The proprietary androgen, 7a-methyl-19-nortestosterone (MENT?) in combination with DMPA progestin is being investigated for male contraception. MENT is 10 fold more effective than testosterone (T) in suppressing gonadotropins and maintaining muscle mass. Therefore, it is possible to deliver a dose of MENT via silastic implants that will be effective in suppressing gonadotropins and spermatogenesis. In addition, MENT will have potential health benefits on prostate, bone and muscle mass and myelin regeneration based on the results of in vitro and animal studies. For example, (1) MENT is resistant to 5a-reduction, therefore, it is less stimulatory on the prostate at a comparable replacement dose;(2) MENT is aromatized to a potent estrogen, thereby, maintains sexual behavior in animals and men;(3) MENT does not bind to sex hormone binding globulin (SHBG) and has similar pharmacokinetics as T;and (4) MENT was recently shown to increase remyelination of neuronal cells (M. Schumacher, unpublished). Hence the long-term use of MENT in men is expected to be superior to T with added health benefits. First generation exogenous treatment regimens using testosterone injection, gel or biodegradable pellet or MENT acetate (MENT Ac) silastic implant showed limited efficacy in male contraceptive clinical trials. Second generation regimens using androgen in combination with a progestin such as levonorgestrel, etonogestrel or DMPA showed higher efficacy in suppressing spermatogenesis. In this research project, we will use a regimen of three MENT Ac implants (releasing ~ 1500 pg/day of MENT Ac) in combination with either a single DMPA injection at the start or multiple injections at 3 month intervals. MENT Ac implants will be manufactured, and the clinical trial will commence during the next funding cycle (pending approval). In addition, pharmacological and mechanistic studies will be conducted to determine the safety and health benefits of MENT and DMPA use. MENT Ac is an acetylated derivative of MENT and is used in implant manufacturing for optimal release rates. MENT and MENT Ac are used interchangeably since MENT Ac released from implants is rapidly hydrolyzed to the active MENT. Depo Provera (DMPA, Pfizer) injectable is an approved female contraceptive and is being investigated for male contraception. Depo provera releases an active progestin, medroxyprogesterone acetate (MPA). MPA will be used in animal and in vitro studies.

Public Health Relevance

; Even though, women have several contraceptive choices, nearly half of them will discontinue use for various reasons. Surveys have indicated that men are willing to participate in contraceptive clinical trials and will use them if safe and effective methods are available. Development of a hormonal male contraceptive method based on MENT Ac implants in combination with DMPA injectable formulation will be particularly relevant for couples to control unintended pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD029990-23
Application #
8720030
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
Chen, Haiqi; Mruk, Dolores D; Xia, Weiliang et al. (2016) Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) - Lesson from Adjudin. Curr Med Chem 23:701-13
Tang, Elizabeth I; Mruk, Dolores D; Cheng, C Yan (2016) Regulation of microtubule (MT)-based cytoskeleton in the seminiferous epithelium during spermatogenesis. Semin Cell Dev Biol 59:35-45
Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M et al. (2016) AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function. Am J Pathol 186:270-84
Li, Nan; Mruk, Dolores D; Lee, Will M et al. (2016) Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis? Semin Cell Dev Biol 59:141-156
Gao, Ying; Lui, Wing-Yee; Lee, Will M et al. (2016) Polarity protein Crumbs homolog-3 (CRB3) regulates ectoplasmic specialization dynamics through its action on F-actin organization in Sertoli cells. Sci Rep 6:28589
Li, Nan; Mruk, Dolores D; Chen, Haiqi et al. (2016) Rescue of perfluorooctanesulfonate (PFOS)-mediated Sertoli cell injury by overexpression of gap junction protein connexin 43. Sci Rep 6:29667
Chen, Haiqi; Mruk, Dolores D; Lee, Will M et al. (2016) Planar Cell Polarity (PCP) Protein Vangl2 Regulates Ectoplasmic Specialization Dynamics via Its Effects on Actin Microfilaments in the Testes of Male Rats. Endocrinology 157:2140-59
Tang, Elizabeth I; Lee, Will M; Cheng, C Yan (2016) Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis. Endocrinology 157:1644-59
Wen, Qing; Cheng, C Yan; Liu, Yi-Xun (2016) Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol 59:89-98
Jesus, Tito T; Oliveira, Pedro F; Silva, Joaquina et al. (2016) Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells. Fertil Steril 105:825-833.e3

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