Genetics of polycystic ovary syndrome.
ABSTRACT Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that result in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression. The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contemporary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary syndrome.
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ABSTRACT: The phenotypic heterogeneity recognized in congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency appears to extend to 21hydroxylase (CYP21) mutation carriers. To begin the search for modifying loci responsible for this phenotypic heterogeneity, we performed CYP21 genotype analysis and assays for three candidate modifier loci on genomic DNA samples obtained from 30 adolescent girls with hyperandrogenism, 14 healthy control women, and 15 female obligate CYP21 mutation carriers. The frequency of heterozygosity for CYP21 mutations was increased in women with symptomatic hyperandrogenism (10/30) compared to healthy controls (1/14). There were no significant differences in the frequencies of the modifier variants among the three groups. Although the small sample size precludes strong conclusions, CYP21 nonsense mutation carriers tend to be asymptomatic while missense mutation carriers, i.e. V281L, appear to manifest a PCOS phenotype. Evaluation of additional modifying loci in larger series of patients will help identify new genetic markers associated with PCOS.Journal of pediatric endocrinology & metabolism: JPEM 02/2000; 13 Suppl 5:1315-7. · 0.75 Impact Factor
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ABSTRACT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. The study was conducted at academic medical centers. We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. The intervention was the drawing of blood for DNA extraction. We employed measures of evidence for linkage and association between PCOS and 19 STRs. Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.Journal of Clinical Endocrinology & Metabolism 12/2005; 90(12):6623-9. · 6.43 Impact Factor
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ABSTRACT: Sex hormone-binding globulin (SHBG) is the major sex steroid-binding protein in human plasma and is produced by the liver. Plasma SHBG levels vary considerably between individuals and are influenced by hormonal, metabolic, and nutritional factors. We have now found that a (TAAAA)(n) pentanucleotide repeat, located within an alu sequence at the 5' boundary of the human SHBG promoter, influences its transcriptional activity in association with downstream elements, including an SP1-binding site. Furthermore, SHBG alleles within the general population contain at least 6-10 TAAAA repeats, and the transcriptional activity of a human SHBG promoter-luciferase reporter construct containing 6 TAAAA repeats was significantly lower than for similar reporter constructs containing 7-10 TAAAA repeats when tested in human HepG2 hepatoblastoma cells. This difference in transcriptional activity reflected the preferential binding of a 46-kDa liver-enriched nuclear factor to an oligonucleotide containing 6 rather than 7-10 TAAAA repeats. Thus, a (TAAAA)(n) element within the human SHBG promoter influences transcriptional activity in HepG2 cells and may contribute to differences in plasma SHBG levels between individuals.Journal of Biological Chemistry 10/2001; 276(39):36383-90. · 4.65 Impact Factor
HIPPOKRATIA 2009, 13, 4: 216-223
Genetics of Polycystic Ovary Syndrome
Prapas N, Karkanaki A, Prapas I, Kalogiannidis I, Katsikis I, Panidis D
Division of Endocrinology and Human Reproduction, 2nd Department of Obstetrics and Gynecology, Aristotle
University of Thessaloniki, Greece
Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that re-
sult in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the
most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial
condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology
of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression.
The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile
women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects
signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation,
insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contem-
porary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary
syndrome. Hippokratia 2009; 13 (4): 216-223
Key words: polycystic ovary syndrome, etiology of PCOS genetics of PCOS
Corresponding author: Karkanaki A, 29B, V Olgas Str, 52422, Thessaloniki, Greece, tel. 6932 315022, e-mail address: artemisk@med.
Polycystic Ovary Syndrome (PCOS) is a familial
condition, as has long been noted1,2. Some clinical genet-
ic studies have pointed to an autosomal dominant inheri-
tance1,3,4 while others showed that it was more likely that
the syndrome is a complex trait with oligogenic basis5,6.
