Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome.
BACKGROUND
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 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) results in compensatory activation of ACTH secretion and adrenal hyperandrogenism. 11beta-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue.


OBJECTIVE
Our objective was to investigate a functional polymorphism in HSD11B1 (T-->G in the third intron rs12086634, which associates with lower 11beta-HSD1 activity) in PCOS with and without obesity.


METHODS
We conducted a case-control study in lean and obese PCOS patients and controls at an academic hospital.


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


METHODS
We assessed 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 ACTH(1-24) (P < 0.001) in all women with PCOS and with higher dehydroepiandrosterone sulfate levels (P < 0.001), greater suppression of dehydroepiandrosterone sulfate by dexamethasone (P < 0.001), and lower fasting plasma low-density lipoprotein cholesterol (P = 0.002) levels in lean PCOS women.


CONCLUSIONS
Genetic variation in 11beta-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.
Gambineri
Alessandra
A
Division of Endocrinology, Department of Internal Medicine, S. Orsola-Malpighi Hospital, via Massarenti 9, 40138 Bologna, Italy. gambineri@aosp.bo.it
Vicennati
Valentina
V
Genghini
Silvia
S
Tomassoni
Federica
F
Pagotto
Uberto
U
Pasquali
Renato
R
Walker
Brian R
BR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D017588:Hyperandrogenism / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*
D008078:Cholesterol, LDL; D019314:Dehydroepiandrosterone Sulfate; D000324:Adrenocorticotropic Hormone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1