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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.

11β-Methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT) with androgenic and progestational activity. (i) Quantify 11β-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11β-MNTDC in men. (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11β-MNTDC or placebo given with or without food. (i) In vitro 11β-MNT/11β-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. 11β-MNT avidly binds and activates human androgen and progesterone receptors, but 11β-MNTDC has minimal activity. Single oral doses of 11β-MNTDC were well tolerated without serious adverse events. Administration of 11β-MNTDC with food markedly increased average 11β-MNTDC and 11β-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). A single, oral dose of 11β-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11β-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Abstract Context Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men. Objective This work aimed to assess changes in bone turnover markers with DMAU administration in a 28-day study. Design A randomized, double-blind, placebo-controlled study was conducted. Setting This study took place at 2 academic medical centers. Participants Healthy men, age 18 to50 years (n = 81), participated. Intervention Men received 0, 100, 200, or 400 mg of oral DMAU for 28 days. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and procollagen type I amino-terminal propeptide (P1NP; bone formation marker) were measured on days 1 and 28. Main Outcome Measures Changes in bone turnover markers and serum hormones over the treatment period were measured. Results On day 28, median serum T and E2 were markedly suppressed in all treatment groups vs placebo (P < .001 for both). Percentage change (%) in serum P1NP significantly differed across treatment groups (P = .007): Serum P1NP significantly increased in the 200 mg (5%, interquartile range [IQR] –7% to 27%) and 400 mg (22%, IQR –1% to 40%) groups relative to placebo (–8%, IQR –20% to 0%). Change (%) in serum CTX did not differ between groups (P = .09). Conclusions DMAU administration for 28 days to healthy men leads to marked suppression of serum T and E2, yet increases P1NP, a serum marker of bone formation. Longer-term studies of the potent androgen DMAU are warranted to determine its impact on bone health in men.

Abstract Context Night-shift work causes circadian misalignment, predicts the development of metabolic diseases, and complicates the interpretation of hormone measurements. Objective To investigate endogenous circadian rhythms, dissociated from behavioral and environmental confounds, in adrenal and gonadal steroids after simulated shift work. Methods Fourteen healthy adults (ages 25.8 ± 3.2 years) were randomized to 3 days of night or day (control) shift work followed by a constant routine protocol designed to experimentally unveil rhythms driven endogenously by the central circadian pacemaker. Blood was sampled every 3 hours for 24 hours during the constant routine to concurrently obtain 16 Δ4 steroid profiles by mass spectrometry. Cosinor analyses of these profiles provided mesor (mean abundance), amplitude (oscillation magnitude), and acrophase (peak timing). Results Night-shift work marginally increased cortisol by 1 μg/dL (P = 0.039), and inactive/weak derivatives cortisone (P = 0.003) and 18-hydroxycortisol (P < 0.001), but did not alter the mesor of potent androgens testosterone and 11-ketotestosterone. Adrenal-derived steroids, including 11-ketotestosterone (P < 0.01), showed robust circadian rhythmicity after either day- or night-shift work. In contrast, testosterone and progesterone showed no circadian pattern after both shift work conditions. Night-shift work did not alter the amplitude or acrophase of any of the steroid profiles. Conclusion Experimental circadian misalignment had minimal effects on steroidogenesis. Adrenal steroids, but not gonadal hormones, showed endogenous circadian regulation robust to prior shift schedule. This dichotomy may predispose night-shift workers to metabolic ill health. Furthermore, adrenal steroids, including cortisol and the main adrenal androgen 11-ketostosterone, should always be evaluated during the biological morning whereas assessment of gonadal steroids, particularly testosterone, is dependent on the shift-work schedule.

Context: 11[beta]-Methyl-19-nortestosterone-17[beta]-dodecylcarbonate (11[beta]-MNTDC) is an orally bioavailable prodrug of 11[beta]-methyl-19-nortestosterone (11[beta]-MNT) with androgenic and progestational activity. Objectives: (i) Quantify 11[beta]-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11[beta]-MNTDC in men. Design and Setting: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Participants and Intervention: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11[beta]-MNTDC or placebo given with or without food. Main Outcome Measures: (i) In vitro 11[beta]-MNT/11[beta]-MNTDC human receptor binding and trans-activation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. Results: 11[beta]-MNT avidly binds and activates human androgen and progesterone receptors, but 11[beta]-MNTDC has minimal activity. Single oral doses of 11[beta]-MNTDC were well tolerated without serious adverse events. Administration of 11[beta]-MNTDC with food markedly increased average 11[beta]-MNTDC and 11[beta]-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). Conclusions: A single, oral dose of 1133-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11[beta]-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive. (J Clin Endocrinol Metab 104: 629-638, 2019)

