Professional Documents
Culture Documents
REVIEW OF LITERATURE
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.
Review of Literature
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.
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.
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.
ratio(U/O)
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.
10
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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.
11
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.
12
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.
13
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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.
14
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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.
Adult
Adolescent
(cm)
C-04
>90% of 88 cm >88
(F/M)
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
>110
>100
>110
>100
15
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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.
16
Review of Literature
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.
17
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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
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.
18
Review of Literature
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.
gonadotrophin
(HCG),
they
showed
hyper
responses
of
17-
agonist;
they
continued
to
exhibit
17-hydroxyprogesteroos
hyperresponsiveness to HCG42.
19
Review of Literature
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.
20
Review of Literature
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.
21
Review of Literature
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
weight
gain,
clinical
hyperandrogenism,
22
Review of Literature
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.
23
Review of Literature
nutritional guidance and a support system may help to change unhealthy lifestyle
choices and lose weight.
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
24
Review of Literature
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
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.
&
Study
Outcome
Year
Reference
number in
original
article54
Rodin DA et al.
PCOS
& metabolic
1998
abnormalities
women is 52%
Zagar et al 2005
Indian women
3
Wijeyaratne et al
2002
Caucasians
Zagar et al 2002
Hisutism in Kashmiri
women
by F-G scoring
Jialal et al 1987
Sundaram et al
PCOD
and
insulin
resistance in non-obese
correlated
2003
7
Kaushal et al
2004
insulin resistance
metabolic syndrome +
Management of metabolic
syndrome
metabolic syndrome +
Deedwania
12
15
16
media thickness+
&
Gupta 2006
9
Hyperandrogeneism and IR
2006
hypertension +
17
18
29
women
10. Babu et al 2004
Genetic polymorphism in
Imbalance in
35
27
Review of Literature
11
Kriplani &
Agarwal, 2004
12
13
Dasgupta
&
Reddy, 2008.
45
Dasgupta et al
2010.
50
Improvement in menstrual
55
cyclicity
Genetic etiology of PCOS
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
46
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
Rotterdam criteria
Non-random ascertainment of
Acertainment bias
famlilies
Obscurity in the mode of
inheritance
Variable penetrance and
expressivity
Locus heterogeneity
Environmental interactions
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.
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.
32
Review of Literature
Table 1. Summary of Diagnostic Criteria for the proband in familial studies
proposed Mode on Inheritance70.
Author
Mode of
Inheritance
Oligomenorrhea,
18 PCOS women
Autosomal
hirsutism, polycystic
dominant with
gynecography, or wedge
a control group
penetrance
3 multigeneration
(?X-linked)
kindreds
dominant
resection)
Givens et al, 1971,
Oligomenorrhea,
1979
control group
dominant
contrast gynecography)
Lunde et al, 1989
Clinical symptoms
Unclear, most
(menstrual irregularities,
consistent with
second-degree
autosomal
relatives and a
dominant
control group
Clinical symptoms
50 PCOS women
(menstrual dysfunction,
hyperandrogenism,
autosomal
group
dominant pattern
Segregation ratios
polycystic ovaries by
transabdominal ultrasound
Carey et al, 1993
Polycystic
ovaries
transabdominal ultrasound)
relatives
dominant with
90% penetrance
Elevated androgens,
5 families with 24
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
Female Relatives
Affected
Affected
Affected
(%)
(%)
(%)
9/19(47%)
4/13(31%)
14/24(58%)
4/13(31%)
oligomenorrhea
Hirsutism
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%)
Hirsutism
8/129(6%)
17/132(13%)
Oligomenorrhea
19/129(15%) 16/132(12%)
Purdie,
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.
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.
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.
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.
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.
Candidate gene
LH and its receptor
Comment
Multicentric study, mutation of
metabolism of
LH receptor, no linkage or
androgens
association
CYP11 -cytochrome
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
Polymorphism, no association
globulin (SHBG)
Other steroidogenic
genes
37
Review of Literature
Genes involved in
action of insulin
IRS2, no association
Insulin-like growth
factors (IGF)
Calpain-10
Genes involved
Dopamine receptor'
in gonadotrophin
genes
action and
Follistatin gene
regulation
Polymorphisms, no association
Genes involved
in obesity and
insulin resistance
(PPAR)
domain-containing 1
no association
gene (SORBS 1)
Paraoxonase (PON1)
Polymorphism, no association
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
No association
gene
Interleukin-6 gene (IL-6) No linkage, or association
IL-6 signal transducer
No association
gpl30(IL-6ST)
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
CYP17 (17-
on ultrasound
alpha
hydroxylase)
stated)
Legro et
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
97/110
Not stated
receptor)
216 allele of
CYPlla
(aromatase)
compared to combined
PCO on ultrasound
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
(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.
42