Polycystic Ovary Syndrome (PCOS) (defined by NIH, Rotterdam or AES criteria) is traditionally viewed as an ovarian disorder that appears in adolescence and may lead to metabolic complications in adulthood. Emerging evidence, however, indicates that PCOS is primarily a disorder of adipose-tissue hyperexpansion that may originate in early life, develop across childhood and puberty, and advance into end-stage disease (including ovulatory dysfunction and ovarian androgen excess) by adolescence ¹. Prepubertal markers pointing to PCOS risk include a viscerally adipose body composition, high levels of circulating triglycerides, insulin, IGF-I, DHEAS and leptin, and low levels of adiponectin and SHBG.

The novel concept on the ontogeny of PCOS does not only harbour the most common (obese and non-obese) phenotypes of PCOS, but implies also a potential to prevent PCOS by preventing the hyperexpansion of adipose tissue in childhood and puberty. This potential has now been tested in a subgroup of non-obese girls that can be identified early as being at high risk for PCOS, namely low-birthweight girls with precocious pubarche ^2. Treatment with metformin across late prepuberty and puberty was associated with postpubertal reductions in visceral, hepatic and total-body adiposity and also with a reduction in the prevalence of PCOS (5% vs 47% by NIH or AES criteria, after 8 yr of study). Welcome epiphenomena of such early metformin intervention were an increment of adult stature (by ~4 cm towards normal) and a delay of menarche (by ~1 yr towards normal).

Another implication of the novel concept is that intervention in adolescent girls with PCOS should not aim primarily at silencing the ovaries (with an oral contraceptive) but rather aim at reducing adipose-tissue hyperexpansion and low-grade inflammation (for example, with a low-dose combination of metformin, flutamide and pioglitazone) thereby allowing for spontaneous resumption of ovulation and also for waning of androgen excess ³.

1. de Zegher F, Lopez-Bermejo A, Ibáñez L. Adipose tissue expandability and the early origins of PCOS. Trends Endocrinol Metab 2009; 20:418-423.[Pubmed]

2. Ibáñez L, Lopez-Bermejo A, Diaz M, Marcos MV, de Zegher F. Early metformin therapy (age 8-12 yr) in girls with precocious pubarche to reduce hirsutism, androgen excess and oligomenorrhea in adolescence. J Clin Endocrinol Metab 2011; 96:E1262-E1267.[Pubmed]

3. Ibáñez L, Diaz M, Sebastiani G, Sánchez-Infantes D, Salvador C, Lopez-Bermejo A, de Zegher F. Treatment of androgen excess in adolescent girls: ethinylestradiol-cyproteroneacetate versus low-dose pioglitazone-flutamide-metformin. J Clin Endocrinol Metab 2011; 96:3361-3366.[Pubmed]