A promising development in hormonal male contraception (HMC) is a class of bifunctional prodrugs that combine both androgenic and progestogenic activities into a single molecule. Examples of these prodrugs currently being studied are dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) (1, 2). The inactive prodrugs are cleaved to release active drug over a 24-hour timeframe, providing once-a-day dosing. As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production and circulating levels. Low testosterone levels might lead to unpleasant symptoms of hypogonadism if DMAU and 11β-MNTDC are not providing sufficient and effective androgenicity. Therefore, we examined the impact of the novel progestogenic androgens on serum testosterone levels and acceptability of varying dosages of these oral prodrugs in a secondary analysis of two Phase 1 placebo-controlled trials. Healthy male participants were randomized to take two or four oral pills of active drug or placebo per day. As DMAU and 11β-MNTDC share similar mechanisms of action and tolerability, we examined the association of dosage as well as testosterone concentrations on combined drug acceptability versus placebo. Survey respondents across the two trials (39 DMAU, 30 11β-MNTDC, 28 combined placebo group) shared similar baseline demographics. After seven days of usage, testosterone levels for those using either prodrug dropped to levels below 100 ng/dL while testosterone levels for those using the placebo (400-600 ng/dL) remained within the reference. Recipients of either DMAU or 11β-MNTDC reported greater willingness to use the active prodrug in the future (75%), compared to placebo recipients (46.4%, p=0. 007). Throughout the 28-day oral pill usage, while average testosterone levels during the period of suppression (day 7 to 28) were very low, they were significantly higher in the 200 mg group than in the 400 mg group (92.7 ng/dL vs. 49.6 ng/dL, p-value <0. 001). Participants using 2 pills (200 mg, n=33) versus 4 pills (400 mg, n=35) of active drug did not report a significant difference in general satisfaction, willingness to use in the future, or recommendation of the study pill to other men (p=0.85, p=0.48, p=0.60). In placebo-controlled trials, men randomized to use active, daily oral progestogenic androgen prodrugs reported greater acceptability with their respective regimens than did men who received placebo pills despite low serum testosterone levels. Oral hormonal male contraceptive pill prototypes, DMAU and 11β-MNTDC, significantly suppress serum testosterone while providing sufficient androgenicity to be acceptable to most men. (1) Thirumalai et al. J Clin Endocrinol Metab. 2019; 104: 423-32. (2) Yuen et al. J Clin Endocrinol Metab. 2020;105. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Background: While the metabolic effects of testosterone have been well studied, the effects of co-administration of an androgen and progestin are less established. Two novel compounds being investigated for male hormonal contraception, dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), have both androgenic and progestational activity. Aim: Characterize the effects of DMAU and 11β-MNTDC on metabolic parameters including weight, lipid parameters, insulin resistance, and adiponectin. Methods: Two randomized, double-blind, placebo-controlled studies in healthy men were previously performed to assess the safety and tolerability of DMAU and 11β-MNTDC taken orally for 28 days. Insulin and adiponectin assays were performed on a subset of banked samples. Changes in weight, LDL-C, HDL-C, fasting glucose, HOMA-IR, and adiponectin were assessed. Two way ANOVA with post hoc Tukey HSD was performed to assess for dosage (0, 200, or 400mg) and drug (DMAU or 11β-MNTDC) effects. Results: A total of 85 subjects were included in this secondary analysis. There was a statistically significant decrease in HDL-C (mean change -11 and -15 mg/dL) and increase in weight (3 and 2 kg) and LDL-C (18 and 23 mg/dL) in the DMAU and 11β-MNTDC 400mg groups respectively. There was no significant difference between the 200 and 400 mg groups nor differences between the two androgens. There were no statistically significant changes in fasting glucose, adiponectin or HOMA-IR. Conclusion: There were mild changes in weight, HDL-C, and LDL-C after 28 days of DMAU and 11β-MNTDC without significant changes in markers of insulin resistance or differences between the two compounds. Changes in metabolic parameters should be monitored and considered during further development of compounds for male hormonal contraception.

