Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive

Abstract

The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer-acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics.

Male hormonal contraception: hope and promise

“…Multiple androgen-progestin drug combinations have been studied 3,14 , but together comprise less than one-fifth of the total hormone exposure 1,10–12 . The vast majority of these studies have utilized testosterone, although two other androgens, 7-alpha-methyl-19-nortestosterone and dimethandrolone undecanoate, are also being evaluated 30,31 . Few androgens alone, or combination androgen-progestin regimens have actually been evaluated for contraceptive efficacy.…”

“…One such androgen is dimethandrolone undecanoate (7alpha, 11beta-methyl-19-nortestosterone), which like other 19-nortestosterone derivatives binds to both androgen and progesterone receptors 31 . This orally bioavailable androgen is 4-fold more potent than testosterone and about half as potent as progesterone, for their respective cognate receptors.…”

“…Global and androgen-regulated gene expression did not differ despite expected differences in intraprostatic dihydrotestosterone, testosterone and androstenedione with 10 weeks of treated prototype MHC therapy: testosterone, testosterone with depot medroxyprogesterone acetate, testosterone with dutasteride or placebo therapy 73 . Testosterone with dutasteride mimics an androgen that is minimally 5 alpha reduced, such as 7-alpha-methyl-19-nortestosterone and dimethandrolone undecanoate 30,31 . Concerns regarding prostate growth due to 5 alpha reduction of androgens in the prostate gland would also be negated by the use of such androgens.…”

Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) – Lesson from Adjudin

“…The approach is to use injectable androgen ( e.g., testosterone undecanoate with or without a progestin such as levonorgestrel or etonogestrel), oral androgen ( e.g., dimethandrolone undecanoate) or androgen implants in men to block spermatogenesis by down-regulating intratesticular testosterone level [15, 17–21], which must be maintained at a level of ~100-fold over the blood level in the systemic circulation in both humans and rodents to sustain spermatogenesis [22–24]. In short, this approach disrupts the hypothalamic-pituitary-testicular axis via an elevated serum testosterone level through the injectable androgen or androgen implants, which shuts down the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, thereby suppressing the secretion of luteinizing hormone (LH) from the pituitary gland, leading to a reduced androgen production by Leydig cells in the interstitium to disrupt spermatogenesis [15, 25].…”

It is time for new male contraceptives!

“…During these last 10 years, the development of male contraception is largely supported by the World Health Organization, Contraceptive Research and Development program, and the Population Council but the strongest and continuous support comes from the Contraceptive Research Branch of Eunice Kennedy Shriver National Institute of Child Health and Human Development. The NICHD is supporting male contraceptive clinical trials in new orally bioavailable androgens (Attardi et al, 2006;Surampudi et al, 2014) and a transdermal method (Ilani et al, 2012) in collaboration with the Population Council. The institute also supports research in identifying and developing new targets of male contraception.…”