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Pharmacogenetic Polymorphisms of the AR and Metabolism and Susceptibility to Hormone- Induced Azoospermia

Department of Medicine, University of Sydney (B.Y., D.J.H.); Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital (B.Y.); and ANZAC Research Institute, Concord Hospital (D.J.H.), Sydney 2139, Australia

Address all correspondence and requests for reprints to: Prof. D. J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}med.usyd.edu.au

Abstract

Clinical trials of hormonal male contraceptive regimens have identified a consistent population polymorphism in susceptibility to hormone-induced azoospermia. Using identical hormonal regimens, fewer men of European origin (approximately two thirds) become azoospermic compared with Asian men who virtually all become azoospermic. This variation within and between populations remains unexplained. To investigate pharmacogenetic differences in androgen metabolism or action that might explain variable susceptibility to hormonal-induced azoospermia, we studied single nucleotide polymorphism in the CYP3A4 gene, which encodes the major hepatic T-inactivating enzyme, and CAG and GGC triplet repeats in the AR gene in 75 Australian volunteers participating in a male hormonal contraceptive study and 106 population controls. These men were classified into groups according to whether 6 months of weekly T enanthate injections produced azoospermia (n = 54), near-azoospermia (n = 7), and nonazoospermia (n = 14). Mutagenically differentiated PCR was designed to identify A/G variants in the promoter region of the CYP3A4 gene. Fluorescent-labeled DNA fragments containing either CAG or GGC repeats were amplified from the genomic DNA, and their sizes were determined based on the capillary electrophoresis. The G allele of CYP3A4 gene was absent from the nonazoospermia and near-azoospermia groups, but overall this single nucleotide polymorphism distribution did not differ significantly between men in the azoospermia group or population controls. There were no significant differences in distribution of CAG and GGC triplet repeats among three groups or between them and the population controls based on the maximum likelihood estimate of the odds ratio and CLUMP II analyses. These results suggested that neither genetic polymorphisms in the AR gene (CAG and GGC repeats) nor that in hepatic androgen metabolism (CYP3A4 A/G variant) were the major contributors to the within-population variations in susceptibility to T-induced azoospermia.

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