EstaMisMmg tlie Mininiuni Effective Dose and Additive Effects of Depot Progestiii i n Suppression of Human Spermatogenesis by a Testosterone Depot *

H contraception for males aims to reduce sperm output reversibly by inhibition of pituitary gonadotropin secretion, which, in turn, depletes intratesticular testosterone and arrests spermatogenesis. Two major muMcenter WHO studies that used as the prototype testosterone regimen, weekly im injections of 200 mg testosterone enanthate (TE), have established that hormonally induced azoospermia or severe oBgozoospermia {<3 mol/L/mL) provides highly effective, sustained, and reversible contraception wilh minimal side-effects for 12 months (1, 2). In those studies, a weekly im injection of 200 mg testosterone enanthate was used as a prototype androgen, but the inconvenience, discomfort, and inflexible pharmacodynamics of Received May 13,1996. Revision received July 11,1996. Accepted July 19,1996. Address all correspondence and requests for reprints to: David J. Handelsman, M.D., Ph.D., Andrology Unit, Royal Prin« Alfred Hospital, Departments of Medidne and Obstetrics/Gynecology (EX)2), University of Sydney, Sydney, New South Wales 2006, Australia. B-mail: djh®ined.su. oz.au. * Presented in part at the Annual Scientific Meeting of the Endocrine Society of Australia, Srisbane, Australia, 1994 and the International Congress of Endocrinology, San Frandsco, CA, 1996. This work was supported by Organon (Australia). TE make it necessary to develop better long acting testosterone depot formulations for practical hormonal male contraceptive regimens. For example, TE injections are often imcomfortable (3), and lower doses or frequency of injections have inferior efficacy in suppression of spermatogenesis. The practical requirement for a longer interinjection interval led to development of new long acting depot testosterone preparations (4-6), but their effects on human spermatogenesis have yet to be determined (7). To fill this gap in knowledge, we have studied the effects of an existing depot testosterone formulation, testosterone pellet implants that have nearideal depot steady state release properties (8,9), to determine the likely effects of a depot testosterone formulation either alone or in conjunction wilh a second gonadotropin-suppressing agent (10), In a previous study we established that use of a depot testosterone formulation allowed achievement of major (>50%) reductions in the delivered testosterone dose while maintaining equally effective suppression of spermatogenesis with similar or fewer metabolic side-effects (11). The testosterone dose used in that first study of testosterone implants (12(X) mg; testosterone delivery, 9 mg/day) was arbitrarily selected toward the upper range of doses used conventionally for androgen replacement therapy. 4113 Downloaded from jcem.endojoumals. org on Febmary 1,2006 4114 HANDELSMAN ET A L . J C E & M • 1996 Vol 81 • No 11 which also correspond with the normal endogenous daily production rale (3-10 mg testosterone/day). Second generation hormonal regimens for male contraception under consideration include androgen alone or in combination with second gonadotropin-suppressing agents, such as progestins or GnRH antagonists (10). As a testosterone depot is the basis of all such hormonal regimens, the properties of long acting depot testosterone formulations alone or in concert with second agents are, therefore, critical to future strategies for the development of hormonal male contraception. This study then aimed to examine lower testosterone doses spatming the range of normal testosterone production rates to determine in healthy men 1) the minimum testosterone dose still consistent with effective spermatogenic suppression and 2) how effectively a depot progestin would be in augmenting the highest suboptimal testosterone dose. Subjects and Methods Study design and procedures The study aimed to 1) undertake a downward dose range to determine the minimum testosterone dose that could maintain effective spermatogenic suppression and 2) to determine the effects of a depot progestin when it was added to the first suboptimally suppressive testosterone dose. The study was undertaken in two stages. First, 20 men were randomized into two groups to receive either two or four 200-mg testosterone implants (total dose, 400 or 800 mg; daily release rate, 3.0 or 6.0 mg/day) (8,9). Once the effecte of both of these testosterone doses were evident, a third group of 10 men was recruited to be treated with the testosterone dose (eventually identified as four 200-mg implants) that showed partial suppression of spermatogenesis plus a single im injection of 300 mg depot medrox5rprogesterone acetate (DMPA; Depo-Provera, Upjohn, Kalamazoo, MI). Volunteers provided two baseline sets of semen and blood samples at least 2 weeks apart before hormone administration. Pellets of fused crystalline testosterone (Organon, Sydney, Australia) were implanted subdermally in the lower abdominal wall xmder local anesthesia as previously described (7, 8). The pellets are composed of crystalline testosterone without exdpient, thereby being fully biodegradable and not requiring removal. Subsequently, all volunteers provided monthly semen and blood samples for 12 months. Recavety was defined as the point when sperm density reached prefcreattnent baseline geometric mean or consistently normal levels (>20 million sperm/mL). The study was approved by the Central Sydney Area Health Service Ethics Review Committee.