Although clustering of cases in families strongly support
the role of genetic factors in the development of PCOS,
heterogeneity of phenotypic features in different families
and even within the same family underscores the impor-
tance of the environmental contribution. Modifications
of molecular structure of gonadotrophins, their receptors
and of the enzymes involved in steroidogenesis, insulin
action and secretion have been under continuous and in-
tense investigation with variable results. Whereas several
positive results have been reported, there are no genes
universally accepted fondamentally important in PCOS
aetiology. This has resulted partially because of various
factors such as the lack of a worldwide accepted diag-
nostic scheme for PCOS, diagnostic capability only in
reproductive-aged women, limited number of patients in
case-control studies, analysis of only one or two variants
of candidate genes and incomplete knowledge of patho-
physiology of the syndrome.
Two possible approaches are used to identify a ge-
netic locus for PCOS genes: (i) association studies where
a predisposing allele is expected to be found more fre-
quently in the affected population than the normal indi-
viduals and (ii) linkage studies where the probands and
their families are investigated to determine if particular
genomic landmarks are distributed independently or in
linkage with the phenotype. While the mode of inheri-
tance is not required for the association studies, it requires
a relatively large set of individuals for a clear conclusion7.
Many genes presented altered expression suggesting thus
that the genetic abnormality in PCOS affects signal trans-
duction ruling steroidogenesis, steroid hormones action,
gonadotrophin action and regulation, insulin action and
secretion, energy homeostasis, chronic inflammation and
Genes involved in ovarian and adrenal
The first step in steroidogenesis is the conversion
of cholesterol into progesterone, catalyzed by the P450
cytochrome side chain cleavage enzyme encoded by CY-
P11a gene located at 15q248. Investigation of CYP11A
gene showed a significant association between serum
testosterone levels and the alleles of the CYP11a with a
5’ untranslated region (UTR) consisting of repeats of a
(tttta)n pentanucleotide, a variable number tandem repeat
(VNTR) polymorphism9. Two other case-control stud-
ies10,11, confirmed these findings in support of the encour-
aging evidence for the association between CYP11a and
PCOS. However, subsequent studies12,13 have failed to
find any significant association between this gene locus
and its VNTR alleles and PCOS. Further investigation is
required due to these controversial results in order to con-
firm a role in the aetiology of PCOS of this gene.
Another part in steroidogenesis is the conversion of
17-hydroxyprogesterone into 11-deoxycortisol which
HIPPOKRATIA 2009, 13, 4
is catalyzed by the 21-hydroxylase enzyme encoded by
CYP21. The deficiency of this enzyme is responsible
for most cases of congenital adrenal hyperplasia and in-
creased serum 17-hydroxyprogesterone levels are corre-
lated with its deficiency. It is a common finding among
women with functional hyperandrogenism or PCOS an
increased serum 17-hydroxyprogesterone response to
ACTH stimulation14,15. Furthermore, patients having both
heterozygote CYP21 mutations and clinical symptoms
exhibit a PCOS-like phenotype16. Accordingly, mutations
of CYP21 have been investigated as a candidate gene in
patients with PCOS. Two studies showed that children
with premature pubarche and adolescent girls with hy-
perandrogenism were heterozygous for mutations in
CYP2116,17. On the other hand, there are other researchers
that found no clear concordance between the CYP21 gen-
otype and the functional origin of androgen excess18,19.
Overall, CYP21 and associated mutations do not seem to
play a key role in the development of PCOS.
The conversion of pregnenolone and progesterone
into 17-hydroxypregnenolone and 17-hydroxyprogester-
one, respectively, and of these steroids into dehydrohe-
piandrosterone (DHEA) and Δ4-Androstendione (Δ4Α)
is catalyzed by the P450c17α enzyme. This enzyme has
both 17α-hydroxylase and 17,20-lyase activities and is
encoded by CYP17 located at 10q24.320. It was reported
increased P450c17α expression and enzymatic activity
in ovarian theca cells from women with PCOS as well
as increased transactivation of the CYP17 promoter21-23.
Moreover, it was showed that CYP17 expression is dys-
regulated at the level of mRNA stability in PCOS theca
cells24. Another study identified a rare T/C single nucle-
otide polymorphism (SNP) in the promoter region of
CYP17 increasing the susceptibility to develop PCOS25.
