Reduced serum testosterone (T), or hypogonadism, is estimated to affect about 5 million American men, including both aging and young. Low serum T has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, and decreased libido. In men with low serum T that results from reduced luteinizing hormone (LH), treatment with hCG will stimulate Leydig cell T formation and thus ameliorate symptoms. Typically, however, decline in serum T is not due to reduced LH, but rather (or in addition) to reduced Leydig cell T production resulting from a primary testicular problem. Administration of hCG to these men rarely elevates serum T. Exogenous T can be administered to raise serum T levels in these men and thus treat symptoms. However, based on a number of alarming recent studies, the FDA issued a report warning that men who take exogenous T-boosting products may face increased risk of stroke and heart attack. Additional recent evidence suggests that exogenous T also might promote prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig cell T production and therefore in reduced intratesticular T and sperm numbers. This makes exogenous T administration inappropriate for men who wish to father children. In this application, we propose to explore a novel method by which to increase serum as well as intratesticular T levels by restoring the ability of Leydig cell themselves to produce young levels of T. Our approach is based on current understanding of the molecular mechanisms involved in Leydig cell T formation. Translocator protein (18-kDa TSPO) is a ubiquitous mitochondrial protein that is expressed at very high levels in Leydig cells. It is clear from in vitro studies of cell lines and primary cells that TSPO drug ligands are able t induce the translocation of cholesterol from the outer to the inner mitochondrial membrane in steroidogenic cells, and thereby stimulate steroid formation. We propose to undertake proof-of-principle, preclinical studies designed to pharmacologically increase cholesterol transfer into the Leydig cell mitochondria in conditions of hypogonadism, and in this way stimulate T production. We will test the hypothesis that drug ligand-induced activation of TSPO will restore Leydig cell T production to higher levels in hypogonadal Brown Norway rats, elevate serum and intratesticular T levels, and maintain spermatogenesis. The effect of treatment on adrenal and brain steroid synthesis, and on prostate and cardiac outcomes, will be assessed, as will overall toxicity. If proven successful and safe, the potential impact of this approach to elevate T could be paradigm shifting for the clinical treatment of hypogonadism in aging men and in all hypogonadal men who desire children.

Public Health Relevance

Reduced serum testosterone (T) occurs commonly in both aging and young men, and often is associated with altered mood, fatigue, decreased lean body mass and bone mineral density, increased visceral fat, and decreased libido. Although exogenous T supplementation can be used to restore T levels and thereby alleviate symptoms of low T, there are reports of significant, negative health effects of this approach, including increased risk of stroke, heart attack and prostate tumorigenesis, as well as suppressive effects on sperm formation. We propose to develop and evaluate the effectiveness and safety of a novel method to elevate serum T in hypogonadal rats by restoring the ability of the Leydig cells themselves to produce their former 'young' levels of T.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Aging Systems and Geriatrics Study Section (ASG)
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Fuldner, Rebecca A
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Johns Hopkins University
Schools of Public Health
United States
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