Endocrine Abstracts

PCOS is a complex endocrine syndrome characterized by the combination of reproductive aberrations, namely hyperandrogenism and chronic anovulation, with metabolic defects. Insulin resistance is a major component in metabolic as well as reproductive aspects of PCOS. The pathogenesis of the syndrome remains under investigation. However, environmental factors appear to unmask a genetically determined susceptibility to PCOS and also determine the specific phenotypic expression of the syndrome. Particularly, environmental triggers acting during early stages of human development, from prenatal life to puberty, may convert a predisposed genotype to the phenotypical manifestation of PCOS. In addition, environmental determinants may modulate the clinical severity of PCOS, ranging from a mild phenotype (nonhyperandrogenic anovulatory, as determined by Rotterdam criteria¹, or normoovulatory hyperandrogenic, as determined by Rotterdam¹ and Androgen Excess Society criteria²) to the full-blown phenotype of classic PCOS.

The environmental component in the pathogenesis of PCOS includes dietary factors and other exogenously derived substances. Overnutrition with consumption of calorie-rich diets leads to obesity which may accelerate the development or aggravate the clinical course of PCOS^3–5. Beyond calorie excess, the high intake of dietary advanced glycation end products (AGEs) may also contribute to the pathogenesis and perpetuation of PCOS. In particular, increased AGEs levels were reported in lean, normoglycemic and non-insulin resistant women with PCOS⁶ and AGEs were found to accumulate in human polycystic ovaries⁷. These bioactive molecules may exert actions on both ovarian compartments, since circulating AGEs levels were positively correlated with serum levels of testosterone⁶ and Antimüllerian hormone (AMH)⁸, a theca cell and a granulosa cell product respectively.

Bisphenol A (BPA) emerges as another environmental contributor to the pathogenesis of PCOS. BPA belongs to endocrine-disrupting chemicals, which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostasis or reproduction. Most importantly, data from experimental animals have demonstrated that neonatal exposure to BPA leads to PCOS development⁹. Extending these findings to humans, a recent study has shown that serum BPA levels are increased in lean and obese PCOS women compared to age and BMI matched controls¹⁰. Moreover, serum BPA levels were positively associated with serum androgen levels and insulin resistance indices¹⁰. The latter finding suggests a role of BPA in androgen synthesis in addition to its potential contribution to insulin resistance in PCOS.

Overall, PCOS may arise from a combination of genetic predisposition and environmental insults that lead to failure of reproductive and metabolic functions. Environmental exposure may start in utero and persist during early life until adolescence, when PCOS becomes clinically evident. Unravelling the specific environmental components of the pathogenesis of PCOS may help to elucidate the etiology and the ideal treatment of the syndrome.

References: 1. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004 19 41–47.

2. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of the Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009 91 (2) 456–488.

3. Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, Homburg R, Hickey T, Franks S, Tapanainen J, Balen A, Abbott DH, Diamanti-Kandarakis E & Legro RS. PCOS forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrinol 2010 Dec 15 [Epub ahead of print].

4. McCartney CR, Blank SK, Prendergast KA, et al. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab 2007 92 430–436.

5. Moran L & Teede H. Metabolic features of the reproductive phenotypes of polycystic ovary syndrome. Hum Reprod Update 2009 15 (4) 477–488.

6. Diamanti-Kandarakis E, Katsikis I, Piperi C, Kandaraki E, Piouka A, Papavassiliou AG & Panidis D. Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS). Clin Endocrinol 2008 69 634–641.

7. Diamanti-Kandarakis E, Piouka A, Livadas S, Piperi C, Katsikis I, Papavassiliou AG & Panidis D. Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome. Eur J Endocrinol 2009 160 (5) 847–853.

8. Diamanti-Kandarakis E, Piperi C, Patsouris E, Korkolopoulou P, Panidis D, Pawelczyk L, Papavassiliou AG & Duleba AJ. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol 2007 127 581–589.

9. Fernandez M, Bourguignon N, Lux-Lantos V & Libertun C. Neonatal exposure to bisphenol A and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect 2010 118 1217–1222.

10. Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, Palimeri S, Panidis D & Diamanti-Kandarakis E. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab 2010 Dec 30 [Epub ahead of print].