Subsequently, more comprehensive studies have failed to
detect a significant linkage between CYP17 and PCOS26-
29. Although CYP17 gene does not seem to be a candidate
gene in the pathophysiology of PCOS, it should be noted
that post-translational regulation of this gene product
might play a role in the pathophysiology of PCOS7.
The enzyme complex aromatase converts androgens
to estrogens. This enzyme complex is composed of the
cytochrome P450 aromatase and the NADPH cytochrome
P450 reductase30, and P450arom is encoded by CYP19
located at 15p21.131. Aromatase deficiency has been re-
ported in a number of hyperandrogenic patients32,33. It
has been demonstrated that granulosa cells obtained from
medium-sized follicles of women with PCOS have little
aromatase activity34. Similarly, it has been showed that
when compared to the control follicles, all PCOS follicles
contained low levels of P450arom mRNA, estradiol, and
lower aromatase stimulating bioactivity35. These findings
indicate that the aromatase activity might be decreased
in PCOS follicles, and that the possible androgen excess
resulting might contribute to abnormal follicle develop-
ment. Association studies utilizing SNPs and haplotypes
showed association with PCOS symptoms and serum tes-
Genes involved in steroid hormone actions
All androgens transmit their signal through the andro-
gen receptor which belongs to a family of nuclear tran-
scription factors. The androgen receptor is encoded by the
gene (AR) located at Xq11-1238 and is composed of three
functional domains: the transactivation domain, the DNA
binding domain, and the ligand-binding domain. A VNTR
polymorphism consisting of CAG repeats in exon-1 en-
coding a polyglutamine chain in the N-terminal transac-
tivation domain is embedded in AR39. The transcriptional
activity of androgen receptor is inversely correlated with
the number of CAG repeats40. Variations of these repeats,
even within the normal polymorphic range, have been
related to various disorders associated with low- or high-
androgenic activities41-43. Therefore, decreased number of
CAG repeats with an increased androgen receptor activ-
ity could explain some of the PCOS phenotype exhibiting
the normal serum androgen levels and hyperandrogenism
symptoms44. Nevertheless, some studies failed to prove
any association between this VNTR and PCOS44,45. On
the contrary, other studies demonstrated a significantly
greater frequency of alleles with longer CAG repeats for
infertile PCOS patients compared with fertile women46.
Concluding, AR gene is not a strong candidate for the
etiology of PCOS.
Serum Sex Hormone-Binding Globulin (SHBG) lev-
els are commonly low in patients with hyperandrogen-
ism, especially in association with PCOS47. SHBG is
composed of a homodimeric glycoprotein produced by
hepatocytes and is encoded by a 4-kb gene at the 17p12-
p1348,49. A pentanucleotide repeat polymorphism, at the
promoter of SHBG gene has been described to influence
the transcriptional activity of SHBG gene50. Consequent-
ly, it has been investigated whether this polymorphism
is associated with PCOS and whether polymorphic vari-
ants of the gene are related to serum SHBG levels in
women with PCOS51. A significant association was found
between this polymorphism and PCOS51. PCOS patients
carrying the longer allele genotypes had lower SHBG
levels. In accordance with the latter result, Cousin et al.52
recently demonstrated that longer alleles lowered serum
SHBG levels in hirsute women when compared with six
repeat alleles. Although Urbanek et al.45 did not find any
association or linkage between a marker close to the lo-
cus and PCOS, it could be concluded that SHBG gene is a
potential candidate gene in the pathogenesis of PCOS7.
Genes involved in gonadotropin action and
The gene encoding the β-subunit of LH which is re-
sponsible for LH specificity, has been explored in PCOS
patients7. Initially, it was identified an abnormal form of
LH with two-point mutations, Trp8Arg and Ilg15Thr,
in the LH β-subunit gene53. In addition, these mutations
produced structural changes in the variant LH molecules
(v-LH)54 and caused v-LH to have an increased in vitro
activity and a decreased in vivo half life compared to that
of non mutant form55. However, in vivo activity of v-LH
could not be explained. The implication of v-LH in both
healthy women and PCOS patients was explored and it
was found that the occurrence of these mutations in LH
β-subunit gene was not higher in PCOS compared with
healthy women7,56. On the other hand, subgroup analy-
sis of this study revealed that obese PCOS patients had
a higher frequency of the heterozygous v-LH compared
with obese controls7,56. However, other studies failed to
find any association with PCOS57-59. The assumption that
an activating mutation in the LH receptor gene could
trigger hyperandrogenism in patients with PCOS having
normal serum LH concentrations and high androgen lev-
els was demolished8. Overall, the functional role of the
v-LHs is unclear but it seems not to be crucial in PCOS
pathogenesis or female infertility.
