Review of Literature - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/32447/3/3.review of literature.pdf · Review of Literature 11 shown that hyperandrogenism partly resolves

Review of Literature

5

REVIEW OF LITERATURE

PCOS, features and diagnosis

Polycystic ovary syndrome (PCOS) is a 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


6

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.


7

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 0.6-

4.3% 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.


8

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

Increased ovarian area or volume

Increased roundness index (ovarian

width/ovarian length ratio)

Reduced uterine width/ovarian length

ratio(U/O)

Internal morphological signs

Number of small, echoless regions

< 10 mm in size per ovary

Peripheral position of microcysts

Increased echogenity of ovarian

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


9

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


10

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


11

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 androgen-

producing 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

.


12

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 PCOS-

phenotype 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


13

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

.


14

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


15

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

ATP III - NHA -04

Adolescent

C- III C-04

Waist circumference

(cm)

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

(F/M)

>90% of 88 cm >88

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

(F/M)

>90% of

130/85mmHg

>90%

130/85

HDL-C (mg%) <50/<40 (F/M) <50/<40

(F/M)

<40 <40

Triglyceride (mg%) >150 >150 >110 >110

Fasting Sugar (mg%) >110 >100 >110 >100


16

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

.


17

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

.


18

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.


19

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 hypothalamic-

pituitary 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 (Δ4A). 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 β-cell function or decreased hepatic clearance of insulin, or a


20

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 β-cells. Regarding β-cell function, some investigators have shown a

defective glucose-stimulated insulin secretion, indicating a primary defect in β-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


21

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,


22

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


23

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 7-

fold 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,


24

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 2½ 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


25

µIU/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.


26

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


27

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 &

Year

Study Outcome Reference

number in

original

article54

1 Rodin DA et al.

1998

PCOS & metabolic

abnormalities

PCOS in immigrant Asian

women is 52%

6

2 Zagar et al 2005 PCOS on USG in north

Indian women

PCOS at 61% level 7

3 Wijeyaratne et al

2002

PCOS in South Asians and

Caucasians

Higher prevalence of

hirsutism, acne, etc.

8

4 Zagar et al 2002 Hisutism in Kashmiri

women

10.5 had hirsutism and 37%

by F-G scoring

12

5 Jialal et al 1987 PCOD and insulin

resistance in non-obese

Hyperandrogeneism and IR

correlated

15

6 Sundaram et al

2003

PCOS & atherosclerosis Hyperinsulinemia, & intima

media thickness+

16

7 Kaushal et al

2004

PCOS & Family studies on

insulin resistance

Insulin resistance and

metabolic syndrome +

17

8 Deedwania &

Gupta 2006

Management of metabolic

syndrome

Insulin resistance and

metabolic syndrome +

18

9 Wijeyaratne et al

2006

PCOS & metabolic

syndrome in South Asian

women

Dyslipidemia, obesity &

hypertension +

29

10. Babu et al 2004 Genetic polymorphism in

south Indian women

Imbalance in

enzyme activities & PCOS +

35


28

11 Kriplani &

Agarwal, 2004

Metformin & PCOS Improvement in menstrual

cyclicity

55

12 Dasgupta &

Reddy, 2008.45

Genetic etiology of PCOS Lack of genetic studies on

Indian population

13 Dasgupta et al

2010.50

Androgen receptor in

PCOS of south Indian

women

14 Aruna et al.

2004.51

Metformin therapy in

PCOS

Improve menstrual

cyclicity.& fertility

15 Maitra et al.

2004.46

Mutational analysis of

CYP11A1 & Leptin in

PCOS

No variation with the exons

of the gene

-


29

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

.


30

Summary of limitations in the susceptibility studies of PCOS

Lack of universally accepted

diagnostic criteria and definition

NICHD criteria, Ultrasonographic criteria,

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

the study population

Potential statistical erroe

Affected reproduction Difficulty in studying more than one generation

Non-random ascertainment of

famlilies

Acertainment bias

Obscurity in the mode of

inheritance

Autosomal dominant, Monogenic, X-linked

Variable penetrance and

expressivity

Difficulty in assignment of the phenotype

(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).


31

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).


32

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.


33

Table 1. Summary of Diagnostic Criteria for the proband in familial studies

proposed Mode on Inheritance70

.

