Daily Oral Administration of the Novel Androgen 11β-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men

Abstract

Background: 11β-methyl-19-nortestosterone (11β-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11β-MNT dodecylcarbonate (11β-MNTDC), was well tolerated in healthy men.

Methods: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11β-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11β-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires).

Results: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11β-MNTDC resulted in a dose-related increase in serum 11β-MNTDC and 11β-MNT concentrations sustained over 24 hours. Administration of 11β-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11β-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11β-MNTDC groups.

Conclusion: Daily oral 11β-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11β-MNTDC as a potential male oral contraceptive.

Trial registration: ClinicalTrials.gov NCT02754687.

Keywords: androgen; gonadotropins; male hormonal contraception; progestin; testosterone suppression.

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Figures

Figure 1.

Disposition of participants in the trial.

Figure 2.

Serum concentrations of 11 β-MNTDC and MNT after oral administration of 0 (placebo), 200, and 400 mg 11 β-MNTDC for 28 days in healthy male volunteers. Twenty-four hour multiple blood sampling was performed on days 1 and 28 and trough concentrations were obtained in between the pharmacokinetic studies. Data are presented as medians and 95% CI. D, day; EOS, end of study

Figure 3.

(A) Serum LH, (B) FSH, (C) T, (D) calculated free T, (E) SHBG, and (F) E2 were suppressed from day 4 to 28 and returned to baseline concentrations at day 49. LH and FSH are displayed on a log scale to enhance visualization of the low values. Dotted lines represent the reference ranges of these hormones. D, day; EOS, end of study

Figure 4.

Percent of men that showed suppression of both serum LH and FSH from days 1 to 31. None of the participants in the placebo group had both LH and FSH suppressed to P = 0.029 using threshold ≤1 mIU/mL). The lower limit of quantification for both LH and FSH is 0.1 IU/L. D, day; EOS, end of study.