Follistatin, a monomeric glycoprotein encoded by a
single gene, is linked functionally through its role as a
high-affinity binding protein for activin60. Activin is di-
meric glycoprotein which belongs to the TGF-β superfam-
ily, induces FSH and insulin secretion, ovarian follicular
maturation and inhibits LH-stimulated ovarian androgen
production60. Actually, overexpression of follistatin in
transgenic mice resulted in suppression of serum levels
of FSH and arrested ovarian folliculogenesis61. Therefore
overwhelming activin neutralization due to increased
follistatin reduces FSH concentrations, arrests follicular
maturation, augments androgen production, and impairs
insulin release. Because all of these changes are typical
features of PCOS62, follistatin gene has been explored as
a candidate gene in PCOS. The results of distinct studies
are conflicting and significant linkage was failed to be
Genes involved in insulin action and secretion
The insulin gene (INS) is located between the genes
for tyrosine hydroxylase and for IGF-II at 11p15.5, and
includes variable tandem repeats (VNTR) embedded at
the 5’regulatory region of INS65. The VNTR polymor-
phism regulates the transcriptional rate of the INS66 and
probably that of the gene encoding IGF-II67. The num-
ber of the repeats of the INS VNTR ranges from 26 to
200, and due to this feature INS VNTR polymorphism
has three size classes. Class-I alleles comprise the short-
er polymorphism, consisting of a length of 40 repeats.
Class-II alleles are composed usually of 80 repeats and
are uncommon in Caucasian. Class-III alleles compose
the longest polymorphic region having an average of 157
repeats68. Transcriptional activity of the longer polymor-
phic region is greater than that of the shorter one66. Be-
sides their effect on regulating INS expression, they have
been implicated in the pathogenesis of type-2 Diabetes
Mellitus (DM) in many studies69,70. The hyperinsulinemia
in PCOS may be the result of primary insulin resistance
or the direct effect of pancreatic β-cell disorder as defects
in both insulin action71, 72 and in pancreatic β-cell func-
tion73,74 have been reported. Therefore, it was evaluated
the linkage and association of the INS VNTR polymor-
phisms in families with affected members with PCOS75.
An association was found between PCOS and al-
lelic variation at the INS VNTR locus in three separate
populations75. Furthermore, it was found that class III
alleles were associated with anovulatory PCOS in two
independent populations and were more frequent among
women with Polycystic Ovaries (PCO) with symptoms
than those without symptoms75. In addition, it was
shown that the fasting serum insulin levels were sig-
nificantly higher in families with evidence of linkage75..
This evidence stands for the assumption that VNTR
polymorphisms affect the presence of hyperinsulinemia
and insulin resistance in some PCOS phenotypes. It was
also reported that class III alleles were transmitted sig-
nificantly more common from fathers than from mothers
to affected daughter suggesting a “parent of origin” ef-
fect75, 76. In support of this evidence, it was demonstrated
that class III alleles and paternal class III allele trans-
missions were significantly related to increased num-
ber of PCOS features and to reduced insulin sensitivity
among women with PCOS77. In other studies, however,
it was not found any evidence for the linkage of INS and
PCOS and for the association of the class III allele and
of hyperandrogenemia78,79. But there was a difference in
these studies. The ultrasonographic criteria were more
commonly used than the NIHCD criteria. These con-
flicting results may be explained by the variant selection
criteria, the different ethnic and geographic distribution
of studied patients, the selection bias and the small size
of the samples.
