DESCRIPTION: (provided by applicant) Benign prostatic hyperplasia (BPH) is the most frequent cause of lower urinary tract symptoms and office visits to urologists among elderly men. Despite this, little is known about the etiology and risk factors for BPH and the only proven risk factors for BPH to date are increasing age and an intact androgen metabolism. Estrogens have also been observed to act synergistically with androgens in the development of BPH. Recent studies suggest that the pathogenesis of BPH is related to a decrease in the serum androgen: estrogen ratio with increasing age. Serum hormone levels, however, have not been consistently associated with BPH risk, possibly because serum levels may not reflect intracellular hormone levels in prostate cells. Since hormone levels within prostate cells may reflect genetic variations, polymorphisms in genes that regulate intracellular androgen and estrogen levels in prostate cells may play an etiologic role in BPH. Several functionally significant polymorphisms have been described for genes that determine androgen and estrogen levels. These polymorphisms may alter the risk of BPH by altering hormone levels or by their effects on androgen and estrogen receptor-mediated events within the prostate. We propose to test the hypothesis that genetic polymorphisms in sex hormone receptors and sex hormone metabolizing enzymes are etiologic risk factors for BPH. In Specific Aim 1 we will test the association between genetic polymorphisms in androgen and estrogen receptor genes and measures of BPH obtained longitudinally in a cohort of men randomly selected from the community. In Specific Aim 2 we will test the association between polymorphisms in genes that encode enzymes involved in androgen and estrogen biosynthesis and activation and measures of BPH in the same cohort. We will evaluate the CYP11A1, CYP17, CYP19, 3Beta hydroxysteroid dehydrogenase, 17BETA hydroxysteroid dehydrogenase types 2,3, 5, and SRD5A2 genes. In SpecificAim 3 we will test the association between polymorphisms in genes that encode enzymes involved in estrogen bioactivation and inactivation and measures of BPH in the same cohort. These genes include CYP1A1, CYP1A2, CYP1B1, catechol 0-methyl transferase, sulfotransferase 1A1, and glutathione S-transferases (M1, P1, and T1). This community-based cohort study should provide insights that should improve our understanding of the genetic control of hormonal mechanisms in the pathogenesis of BPH.
|Effective start/end date||3/16/02 → 1/31/06|
- National Institutes of Health: $133,482.00
- National Institutes of Health: $163,104.00
- National Institutes of Health: $201,818.00