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

Yuen, Fiona; Thirumalai, Arthi; Pham, Cindy; Swerdloff, Ronald S.; Anawalt, Bradley D.; Liu, Peter Y; Amory, John K.; Bremner, William J.; Dart, Clint; Wu, Hongsheng; Hull, Laura; Blithe, Diana L.; Long, Jill; Wang, Christina; Page, Stephanie T.

doi:10.1210/clinem/dgaa032

Cited by 33 publications

(25 citation statements)

References 56 publications

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“…Analysis of the metabolic effects of these two compounds in our subset of participants agreed with previously published results. 28,29 The combined analyses did not show significant differences between these two progestational androgens. Both drugs increased body weight compared to placebo, with a median weight increase of 3 kg in the 400 mg groups.…”

Section: Reprodumentioning

confidence: 80%

“…The Lundquist Institute at Harbor-UCLA Medical Center using validated methods. 28,29 This same central laboratory also measured in- Numerous viruses have been detected in human semen. 6 Viruses may persist in semen and last longer in seminal fluid than in other body fluids due to the immune privilege of the testes and the contribution of the blood-testes barrier to resistance to therapeutic agents.…”

Section: Methodsmentioning

confidence: 99%

“…27 Phase 1 studies of oral DMAU and 11β-MNTDC in healthy men have demonstrated safety and tolerability when taken daily for 28 days. 28,29 The effects of DMAU and 11β-MNTDC on weight and lipid profile were previously reported as safety information, 28,29 but never directly compared in a combined analysis. The effects of these two compounds on insulin resistance and adiponectin have never been examined in men.…”

Section: Introductionmentioning

confidence: 99%

“…These two 19‐nortestosterone derivatives are not aromatizable and thus do not have estrogenic activity in vitro 27 . Phase 1 studies of oral DMAU and 11β‐MNTDC in healthy men have demonstrated safety and tolerability when taken daily for 28 days 28,29 …”

Section: Introductionmentioning

confidence: 99%

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Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β‐MNTDC in healthy men

et al. 2021

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Background: Dimethandrolone (DMA) and 11β-methyl-19-nortestosterone (11β-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men.Objective: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. Materials/Methods:In two clinical trials of DMA undecanoate (DMAU) and 11β-MNT dodecylcarbonate (11β-MNTDC), oral prodrugs of DMA and 11β-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo.Results: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11β-MNTDC. An increase in LDL-C was seen with 11β-MNTDC but not with DMAU.Discussion: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. Conclusion:Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

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Section: Reprodumentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β‐MNTDC in healthy men

et al. 2021

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“…As a consequence of the low intratesticular testosterone concentration, spermatogenesis is arrested at the premeiotic stage and testicular volume remains small (Coviello et al, 2004;Rey, 2014). In fact, modified testosterone compounds with androgenic and progestational activities, like dimethandrolone undecanoate (DMAU) and 11β-MNT dodecylcarbonate (11β-MNTDC), are being tested as hormonal male contraceptives (Ayoub et al, 2017;Yuen et al, 2020). Therefore, gonadotropin rather than androgen therapy is indicated when fertility is pursued in patients with central hypogonadism (Young et al, 2019).…”

Section: Androgen Treatmentmentioning

confidence: 99%

Androgen Treatment in Adolescent Males With Hypogonadism

Rey

Grinspon

2020

Am J Mens Health

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During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic–pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty. Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations. Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.

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Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non‐hormonal Male Contraceptive Targets

Garcia,

Matzuk

2024

Molecular Reproduction Devel

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The development of novel non‐hormonal male contraceptives represents a pivotal frontier in reproductive health, driven by the need for safe, effective, and reversible contraceptive methods. This comprehensive review explores the genetic underpinnings of male fertility, emphasizing the crucial roles of specific genes and structural variants (SVs) identified through advanced sequencing technologies such as long‐read sequencing (LRS). LRS has revolutionized the detection of structural variants and complex genomic regions, offering unprecedented precision and resolution over traditional next‐generation sequencing (NGS). Key genetic targets, including those implicated in spermatogenesis and sperm motility, are highlighted, showcasing their potential as non‐hormonal contraceptive targets. The review delves into the systematic identification and validation of male reproductive tract‐specific genes, utilizing advanced transcriptomics and genomics studies with validation using novel knockout mouse models. We discuss the innovative application of small molecule inhibitors, developed through platforms like DNA‐encoded chemistry technology (DEC‐Tec), which have shown significant promise in preclinical models. Notable examples include inhibitors targeting serine/threonine kinase 33 (STK33), soluble adenylyl cyclase (sAC), cyclin‐dependent kinase 2 (CDK2), and bromodomain testis associated (BRDT), each demonstrating nanomolar affinity and potential for reversible and specific inhibition of male fertility. This review also honors the contributions of Dr. David L. Garbers whose foundational work has paved the way for these advancements. The integration of genomic, proteomic, and chemical biology approaches, supported by interdisciplinary collaboration, is poised to transform male contraceptive development. Future perspectives emphasize the need for continued innovation and rigorous testing to bring these novel contraceptives from the laboratory to clinical application, promising a new era of male reproductive health management.

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

Cited by 33 publications

References 56 publications

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β‐MNTDC in healthy men

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β‐MNTDC in healthy men

Androgen Treatment in Adolescent Males With Hypogonadism

Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non‐hormonal Male Contraceptive Targets

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