The insulin receptor is a heterotetrameric glyco-
protein comprised of two α and two β-subunits and is
encoded by the insulin receptor gene (INSR) located at
the chromosome 1980. Many researchers have tried to
explore whether the mutations of INSR could explain
insulin resistance in PCOS. The first studies of sequenc-
ing the INSR, the tyrosine kinase domain of INSR and
the mutations by molecular scanning of the entire coding
region of INS did not reveal any mutations81-83. More re-
cently, a comprehensive study published by Urbanek et
al.84 demonstrated a linkage with PCOS 367 well-char-
acterized families from Europe. Another study investi-
gating a broad region of the chromosome 19p13.2 found
strong evidence for association with D19S884, support-
ing thus the previous findings84. In a recent study, Sie-
gel et al.85. examined an SNP at the tyrosine kinase do-
main of INSR and found an association in lean patients
with PCOS. This SNP could be a susceptible variant for
PCOS, or a result of linkage disequilibrium with another
The activation of the insulin receptor after insulin
binding requires the autophosphorylation of the β-sub-
unit of the insulin receptor86. The following tyrosine
kinase activity produced after autophosphorylation
phosphorylates insulin receptor substrates (IRS), such
as IRS-1 and IRS-287. Then, IRS-1 and IRS-2 bind and
activate downstream effectors, such as phosphoinositide
3-kinase, to promote the metabolic and mitogenic ac-
tions of insulin. When IRS-1 is dysfunctional, IRS-2 is
HIPPOKRATIA 2009, 13, 4
the main messenger for the intracellular transmission of
the insulin signal but it demands higher insulin concen-
tration for activation88. Several polymorphisms of IRS1
and IRS2 genes (IRS1and IRS2) have been implicated
in insulin resistance. The Gly972Arg polymorphism for
IRS-1 and Gly1057Asp for IRS-2 have been shown to
increase susceptibility to type-2 diabetes mellitus89,90.
Initially, no difference could be found in the distribution
of IRS-1 Gly972Arg and IRS-2 Gly1057Asp alleles in
PCOS patients and controls45, 91; however, it was demon-
strated that the Gly972Arg IRS-1 was more prevalent in
insulin-resistant patients compared with the non-insulin
resistant patients or controls. Many studies following
failed to prove any strong relationship or confirmation of
any possible correlation between polymorphisms of IRS-
1 and IRS-2 and PCOS91-93.
In a recent study Dilek et al.94 reported a higher fre-
quency of the Gly972Arg polymorphism for IRS-1 in
women with PCOS. Furthermore, similar to previous
studies91,93 they found that the Gly972Arg carriers were
more obese, more insulin-resistant and had higher fast-
ing insulin levels in comparison to other PCOS patients
and controls94. These investigators also studied the same
PCOS patients for the potential differential effects of
metformin therapy on the basis of IRS-1 genotype95. Met-
formin administration resulted in lower LH, DHEAS, T,
and fasting insulin levels and decreased insulin resistance
and FAI in Gly972Arg-negative PCOS women more ef-
fectively and significantly when compared with the
Gly972Arg-positive women95. These findings could be
considered a rough indicator of the relationship between
the IRS-1 genotype and the insulin resistance phenotype
of PCOS. Ertunc et al.95 studied the hypothesis that a pos-
sible mechanism for the action of metformin may be aug-
mentation of the tyrosine phosphorylation of the insulin
receptor β-subunit and IRS proteins and the increase of
the insulin-dependent and nondependent cellular glucose
uptake through the family of glucose transporter proteins.
They hypothesized that variant IRS-1 proteins could not
transmit signals in order to increase the glucose uptake of
muscle and adipose cells. This may be an explanation of
the association of IRS-1 genotype with insulin resistance
in some of PCOS patients. The IRS polymorphisms of
these studies seem to be related mostly with insulin resis-
tance rather than PCOS.
