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This version published online on March 21, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2222
A more recent version of this article appeared on June 1, 2006
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Submitted on October 7, 2005
Accepted on March 13, 2006

GENETIC VARIATION IN 11{beta}-HYDROXYSTEROID DEHYDROGENASE TYPE 1 PREDICTS ADRENAL HYPERANDROGENISM AMONGST LEAN WOMEN WITH POLYCYSTIC OVARY SYNDROME

Alessandra Gambineri*, Valentina Vicennati, Silvia Genghini, Federica Tomassoni, Uberto Pagotto, Renato Pasquali, and Brian R Walker

Division of Endocrinology, Dept. of Internal Medicine, and Centre for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, University of Bologna, Italy (A.G., V.V., S.G., F.T., U.P., R.P.), Endocrinology Unit, Centre for Cardiovascular Sciences, University of Edinburgh, UK (B.R.W.)

* To whom correspondence should be addressed. E-mail: gambineri{at}aosp.bo.it.

Context: Elevated adrenal androgen levels are common in polycystic ovary syndrome (PCOS) but the underlying pathogenetic mechanism is poorly understood. In the rare cortisone reductase deficiency impaired regeneration of active cortisol from inert cortisone by 11{beta}-hydroxysteroid dehydrogenase (11{beta}-HSD1) results in compensatory activation of ACTH secretion and adrenal hyperandrogenism. 11{beta}-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue.

Objective: To investigate a functional polymorphism in HSD11B1 (T->G in the 3rd intron rs12086634, which associates with lower 11{beta}-HSD1 activity) in PCOS with and without obesity.

Design: Case-control study in lean and obese PCOS patients and controls.

Setting: Academic Hospital.

Participants: 102 Caucasian PCOS patients and 98 controls comparable for age, weight and race.

Main outcome measures: Genotype distribution and influence of genotypes on clinical, hormonal and metabolic parameters.

Results: The G allele was significantly related to PCOS status (P = 0.041), and this association was mainly attributable to lean (P = 0.025), rather than obese (P = 0.424), PCOS patients. The G allele was associated with lower 0800-0830 h plasma cortisol (P < 0.001) and higher cortisol response to ACTH1-24 (P < 0.001) in all women with PCOS, and with higher DHEA-S levels (P < 0.001), greater suppression of DHEA-S by dexamethasone (P < 0.001), and lower fasting plasma LDL-cholesterol (P = 0.002) levels in lean PCOS women.

Conclusions: Genetic variation in 11{beta}-HSD1 contributes to enhanced cortisol clearance and compensatory adrenal hyperandrogenism in lean patients with PCOS, but may be protective against obesity and some features of the metabolic syndrome.
Key words: HSD11B1 variants • PCOS • adrenal androgen excess




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