Aromatase inhibitor methyl testosterone and testosterone induced bone sparing

Yale University, New Haven CT

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Abstract

Osteoporosis is a common disease in postmenopausal women and aging men resulting in considerably morbidity and mortality. While estrogen is a recognized bone-sparing agent, reports on the effect of testosterone (T) on bone mass are controversial and variable. T's variable action on bones could be due to the requirement of aromatization of T to estrogen, followed by action on bone cell estrogen receptors: This laboratory was first to report the presence of immunoreactive aromatase in osteoblasts in culture. 17alpha-methyl testosterone (MT) is a synthetic steroidal androgen with low affinity for the androgen receptor. It is widely used in hormone replacement therapy in women. MT is also a powerful aromatase (estrogen synthetase) inhibitor that may block local estrogen formation. We have shown that MT inhibits both aromatization of androstenedione and T-induced proliferation of breast cancer cells by inhibiting aromatase. We propose to use a similar preclinical experimental approach to assess the mechanism of action of T on rat bone mass: We will test the effect of T alone and of T plus MT on bone maintenance in ovariectomized female rats. If MT blocks T's bone maintenance, this will indicate that T's action is indirect, via aromatization, and justify clinical studies.