Background: Injectable hormonal male contraceptives (HMC) injectables appear safe and are effective in clinical trials, but global surveys suggest men would prefer an oral pill. 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is orally bioavailable and well-tolerated. When taken daily with food for 28 days, the drug decreases serum gonadotropins and testosterone without significant impact on mood. If ongoing studies demonstrate that daily 11β-MNTDC consistently suppresses spermatogenesis to <1 million/mL in healthy men, oral 11β-MNTDC could be an effective HMC pill. Surveys of participant satisfaction and method acceptability for promising HMC pill prototypes, like oral 11β-MNTDC, are needed. Objective : To determine satisfaction with and acceptability of a daily oral 11β-MNTDC HMC pill Study Design: In a double-blind, randomized, placebo-controlled trial of a 28-day regimen of daily oral 11β-MNTDC at two academic medical centers, healthy male volunteers completed baseline and end-of-treatment surveys assessing their experience, satisfaction with, and willingness to use daily oral 11β-MNTDC. Results: Of 42 participants, 40 (30 11β-MNTDC, 10 placebo) completed end-of-treatment surveys. Respondents were primarily college-educated, sexually active white men between 21-40 years old. Less than 20% of participants cited initial concerns about safety and missing doses. Following treatment, nearly 90% of participants affirmed that taking the pill was easy to remember and did not interfere with their daily routine. Although one-third (37% 11β-MNTDC vs. 20% placebo, p=0.45) reported bothersome side effects, and 28% (30% 11β-MNTDC vs. 20% placebo, p=0.66) reported potential concerns about safety, these rates were neither statistically different in those taking active drug versus placebo nor associated with method satisfaction. The majority of participants reported satisfaction with the method (73% 11β-MNTDC vs. 70% placebo, p=0.84), that they would recommend it to others (90% 11β-MNTDC vs. 100% placebo, p=0.56), and that they would use the drug regimen as their primary contraceptive even if having to pay (67% 11β-MNTDC vs. 50% placebo, p=0.35). Half of participants (50% 11β-MNTDC vs. 67% placebo, p=0.51) affirmed that the method exceeded initial expectations. Respondents who reported being more likely to miss a dose were also more likely to report dissatisfaction with the study drug (p=0.03). Conclusion: The majority of participants in a 28-day trial of daily, oral 11β-MNTDC pills were satisfied with the regimen, would recommend the drug to others, and would pay to use the drug even when adverse or off-target effects (e.g. changes in libido and/or mood) were considered. If 11β-MNTDC is demonstrated to suppress spermatogenesis uniformly to very low levels, it would be acceptable to men desiring reversible contraception.

Background: 11β-MNTDC is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT). It is a modified testosterone (T) with androgenic and progestational activity being developed as a male contraceptive. 11β-MNTDC suppressed serum T and gonadotropin production while maintaining androgenic functions in preclinical studies. Single oral doses of 11β-MNTDC (up to 800 mg) were well-tolerated in healthy men and reversibly suppressed serum T. Methods: We conducted a placebo-controlled, double-blind study at two academic medical centers. 40 healthy men (18-50 years) were randomized to receive either oral placebo (P, n=10) or 11β-MNTDC 200 (n=14) or 400 (n=16) mg dosed daily for 28 consecutive days and completed the study. Participants presented twice weekly for assessment of the primary outcome measures, namely safety parameters (vital signs, hematocrit, liver function tests, lipids, EKG, QTc interval, adverse events). Subjects also underwent serial blood sampling over 24h on Day 1 and 28 to assess the pharmacokinetic and pharmacodynamic effects of oral 11β-MNTDC, including 24h serum drug concentrations, T, LH and FSH suppression (secondary outcomes). Potential effects on mood (PHQ-9) and sexual function (PDQ) were evaluated at baseline, day 28, and end of study via standardized questionnaires. Results: 11β-MNTDC was well tolerated. There were no serious adverse events or significant clinical concerns. None of the participants discontinued due to an adverse event. Administration of 11β-MNTDC resulted in a dose-proportional increase in serum 11β-MNTDC and 11β-MNT concentrations over 24h. This was accompanied by a dose-related profound suppression of serum Cavg24h T (median P 461.1 vs 200mg 22.3, 400mg 7.6 ng/dL), LH (median P 6.0 vs 200mg 1.9, 400mg 0.3 IU/L) and FSH (median P 3.1 vs 200mg 1.2, 400mg 0.2 IU/L) on day 28. Treatment related adverse events occurred in 3 participants in the placebo compared to 22 participants administered 11β-MNTDC including 4 with fatigue, 6 with headache, 5 with acne, 5 with decreased libido and 2 with mild erectile dysfunction. There were no significant changes in blood pressure, liver enzymes, EKG, and QTc. Depression (PHQ-9) scores did not change. On a scale of 0-7, sexual desire score was reduced (median -0.80) without changes in sexual activity in the 400 mg group. As anticipated, there were significant dose-related increases in weight (median change P 0.6 vs 200mg 1.3 and 400mg 1.9 kg), hematocrit (median change P 0 vs 200mg 1.2, 400mg 1.0%), LDL-C (median change P 3 vs 200mg 10, 400mg 18 mg/dL), and decrease in HDL-C (median change P 3 vs 200mg 9, 400mg 11.5 mg/dL). Conclusion: Daily oral administration of 11β-MNTDC for 28 days in healthy men is well tolerated and resulted in marked suppression of endogenous testosterone and gonadotropin production. These results warrant further evaluation of 11β-MNTDC as a potential oral male contraceptive. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.