Calpain-10 is a cysteine protease that participates in
insulin secretion and action96, and genetic studies have
shown that variation in the gene (CAPN10) encoding cal-
pain-10 is associated with type-2 diabetes97. There was
an effort to determine whether variation in the CAPN10
is associated with quantitative traits related to the patho-
genesis of PCOS and type-2 diabetes98. It was found as-
sociation between the 112/121 haplotype of this gene
and higher insulin levels in African-American women
and an increased risk of PCOS in both African-Ameri-
can and white women7,98. Consecutive studies have had
conflicting results about the relation of polymorphisms
Genes involved in energy homeostasis
During the last years it has been recognized that the
adipose tissue is not only a connective tissue but is also
one of the active endocrine organs which secretes a wide
variety of products called adipocytokines102. As a large
proportion of women with PCOS are overweight, obese
and extremely obese some genes of the most popular adi-
pocytokines have been investigated as candidate genes in
the pathogenesis of PCOS. Sequencing the leptin gene in
a small group of PCOS patients failed to detect any muta-
tions of the coding exons103. In this study, the leptin re-
ceptor gene was also sequenced and revealed previously
identified amino acid variants in exons 2, 4, 12 and the
pentanucleotide insertion in the 3’-untranslated region103.
However, the allele frequencies of these polymorphisms
did not differ from those in the general population.
Recent studies have focused on two polymorphisms,
T45G in exon 2 and G276T in intron 2. It was demon-
strated that these polymorphisms associate with obesity,
insulin resistance, and the risk of developing type-2 dia-
betes104-106. In a study investigating the relationship of
PCOS with 15 genomic variants previously described to
influence insulin resistance, obesity, and type-2 diabetes
mellitus, there was no association between PCOS and
these two common polymorphisms of the adiponectin
gene107. Panidis et al. investigated the possible associa-
tion of the T45G adiponectin gene polymorphisms with
PCOS108. A significant difference was observed between
the groups when genotypes GG and TG were assessed
together109. It was also showed that the carriers of the G
allele had a tendency for lower serum adiponectin levels
in PCOS group109. More recently, the probability that the
T45G and G276T polymorphisms of adiponectin gene
could be associated with PCOS was disputed by two stud-
ies109, 110. Concluding, the adiponectin gene do not seem to
play a causative role in the pathogenesis of PCOS, rather
seem to reflect the severity of the syndrome, at least con-
cerning the metabolic disturbances and to have a role in
the phenotypic variability of PCOS.
Genes involved in chronic inflammation
Tumor necrosis factor (TNF)-α is a cytokine secreted
by adipose tissue with an important role in insulin resis-
tance111. The polymorphisms in the TNF-α gene do not
seem to have a key role in the etiology of PCOS. In one
study the carriers of the mutation 308 A alleles showed
increased androgen and 17-hydroxyprogesterone levels
before and after GnRH stimulation112. These data may
be indicative of the hypothesis that TNF-α gene poly-
morphism might be a modifying factor for phenotypic
features. Other genes involved in chronic inflammation,
such as TNFR2 (type-2 TNF receptor) gene113, IL-6114,
IL-6 signal transducer gp 130115, IL-6 receptor115 genes
have also been investigated for association with PCOS,
but without significant results.
Abnormalities in the coagulation and fibrinolytic
pathways contribute to the development of cardiovas-
cular disease in PCOS patients116. Elevated plasminogen
activator inhibitor-1 (PAI-1) levels are associated with in-
creased cardiovascular risk and increased thrombogenic
tendency. Women with PCOS also present an increased
activity of PAI-1117. In order to investigate the role of the
PAI-1 polymorphism in PCOS patients, the polymorphism
4G/5G which is associated with higher PAI-1 concentra-
tions, was evaluated in Greek women with PCOS and it
was found a higher frequency in PCOS women compared
with controls118. It was also reported that PCOS women
have higher levels of PAI-1 and that the presence of the
4G allele in the PAI-1 promoter region of the gene further
increases the PAI-1 levels118.
In addition to the genes mentioned above, many dif-
ferent genes such as HSD3B2119, 17α-hydroxysteroid
dehydrogenases120, dopamine receptor121,122, IGF107, al-
dosterone synthetase123, paraoxonase123, glycogen syn-
thetase124, resistin125, apoprotein E126 have been studied.
Results were either controversial or without clear conclu-
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