Evaluation of Endocrine and Metabolic Parameters in the New Diagnostic Phenotypes of 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. In 2003 a committee of experts joined in Rotterdam under the auspice of the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology, defined diagnostic criteria. It should include unless two of the following: menstrual irregularities; excess of male hormones (clinic or biochemical) and polycystic ovaries under ultrasound examination; 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. PCOS shares components of Metabolic Syndrome for the high prevalence of insulin resistance (abdominal obesity, impaired glucose tolerance, type 2 diabetes, hypertension, endothelial dysfunction, impaired lipid profile and probably cardiovascular disease). All these findings lead us to assume that women with PCOS could have an increased risk of developing cardiovascular disease. Nevertheless 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.

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.

Eligibility Criteria:
Inclusion Criteria:

Two of the following

* Ovulatory Dysfunction: Clinically defined by oligomenorrhea (menstrual cycles lasting more than 35 days) or amenorrhea (lacking of menstruations in the last 90 days). In patients with menstrual cycles between 25 and 35 days, a serum level of progesterone drawn during days 21 to 23 of cycle \< a 4 ng/ml.
* Clinical hyperandrogenism defined for the presence of hirsutism, acne, androgenic alopecia) and or biochemical (increases in total testosterone, bioavailable testosterone or free androgen index).
* Polycystic Ovaries: Defined by the presence, in as less one ovary, of 12 or more follicles (measuring 2 to 9 mm in diameter) and or increased ovarian volume \> 10 mL).

Exclusion Criteria:

* Hyperprolactinemia
* Hypothyroidism
* Other causes of hyperandrogenism like Cushing's Syndrome, congenital adrenal hyperplasia, androgens secreting tumors
* Drug therapy used three months previous to enrollment in the study