Endocrine Abstracts

PCOS is a common endocrinopathy in women that has traditionally been viewed as an ovarian disorder. Accordingly, the classic therapeutic approach, even in adolescents without pregnancy risk, is to silence the ovaries with an oral contraceptive (OC). Recent evidence indicates that PCOS is primarily a disorder of adipose-tissue hyperexpansion that may originate in early life, develop across childhood and puberty, and reach a full-blown stage in adolescence, manifesting with ovulatory dysfunction and symptoms of androgen excess. This novel concept implies that intervention should rather aim at reducing adipose-tissue hyperexpansion, and thus at correcting the associated insulin resistance, visceral adiposity and low-grade inflammation.

In non-obese PCOS adolescents without pregnancy risk, a low-dose combination of flutamide (Flu, an androgen-receptor blocker) and metformin (Met, an insulin-sensitizer) proved superior to a drospirenone-OC in correcting the endocrine-metabolic and body-composition anomalies. In young PCOS women receiving OCs, the addition of low-dose pioglitazone (Pio), to the FluMet combination further increased lean body mass and HMW-adiponectin, and further reduced carotid intima-media thickness (cIMT).

Recently, we compared the effects of low-dose PioFluMet to those of an OC containing ethinylestradiol-cyproteroneacetate (EE-CA). Both treatments reduced androgen excess similarly, but had divergent effects on glucose-induced insulinemia, visceral adiposity, low-grade inflammation, cIMT, menstrual regularity, and on the expression in subcutaneous fat of genes related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism. These divergences were to the advantage of PioFluMet, and were still evident 6 mo post-treatment.

In conclusion, the intervention for reducing androgen excess in adolescence influences the post-treatment phenotype, as judged by markers of insulin sensitivity, visceral adiposity, arterial health, low-grade inflammation and menstrual regularity. A novel low-dose combination of insulin sensitizers plus an anti-androgen holds potential as a pathophysiology-based treatment of PCOS in adolescence and prevents part of the androgen-excess phenotype in adulthood, including adiposity and subfertility.