World population continues to grow at an astonishing rate and surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive options as they have high efficacy rates (over 95%) and are fully reversible. However, little is known about the extra-gonadal effects of exogenous hormone administration in men. We propose two randomized, placebo-controlled trials that will further our understanding of the potential benefits and risks of androgens and progestins on the prostate and cardiovascular system, organ systems with high disease prevalence in men that might be modulated by androgens and progestins. We have recently developed technical expertise performing molecular analyses on prostate tissue specimens obtained from normal volunteers after hormone manipulation. We propose in Study 1 to determine intraprostatic hormone levels, cell turnover, and cell-specific gene expression in men treated with 3 months of testosterone (T) gel, T + dutasteride, a drug that blocks the conversion of T to the more potent androgen dihydrotestosterone and may contribute to prostate cancer prevention, or T + intramuscular depomedroxyprogesterone (IM DMPA), a promising male hormonal contraceptive regimen. This study will provide significant insights into the impact of hormonal manipulation on the prostate at the molecular level in normal, healthy men. Exogenous testosterone and progestins suppress serum high density lipoprotein (HDL) and cause weight gain. These changes may be associated with increased visceral adiposity, systemic inflammation, insulin resistance and increased risk of cardiovascular disease. Because there have been no systematic studies done on the effects of androgens + progestins on these cardiovascular risk factors, we propose in Study 2 to compare the effects of 6 months of treatment with T gel alone vs. T + IM DMPA vs. T + oral MPA on serum HDL, body composition, inflammatory markers, insulin sensitivity, and spermatogenesis. In Study 2, we will determine how T alone and T + IM DMPA affect these measures, and whether oral administration of the progestin MPA impacts these cardiovascular risk factors, and spermatogenesis, differently, due to first-pass hepatic effects. Together these studies will significantly advance our knowledge of the potential risks and benefits of T-based contraceptive regimens and T + MPA, a promising male hormonal contraceptive regimen.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD042454-07
Application #
7631252
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
7
Fiscal Year
2008
Total Cost
$63,813
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Berkseth, Kathryn E; Rubinow, Katya B; Melhorn, Susan J et al. (2018) Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. Obesity (Silver Spring) 26:1898-1904
Rubinow, Katya B; Houston, Barbara; Wang, Shari et al. (2018) Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice. Asian J Androl 20:276-283
Chen, Yan; Zhu, Jin-Yi; Hong, Kwon Ho et al. (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13:582-590
Paik, Jisun; Treuting, Piper M; Haenisch, Michael et al. (2018) Can inhibition of retinoic acid biosynthesis function as a non-hormonal female contraceptive? Contraception :
Sharma, Manju; Braun, Robert E (2018) Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. Development 145:
Rubinow, Katya B; Vaisar, Tomas; Chao, Jing H et al. (2018) Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J Clin Lipidol 12:1072-1082
Haenisch, Michael; Treuting, Piper M; Brabb, Thea et al. (2018) Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract 12:93-101
Swerdloff, Ronald S; Dudley, Robert E; Page, Stephanie T et al. (2017) Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr Rev 38:220-254
Ayoub, R; Page, S T; Swerdloff, R S et al. (2017) Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology 5:278-285
Rubinow, Katya B; Chao, Jing H; Hagman, Derek et al. (2017) Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men. Am J Physiol Endocrinol Metab 313:E528-E539

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