Trial Information

Descriptive, Transversal Study of Evaluation of Cardiovascular Risks Factors and Prevalence of Metabolic Syndrome in the Different Phenotypes of Women With Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a very frequent endocrine disease of women in
reproductive age, with an estimated prevalence of 5 to 10 % according to the studied
population.

Its cause remains not fully understood. PCOS is characterized by hyperandrogenism, chronic
anovulation and / or polycystic ovaries. Patients, in a high percentage of cases show
obesity, hirsutism, acne, menstrual irregularities and infertility. Clinically and
biologically PCOS is a heterogeneous disorder with a not yet clear pathogenesis. Therefore,
discussions on its definition and diagnosis still subsist. Seventy years ago Stein and
Leventhal published their findings in 7 women with amenorrhea, hirsutism, acne, obesity and
polycystic appearance of their ovaries. Since then, diagnostic criteria for PCOS suffered
multiple modifications.

In 1990 a group of experts under the auspices of the National Institutes of Health (NIH)
considered affected by PCOS every woman with hyperandrogenism and chronic anovulation; after
having excluded other specific diseases that mimic that clinic like Cushing's syndrome,
androgen secreting tumors and congenital adrenal hyperplasia (NIH criteria). The presence of
polycystic ovaries under ultrasound exploration was considered controversial criteria and
was not included for diagnosis. In May 2003 a new committee of experts joined in Rotterdam
under the auspice of the American Society for Reproductive Medicine (ASRM) and the European
Society for Human Reproduction and Embryology (ESHRE), included polycystic ovaries by
ultrasound to the physiologic abnormalities for diagnosis. Thus, diagnosis should include
unless two of the following: oligo or anovulation; hyperandrogenism (clinic or biochemical)
and polycystic ovaries under ultrasound examination.

Rotterdam consensus widened the definition already proposed by NIH in 1990 giving rise to
four subgroups or phenotypes:

1- Women with polycystic ovaries, hyperandrogenism and oligoamenorrhea. 2. Women with normal
ovaries, hyperandrogenism and oligoamenorrhea. 3- Women with polycystic ovaries,
oligoamenorrhea without hyperandrogenism. 4- Women with polycystic ovaries, hyperandrogenism
with normal menses. This new criteria increase de prevalence, diversity and also controversy
about PCOS. Some authors like Franks accept that the new consensus gave significant advances
in the etiological knowledge of the syndrome. Others, like Azziz, proposed that is premature
to include ovulating women and the ones with no clear evidence of androgens excess. In the
last subgroups is no clear if they have an increased risk of cardiovascular and / or
metabolic diseases.

The clinical heterogeneity of the syndrome is the product of a multifaceted process; where
converge genetic and environmental influences. Many hypotheses try to explain the primary
defect; but insulin resistance (IR) seems the most suitable according to most of studies. IR
is present in 60 to 70 % of patients independently of obesity. Compensatory hyperinsulinism
has a fundamental role in the pathology of PCOS. In vitro insulin stimulates androgen
synthesis in ovary theca cells, acting on its own receptor and inhibits hepatic synthesis of
sex hormone binding globulin (SHBG), increasing free testosterone. It also leads to the
amplification of LH induced expression of cytochrome P450c 17 alfa (a limiting enzyme in
androgen synthesis).

PCOS shares components of Metabolic Syndrome for the high prevalence of IR (abdominal
obesity, impaired glucose tolerance, type 2 diabetes, hypertension, endothelial dysfunction,
impaired lipid profile and probably cardiovascular disease). Dunaif and Sam using NIH
criteria for PCOS diagnosis suggested a sole entity called XX syndrome. Central adiposity
seems to play an important role in the development of this metabolic phenotype trough the
production of many cytokines and adipocytes derived proteins, known as "adipocytokines".
Failures on its regulation could contribute to the development of IR. The late one for
itself or trough metabolic disturbances is associated with endothelial dysfunction and
atherosclerosis.

Adiponectin is exclusively secreted in adipose tissue and could inhibit the expression of
vascular endothelial adhesion molecules induced by TNF-alfa. So, it could be an anti
atherogenic effect of adiponectin. In obese subjects and those with type 2 diabetes and IR
(whom has a high incidence of coronary atherosclerosis) it was found low plasma levels of
adiponectin. Recent studies propose low serum levels of adiponectin as an early marker for
metabolic risk in women with PCOS.

C Reactive Protein (CRP), a low grade inflammation marker, has been suggested as an
independent predictor of cardiovascular event in women; even more relevant than LDL
cholesterol. Those facts have been reassured in the recent publication of Reynolds risk
score which adds to the classical ATP III´s Framingham score; the usage of CRP in women,
increasing its prognostic value. Higher levels of CRP have been described in women with PCOS
compared with normal controls.

All these findings lead us to assume that women with PCOS have an increased risk of
developing cardiovascular disease. As there is no universally accepted definition for PCOS,
studies that show an association between PCOS and cardiovascular disease are of relative
value. Legro stated that "It is premature to assume that every PCOS phenotype has the same
cardiac and metabolic risk factors".

So, it is important to evaluate the endocrine and metabolic characteristic in different
phenotypes of PCOS to prevent the co morbidities that predispose to cardiovascular disease.
And of course to avoid unnecessary measures in groups that could not show increased risk.