Endocrine Abstracts (2010) 21 SIG3.1

Androgen activation by 5[alpha]-reductase in patients with PCOS

Jeremy Tomlinson

University of Birmingham, Birmingham, UK.

Polycystic ovary syndrome (PCOS) is one of the most prevalent conditions facing the clinical endocrinologist, affecting 5–10% of all women. The condition is characterized in part, by clinical and / or biochemical androgen excess. Despite its prevalence, the molecular mechanisms that contribute to its pathogenesis remain relatively poorly understood. Whilst androgen excess forms part of the diagnostic criteria, the source of the androgen excess is unclear, and ovarian, adrenal and adipose tissue have all been implicated.

The 5α-reductases (5αR) are a series of enzymes that are able to activate testosterone to dihydrotestosterone and three separate isoforms have been identified. Type 1 (5αR1) is located in skin hair follicles and liver, whereas type 2 (5αR2) is highly expressed in the prostate in men, liver and urogenital epithelium. Both isoforms are expressed in the granulosa cells of the ovary. Recently, type 3 (5αR3) has been identified, although is pattern of expression and biological function remain to be determined. Importantly, in addition to activating androgens, these enzymes are also crucial in clearing and inactivating cortisol and this has been implicated in the pathogenesis of PCOS.

5αR activity is increased in patients with PCOS compared with BMI-matched controls indicative of enhanced androgen activation. Furthermore, 5αR inhibitors including Finasteride (selective 5αR2 inhibitor) have been shown to be efficacious in treating symptomatic hyperandrogenism. Finally, increased 5αR activity has also been linked to the metabolic phenotype associated with PCOS, in particular, insulin resistance and obesity. Whilst it is possible that this observation may relate solely to the generation of potent androgens, the contribution of enhanced glucocorticoid clearance to the metabolic phenotype needs to be considered.

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