study on functional polymorphism of 11-B-HSD1 in PCOS done by
Alessandra Gambineri et al showed genetic variation in 11-B-HSD1 may underlie
adrenal hyperandrogenism in lean patients with PCOS but may protect against obesity
and associated metabolic dysfunction. These observations lend additional support to
the concept that the pathogenesis of PCOS is different among the different phenotypes
of the syndrome.
In another study Alessandra Gambineri et al concluded that in southern
European Caucasian women with or without PCOS, alleles of 11BHSD1 containing
the two SNPs rs846910 A and rs12086634T confer increased 11BHSD1 expression
and activity, which associated with metabolic syndrome.

40

Review of Literature
Comparison data of Clinical, hormonal, and metabolic characteristics in PCOS
women and controls between lean and obese pco subjects is shown below D

TABLE l. Clinical, hormonal, and metabolic characteristics in PCOS women and controls

Variables

PGOS (n = 38)

Age(yr)
23.9 4.7
BMKkgfrn3)
22.9 2.1
Waist circumference (cm)
74,3 6.1
Total abdominal fat (cm2)
263 98
Visceral abdominal fat (cm3)
37 17
sc abdominal fat (cm2)
226 95
Fasting 0800-0830 h plasma
Total testosterone (ng/dl)
67.5 18.9
Androstenedione (ng/dl)
349 127
DHEA-S (fig/ml)
2.31 1.14
SHBG (mraol/liter)
35.3 14.1
Cortisol (g/dl)
12.4 6.3
ACTH1-24 stimulation test
% (60-0) Cortisol
170 122
% (80-0) DHEA
157 282
% (60-0) androstenedione
27 37
% (60-0) 17OH-progesterone
120 94
Dexameihasone suppression test
% (60-0) Cortisol
-93 4
% (80-0) DHEA
-67 36
% (60-0) androstenedione
-38 + 29
% (60-0) 17OH-progesterone
-23 69
Oral glucose tolerance test
GlucoseAUC (rag/dl-min)
17,624+ 3,108
InsutinAUC (IU/ml-min)
9,373 9,067
QU1CKI
0.366 + 0.042
ISI
8.43 + 4.66
LDL-cholesterol (mg/dl)
76.4 + 24.8
HDL-cholesterol (mg/dl)
56.2 12.9
Triglycerides (mg/dl)
68.7 + 25.7

Lean
Controls
(n = 38)
23.9 4.1
20.8 1.8
69.1 5.8
259 97
34 16
225 92

P value

PCOS (n = 64)

0.972
0.280
0.490
0.936
0.836
0.997

25.9 + 6.6
35.8 5.2
10L2 + 12.3
.607 155
108 61
499 + 121

Obese
Controls
(n = 60}
26.6 6.7
36.4 4.7
102.5 10.5
598 81
101 39
497 64

45.0 16.4
238 79
1.90 0.60
63.2 25.1
15.4 4.1

<0.001
<0.001
0.046
<0.001
0.029

68.3 + 28.0
338 142
2.22 1.08
23.5 15.3
12.9 5.1

48.2 12.8
223 64
1.77 0.62
35.5 19.8
13.0 2.5

<0.001
<0.001
0.011
0.001
0.9S6

97 67
109 103
37 44
220 246

0.009
0.294
0.347
0.062

166 + 109
134 102
42 40
183 134

117 33
114 116
35 41
ISO 203

0.317
0.633
0.472
0.949

-94 3
-83 7
-35 24
-38 43

0.376
0.060
0.306
0.323

-93 + 4
-77 11
-36 37
-26 48

-93 3
-82 7
-39 25
-38 40

0.838
0.287
0.644
0.416

17.948 2,716
6,248 3,056
0.374 + 0.031
13.75 9.02
77.0 16.8
60.5 14.6
60.7 + 25.2

0.798
0.324
0.391
<0.001
0.915
0.144
0.421

21,565 5,714
19,154 16,725
0.317 0.02S
3.61 2.36
111.6 32.9
47.2 11.7
102.4 49.1

23,404 5,343
12,664 8,902
0,339 0,059
5.98 5.50
116.0 22.3
54.2 10.7
119.5 47.3

0.06S
0.005
0,004
0.018
0.358
0.002
0,062

P value
0.483
0,433
0.474
0.765
0.591
0.905

There was a relative dearth of twin studies of PCOS. However, case reports
have identified affected sets of female twins. A twin study by Jahanfar and
colleagues79 reported on both mono- and dizygotic twins noted a high degree of
discordance among the twins for polycystic ovaries on ultrasound. The study
suggested that PCOS may have a more complex inheritance pattern than autosomal
dominant, perhaps X-linked or polygenic. It also suggested that environmental factors
may play a significant role. There also appeared to be a significant genetic component

41

Review of Literature
to the fasting insulin level, further supporting insulin resistance as a potential familial
characteristic.

In summary it may be stated that a major challenge to gene-finding efforts in


complex diseases is that each gene typically contributes modestly to disease risk. For
example, most of the recently discovered genes for type 2 DM affect risk by only 2535%80, necessitating large sample sizes for adequate power to discover the genes.
PCOS genetics is also faced with other hurdles unique to the syndrome, such as
impaired fertility potentially leading to small family sizes, lack of a clear phenotype in
men, and in prepubertal and menopausal women, and the absence of universally
accepted diagnostic criteria64. Although several positive results have been reported in
PCOS, no gene or genes is universally accepted as important in PCOS pathogenesis
though the numbers of candidate genes are steadily increasing.

Despite these shortcomings, the study of familial aggregates has consistently


suggested that the mode of inheritance appears to be dominant. This fact would tend
to exclude many of the other rare etiologies of hyperandrogenism, such as
steroidogenic enzyme deficiencies, which are autosomal recessive. Currently, PCOS
is considered a polygenic trait that might result from the interaction of susceptible and
protective genomic variants under the influence of environmental factors. Candidate
genes cover a broad spectrum of an endless list of molecules which participate on
every step of reproductive and metabolic pathways of this syndrome. The current
view supports the notion that PCOS is likely to represent a complex oligogenic trait
with multiple genetic defects81.

42