Author Diagnostic Criteria for I

PCOS

Number Studied Mode of

Inheritance

Cooper et al, 1968 Oligomenorrhea,

hirsutism, polycystic

ovaries (by culdoscopy,

gynecography, or wedge

resection)

18 PCOS women

and their first-

degree relatives and

a control group

Autosomal

dominant with

reduced

penetrance

Givens et al, 1971,

1975, 1988; Cohen et

al, 1975

Oligomenorrhea,

hirsutism, and polycystic

ovaries (exam and surgery)

3 multigeneration

kindreds

(?X-linked)

dominant

Ferriman and Purdie,

1979

Hirsutism and/or

oligomenorrhea, 60% with

polycystic ovaries (by air-

contrast gynecography)

381 PCOS women,

and relatives and a

control group

Modified

dominant

Lunde et al, 1989 Clinical symptoms

(menstrual irregularities,

hirsutism, infertility, and

obesity) and multicystic

ovaries on wedge resection

132 PCOS women

and first- and

second-degree

relatives and a

control group

Unclear, most

consistent with

autosomal

dominant

Hague et al, 1988 Clinical symptoms

(menstrual dysfunction,

hyperandrogenism,

obesity, and infertility) and

polycystic ovaries by

transabdominal ultrasound

50 PCOS women

and 17 women with

CAH and a control

group

Segregation ratios

exceeded

autosomal

dominant pattern

Carey et al, 1993 Polycystic ovaries (by

transabdominal ultrasound)

10 kindreds and 62

relatives

Autosomal

dominant with

90% penetrance

Norman et al, 1996 Elevated androgens,

decreased SHBG, and

polycystic ovaries on

ultrasound

5 families with 24

females and 8 males

Not stated


34

Table 2. Summary of Female Relative Affected by trait in Families of proband of PCOS70

.

Sisters Mothers Female Relatives

Affected Affected Affected

Author Trait (%) (%) (%)

Cooper et al, 1968 History of

oligomenorrhea

9/19(47%) 4/13(31%)

Hirsutism 14/24(58%) 4/13(31%)

Elevated 24-hr urinary

17-ketosteroids

12/19(63%) 2/7(29%)

Enlarged ovaries 10/19(53%) 0/7(0%)

Givens, 1988 Oligomenorrhea 16/67(24%)

Hirsutism 28/54(52%)

Ferriman and

Purdie,

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%)

Hague et al, 1988 Hirsutism (28/107(26%)

Oligomenorrhea 19/107(18%)

Carey et al, 1993 Polycystic ovary

morphology on

ultrasound

37/50(74%)

(Elevated

testosterone

16/50(32%)

Norman et al

1996

Polycystic ovary

morphology on

ultrasound

111/15(73%) 77T

Increased testosterone

or landrostenedione

113/15(87%) 1/5(20%)

Hyperinsulinemia 10/15(66%) 5/5(100%) )


35

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.


36

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.


37

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 Candidate gene Comment

Biosynthesis and

metabolism of

androgens

LH and its receptor Multicentric study, mutation of

LH receptor, no linkage or

association

CYP11 α-cytochrome

P450 side chain

cleavage enzyme

Randomized clinical study,

partial association

CYP 17-cytochrome

P450 17α

hydroxylase/17,20 lyase

No association or linkage

CYP21-cytochrome

P450 21-hydroxylase

Mutation, no association

Androgen receptor Family studies, no association

Sex hormone binding

globulin (SHBG)

Polymorphism, no association

Other steroidogenic

genes

Family study, no association


38

Genes involved in

the secretion and

action of insulin

Insulin gene VNTR One study showed linkage and

association of VNTR with

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

(IRS) proteins

Polymorphisms in IRS1 and

IRS2, no association

Insulin-like growth

factors (IGF)

Association with IGF2 and

PCOS in Spain, no linkage

Calpain-10 Contradictory data, association

in Spanish population

Genes involved

in gonadotrophin

action and

regulation

Dopamine receptor'

genes

Polymorphisms, no association

Follistatin gene Family studies, no clear

association or linkage

Genes involved

in obesity and

insulin resistance

Peroxisome proliferator-

activated receptor-γ gene

(PPARγ)

Polymorphism, prevalence in

finish population, no

association in US and Spain

Human sorbin and SH3

domain-containing 1

gene (SORBS 1)

Multicentric european study,

no association

Paraoxonase (PON1) Polymorphism, no association

Genes encoding other

molecules related to

insulin resistance

No association or linkage


39

Genes involved

in chronic

inflammation

Plasminogen activator

inhibitor-1 (PAI-1)

Association of 4G5G

polymorphism in Greek

population of PCOS women

Tumour Necrosis Factor-

α (TNFα)

No association

Type 2 TNF Receptor

gene

No association

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

IL-6 signal transducer

gpl30(IL-6ST)

No association

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

Allele

Significance

Carey et

al, 1994*

Anovulation and/or

hirsutism and PCO

on ultrasound

71/24 Not stated A2 allele of

CYP17 (17-

alpha

hydroxylase)

OR of 3.57 of being

affected with one allele

(confidence intervals not

stated)

Legro et

al, 1995

Elevated testosterone

and chronic

anovulation

47/42 Hispanic

only

2 allele of

DRD3

(dopamine D3

receptor)

OR of 3.72 (95% CI

1.2-12.8) of being

affected if homozygous

for the 22 allele

Gharani

et al, 1997

Menstrual

disturbances

and/or hirsutism and

PCO on ultrasound

97/110 Not stated 216 allele of

CYPlla

(aromatase)

p value <0.03 for PCOS

with 216 allele

compared to combined

control group of cycling

women without PCO on

ultrasound and

asymptomatic PCO

women

Waterwort

h etal,

1997

Menstrual

disturbances

and/or hirsutism and

PCO on ultrasound

25/54 Not stated III allele of

INS VNTR

(insuline)

OR of 8.20(1.83-50) for

anovulatory PCOS

compared to cycling

women


40

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.


