Evaluation of Endocrine and Metabolic Parameters in the New Diagnostic Phenotypes of Polycystic Ovary Syndrome
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.
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