Male contraceptives: One step closer?

• The high failure rate of condoms and the unreliability of vasectomy reversals highlight the need for effective and easy-to-use male contraceptives.
• Results from recent phase 1 clinical trials suggest that two candidate male contraceptive pills — DMAU and 11 beta-MNTDC — are safe and well-tolerated.
• Further analysis of data from these studies suggests that these contraceptive pills produce the desired decrease in hormones that stimulate sperm production.
• The analysis also reveals that individuals using these novel compounds showed greater willingness to use these drugs than placebo, suggesting that these drugs may have promise as oral contraceptive agents.

A study presented at the recent Endocrine Society annual conference in Atlanta, GA, reports that two oral male contraceptive candidates were effective in suppressing hormones needed for sperm production and received a favorable response from most users.

These novel synthetic compounds dimethandrolone undecanoate (DMAU) or 11 beta-methyl-19-nortestosterone-17 beta-dodecylcarbonate (MNTDC) have properties that mostly resemble androgens but are also similar to a lesser extent to progesterone.

The lead author, Tamar Jacobsohn, an M.D. candidate at New York University, told Medical News Today that “[f]urther research on this novel class of prodrugs, progestogenic androgens, may lead to the first single agent, hormonal contraceptive pill — or even the first male contraceptive pill generally.”

These drugs may also help treat hypogonadism, Jacobsohn added.

Need for male contraceptives

Estimates based on data from 2011 suggest that around 45% of pregnancies in the United States are unintended, with 42% of such unintentional pregnancies resulting in abortions. Moreover, the burden of responsibility for preventing pregnancies is unevenly borne by women. Thus, there is a need for effective male contraceptive agents.

Currently, the most commonly used male contraceptives include condoms and vasectomy. However, condoms are associated with a high failure rate, and many men are worried about getting vasectomies.

Additionally, the effects of vasectomy are not completely reversible. Thus, there is a need for effective, reversible, and easy-to-use male contraceptives.

“The development of contraceptive products for men will both increase available options for men and allow for many women to have more options in sharing the contraceptive burden,” Jacobsohn said.

Male sex hormone contraceptives

The hypothalamus is a small brain region that regulates the release of various hormones from the pituitary gland. For instance, the hypothalamus controls the release of gonadotropin hormones from the pituitary gland.

These gonadotropins stimulate the testes, resulting in the release of the male sex hormone testosterone and sperm production. Testosterone, in turn, acts on the hypothalamus and the pituitary gland to prevent excessive production of gonadotropins, thus helping to maintain testosterone levels within a normal range.

Exploiting this negative feedback mechanism, researchers have shown that the administration of androgens, which include testosterone and other natural and synthetic male sex hormones, can have contraceptive effects. For instance, the administration of testosterone can block the production of gonadotropins and subsequently inhibit both testosterone and sperm production by the testes.

Besides suppressing sperm production, these androgens also help maintain healthy muscle, bones, and physiological processes, including those responsible for sexual function, that rely on testosterone.

However, high doses of testosterone are needed to produce the desired inhibition of sperm production. Researchers have shown that testosterone in combination with progestin, a synthetic form of progesterone, has a better ability to suppress sperm production than testosterone alone. Yet even these drugs have to be taken 2-3 times a day to achieve the desired levels of inhibition of sperm production.

Prof. Robert McLachlan, a reproductive endocrinologist at Monash University, explained that “[t]he trouble is that all testosterone molecules are often not well absorbed or broken down in the body to be ineffective and not provide proper replacement therapy.”

This highlights the need for better oral male contraceptives. Two oral male hormone contraceptive candidates — DMAU and 11 beta-MNTDC — have shown promise in animal studies. Moreover, recent placebo-controlled, phase 1 randomized clinical trials have shown that DMAU and 11 beta-MNTDC are safe and well-tolerated.

These drugs exist in their inactive form and are slowly broken down into their active form over a 24-hour period, allowing for a single daily dose schedule.

Acceptability of the novel compounds

Using data from these phase 1 trials, the researchers evaluated the acceptability of these drugs, which is a measure of the willingness and the ability of the patient to use the medicine as intended. The acceptability of a drug is important in ensuring adherence to the recommended course of treatment.

The researchers combined data from the DMAU and 11 beta-MNTDC treatment groups from the phase 1 trials due to their similar mechanism of action.

The participants received either 2 (200 milligrams) or 4 (400 milligrams) pills of DMAU or 11 beta-MNTDC daily for 28 days and their serum testosterone levels were monitored every 24 hours.

The researchers found that using either 2 or 4 pills of one of the two drugs resulted in lower serum testosterone levels than placebo at 7 days after treatment onset and these suppressed testosterone levels were sustained until the end of the study.

A larger number of participants using these contraceptive agents were willing to use these drugs in the future than the placebo group. Although individuals using 4 pills showed lower testosterone levels than those using 2 pills, both groups reported similar levels of general satisfaction, and willingness to use these candidate contraceptive agents or recommend them to other men.

Dr. Christina Wang, an endocrinologist at the University of California Los Angeles, commented on this study, saying:

“Using these novel compounds despite the lowering of serum testosterone levels to very low levels, the participants did not complain of symptoms of testosterone deficiency. This suggests that both compounds are very androgenic and we need to show in longer-term studies that the compounds suppress spermatogenesis.”

Dr.McLachlan also noted: “I am encouraged to see that these molecules provide both gonadotropic suppression and also maintain the apparent effects on the volunteers over a period of a month. So these two molecules are certainly prototypes for further development for all formulations. There’s a great deal of work yet to be performed, in terms of establishing the correct dose, when there’s individual variability in response and any side effects.”

The researchers intend to investigate these two compounds further in phase 2 clinical trials.

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