The need for effective and reversible methods of fertility control for men, such as those available to women, is widely recognized. Suppression of spermatogenesis by blocking gonadotropin secretion using an implant that delivers an LHRH analog represents one promising approach. However, the loss of gonadotropins results in diminished testosterone synthesis and release, requiring the long-term concomitant administration of an androgen.
The aim of this project is to develop a convenient method of androgen supplementation via an implant. For this purpose we plan to utilize 7alpha-methyl-19-nortestosterone (MENT) a synthetic androgen that is considerably more potent than testosterone. We estimate the daily dose of MENT to be 300-500 mug/day, delivered subdermally via controlled release formulation. We plan to manufacture subdermal implants that would deliver this dose of MENT for up to one year. In addition to its greater potency relative to testosterone, MENT has an advantage over testosterone and its esters which are widely used as androgen supplements. The biological potency of testosterone is amplified 3 to 5 fold in the prostate, seminal vesicles, and sexual skin by its conversion to dihydrotestosterone (DHT). Although the physiological requirement for DHT in the adult male has not be established, it is suspected to be an important factor in the development of prostatic hyperplasia and prostate cancer. MENT does not undergo 5alpha-reduction in the prostate; therefore, its action is not amplified in this organ. Hence, MENT can be used at doses that can adequately maintain muscle mass, potency, and libido without overstimulating the prostate. In the studies proposed here, we will initially determine the biological and toxicological actions of MENT in animals and then conduct Phase 1 and 2 clinical trials in men. We will study the pharmacologic profile of MENT to determine whether, apart from its androgenic actions, MENT has residual estrogenic, progestogenic, or corticosteroid-like actions. In addition, we will study the distribution and disposition of MENT in rats. Provided that no adverse effects are seen in animal studies, pharmacokinetic studies to determine the metabolic clearance rate and bioavailability of MENT in men following intravenous and subdermal injection will be performed. In addition, MENT and testosterone will be compared for their anti- gonadotropic actions in men. One of our aims is to develop and manufacture MENT implants that would deliver a pre-determined dose in a sustained fashion for at least one year and conduct Phase 2 studies. Chronic toxicity studies will be done in rabbits and monkeys to determine the long- term safety of MENT so that the MENT implant method of androgen supplementation can proceed to large-scale clinical trials. Development of a MENT implant would not only be an important component of a male contraceptive, but such a contraceptive could be viewed as health promoting with respect to the development of prostatic disease.
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