41

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

Lean Obese

PGOS (n = 38) Controls

(n = 38) P value PCOS (n = 64)

Controls

(n = 60} P value

Age(yr) 23.9 ± 4.7 23.9 ± 4.1 0.972 25.9 + 6.6 26.6 ± 6.7 0.483

BMKkgfrn3) 22.9 ± 2.1 20.8 ± 1.8 0.280 35.8 ± 5.2 36.4 ± 4.7 0,433

Waist circumference (cm) 74,3 ± 6.1 69.1 ± 5.8 0.490 10L2 + 12.3 102.5 ± 10.5 0.474

Total abdominal fat (cm2) 263 ±98 259 ± 97 0.936 .607 ± 155 598 ± 81 0.765

Visceral abdominal fat (cm3) 37 ±17 34 ± 16 0.836 108 ±61 101 ± 39 0.591

sc abdominal fat (cm2) 226 ±95 225 ± 92 0.997 499 + 121 497 ± 64 0.905

Fasting 0800-0830 h plasma

Total testosterone (ng/dl) 67.5 ± 18.9 45.0 ± 16.4 <0.001 68.3 + 28.0 48.2 ± 12.8 <0.001

Androstenedione (ng/dl) 349 ± 127 238 ± 79 <0.001 338 ±142 223 ±64 <0.001

DHEA-S (fig/ml) 2.31 ± 1.14 1.90 ± 0.60 0.046 2.22 ± 1.08 1.77 ± 0.62 0.011

SHBG (mraol/liter) 35.3 ± 14.1 63.2 ± 25.1 <0.001 23.5 ± 15.3 35.5 ± 19.8 0.001

Cortisol (µg/dl) 12.4 ± 6.3 15.4 ± 4.1 0.029 12.9 ± 5.1 13.0 ± 2.5 0.9S6

ACTH1-24 stimulation test

% Δ(60-0) Cortisol 170 ± 122 97 ±67 0.009 166 + 109 117 ±33 0.317

% Δ(80-0) DHEA 157 ± 282 109 ± 103 0.294 134 ± 102 114 ± 116 0.633

% Δ(60-0) androstenedione 27 ±37 37 ± 44 0.347 42 ± 40 35 ±41 0.472

% Δ(60-0) 17OH-progesterone 120 ± 94 220 ± 246 0.062 183 ± 134 ISO ± 203 0.949

Dexameihasone suppression test

% Δ(60-0) Cortisol -93 ± 4 -94 ± 3 0.376 -93 + 4 -93 ±3 0.838

% Δ(80-0) DHEA -67 ± 36 -83 ± 7 0.060 -77 ± 11 -82 ± 7 0.287

% Δ(60-0) androstenedione -38 + 29 -35 ± 24 0.306 -36 ±37 -39 ± 25 0.644

% Δ(60-0) 17OH-progesterone -23 ± 69 -38 ± 43 0.323 -26 ±48 -38 ± 40 0.416

Oral glucose tolerance test

GlucoseAUC (rag/dl-min) 17,624+ 3,108 17.948 ± 2,716 0.798 21,565 ± 5,714 23,404 ± 5,343 0.06S

InsutinAUC (µIU/ml-min) 9,373 ± 9,067 6,248 ± 3,056 0.324 19,154 ± 16,725 12,664 ± 8,902 0.005

QU1CKI 0.366 + 0.042 0.374 + 0.031 0.391 0.317 ± 0.02S 0,339 ± 0,059 0,004

ISI 8.43 + 4.66 13.75 ± 9.02 <0.001 3.61 ± 2.36 5.98 ± 5.50 0.018

LDL-cholesterol (mg/dl) 76.4 + 24.8 77.0 ± 16.8 0.915 111.6 ±32.9 116.0 ± 22.3 0.358

HDL-cholesterol (mg/dl) 56.2 ± 12.9 60.5 ± 14.6 0.144 47.2 ± 11.7 54.2 ± 10.7 0.002

Triglycerides (mg/dl) 68.7 + 25.7 60.7 + 25.2 0.421 102.4 ± 49.1 119.5 ± 47.3 0,062

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


42

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 25-

35%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

.

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Review of Literature - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/32447/3/3.review of literature.pdf · Review of Literature 11 shown that hyperandrogenism partly resolves