Global population continues to grow at an astonishing rate. Surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive as they have high efficacy rates, are fully reversible, and, among novel male contraceptives, are the most advanced in clinical development. There are concerns, however, regarding the extra-gonadal effects of exogenous hormone administration in men, particularly surrounding long-term risk for cardiovascular disease (CVD). Data regarding the impact of androgens and progestins on risk factors for CVD are mixed. On the one hand, male hormonal contraceptives lower high-density lipoprotein (HDL), a cardioprotective lipoprotein, and can cause weight gain that might increase insulin resistance over time. In contrast, low levels of serum testosterone are associated with elevated risk for CVD, insulin resistance, and mortality, calling into question the notion that exogenous androgens necessarily increase CVD risk in a dose dependent manner. The overall objective of this proposal is to clarify the impact of male hormonal contraceptives on three important risk factors for CVD in vivo. We will focus on the effects of androgens and progestins on 1) HDL-mediated cholesterol efflux, a key cardioprotective function of HDL, 2) HDL-associated protein composition, and 3) adipose tissue inflammation, a critical mediator of insulin resistance. Emerging data implicates each of these in the pathogenesis of CVD and each is likely modified by exogenous steroids. We will conduct a placebo-controlled trial in healthy men to directly quantify the effects of increasing levels of serum testosterone alone or combine with an effective contraceptive progestin, depomedroxyprogessterone acetatate (DMPA), on human HDL and adipose tissue. To compliment our human study, we will use genetically modified mice to determine whether androgens reduce CVD risk via effects on adipose tissue macrophages, a central cell type in orchestrating adipose tissue inflammation and insulin resistance. The proposed studies will provide both clinical and mechanistic data regarding the impact of androgens and progestins on male metabolism and CVD risk.
Male contraceptives with non-contraceptive health benefits would be ideal. Cardiovascular disease is very prevalent in men;long-term data regarding effects of androgens and progestins on cardiovascular disease risk in men are lacking. Combining androgens with progestins is a promising male hormonal contraceptive strategy. The proposed studies will significantly advance our knowledge of the potential risks and benefits of androgen/progestin-based regimens on male metabolism and cardiovascular disease risk.
|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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