Male Hypogonadism: Emerging Research and Trials to Watch

The Cardiovascular Question Is Largely Settled

For over a decade, prescribers hesitated to initiate testosterone replacement therapy (TRT) because of conflicting cardiovascular safety signals. The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men; N=5,246) ended that uncertainty. Published in The New England Journal of Medicine in 2023, TRAVERSE randomized men aged 45-80 with hypogonadism and preexisting or high risk of cardiovascular disease to transdermal testosterone 1.62% gel or placebo for a mean follow-up of 33 months 1.

The primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke occurred in 7.0% of the testosterone group vs. 7.3% of the placebo group (hazard ratio 0.96; 95% CI, 0.78-1.17). This met the prespecified non-inferiority margin. The Endocrine Society's 2018 guideline had already recommended TRT for symptomatic men with confirmed low testosterone 2, and post-TRAVERSE consensus statements have reinforced that recommendation with greater confidence.

One notable caveat: TRAVERSE did identify an increased incidence of atrial fibrillation (3.5% vs. 2.4%), pulmonary embolism (0.9% vs. 0.5%), and acute kidney injury in the testosterone arm 1. These secondary findings require monitoring but did not change the primary MACE conclusion.

Oral Testosterone Formulations: Beyond Injections

Traditional oral methyltestosterone carried hepatotoxicity risk because of first-pass metabolism. That problem has been solved. Testosterone undecanoate (Jatenzo), approved by the FDA in March 2019, uses a lipophilic self-emulsifying drug delivery system (SEDDS) that routes absorption through the lymphatic system, bypassing the liver 3.

In its key trial, 87% of men with hypogonadism achieved average testosterone concentrations within the normal range (300-1,100 ng/dL) by week 12 on twice-daily dosing 4. The convenience of an oral capsule, taken with food, addresses one of the most persistent barriers to TRT adherence: injection aversion.

A second oral agent, oral testosterone undecanoate (Tlando), received FDA approval in 2022 with a different pharmacokinetic profile and no food requirement at certain doses 5. A third candidate, oral testosterone enanthate with dodecylphosphocholine (LPCN 1144), is being studied for both testosterone replacement and nonalcoholic steatohepatitis. Phase II data presented at ENDO 2023 showed reductions in liver fat alongside testosterone normalization 6.

These oral options signal a shift. The American Urological Association notes that route of administration should be tailored to patient preference, cost, and monitoring feasibility 7.

Selective Androgen Receptor Modulators: Tissue-Targeted Action

SARMs bind the androgen receptor with tissue selectivity, producing anabolic effects on muscle and bone while limiting stimulation of the prostate and sebaceous glands. This selectivity has made them a focus of drug development for conditions including sarcopenia, cancer cachexia, and hypogonadism.

Enobosarm (ostarine, GTx-024) completed phase III trials for cancer-related muscle wasting, showing statistically significant lean body mass gains (1.5 kg vs. placebo, P<0.001) 8. Though those trials targeted cachexia rather than classic hypogonadism, the compound demonstrated dose-dependent testosterone suppression at higher doses, confirming meaningful androgenic activity.

LGD-4033 (ligandol) showed dose-proportional increases in lean mass (1.21 kg at 1.0 mg/day over 21 days, P<0.05) in a phase I trial of healthy volunteers 9. No serious adverse events occurred, though suppression of sex hormone-binding globulin (SHBG) and total testosterone was observed.

No SARM has yet received FDA approval for hypogonadism. The Endocrine Society's 2018 guideline explicitly recommends against SARM use outside of clinical trials 2. Black-market SARMs, often contaminated or mislabeled, remain a distinct patient safety concern. The FDA has issued multiple warning letters to companies selling SARMs as dietary supplements 10.

Kisspeptin and GnRH-Based Therapies: Restoring the Axis

Rather than replacing testosterone exogenously, kisspeptin-based strategies aim to restart the hypothalamic-pituitary-gonadal (HPG) axis from the top. Kisspeptin is a neuropeptide that stimulates GnRH neurons in the hypothalamus. In men with functional hypogonadotropic hypogonadism, exogenous kisspeptin-54 administered as a subcutaneous infusion restored pulsatile LH secretion and increased testosterone levels in proof-of-concept studies at Imperial College London 11.

The therapeutic appeal is straightforward. Because kisspeptin drives endogenous testosterone production, it preserves spermatogenesis. TRT, by contrast, suppresses the HPG axis and can reduce sperm counts to azoospermic levels within 3-6 months.

MVT-602, a kisspeptin-1 receptor agonist with a longer half-life than native kisspeptin-54, completed phase II dose-ranging trials. Published data showed predictable, dose-dependent LH pulses with a favorable safety profile 12. The challenge for kisspeptin therapeutics remains delivery: the peptide requires parenteral administration, and oral bioavailability is negligible. Small-molecule kisspeptin receptor agonists are in preclinical development.

Enclomiphene: The Fertility-Preserving Alternative

Enclomiphene citrate, the trans-isomer of clomiphene, blocks estrogen receptors at the hypothalamus and pituitary, increasing GnRH pulse frequency and downstream LH/FSH secretion. Unlike zuclomiphene (the cis-isomer in standard clomiphene citrate), enclomiphene does not accumulate and is cleared within days.

Phase III data from the ZA-304 trial showed that enclomiphene 25 mg daily raised total testosterone from a baseline mean of approximately 228 ng/dL to above 300 ng/dL in 83% of men with secondary hypogonadism at 16 weeks, while maintaining or improving sperm parameters 13. FSH levels rose concurrently, confirming HPG axis stimulation rather than suppression.

The compound has not received FDA approval as of 2026. Repros Therapeutics submitted a New Drug Application that received a Complete Response Letter in 2015, and the program has since changed corporate hands. Off-label use of compounded enclomiphene is common in men's health clinics, though the Endocrine Society has not endorsed it in formal guidelines.

For younger men with hypogonadism who want to preserve fertility, enclomiphene fills a genuine therapeutic gap. Standard clomiphene citrate is used off-label for the same purpose, but its mixed isomer profile and longer half-life of zuclomiphene raise concerns about estrogenic side effects including visual disturbances 14.

Dimethandrolone Undecanoate: A Dual-Purpose Compound

Dimethandrolone undecanoate (DMAU) is an oral androgen-progestin that binds both androgen and progesterone receptors. It was originally developed as a male hormonal contraceptive, but its ability to maintain serum androgen activity while suppressing gonadotropins makes it a candidate for testosterone replacement as well.

A 28-day phase I study in healthy men (N=100) demonstrated dose-dependent suppression of LH and FSH to near-undetectable levels, with maintenance of androgenic markers including sexual function scores 15. At the 400 mg daily dose taken with food, testosterone and dihydrotestosterone fell (expected, given gonadotropin suppression), but dimethandrolone itself provided sufficient androgenic activity to prevent hypogonadal symptoms.

The National Institute of Child Health and Human Development (NICHD) Contraceptive Clinical Trials Network is coordinating longer-duration phase II studies. If DMAU proves safe over 6-12 months, it could become the first single oral agent offering both contraception and testosterone replacement for men who do not need fertility preservation.

Nasal and Long-Acting Delivery Systems

Natesto (testosterone nasal gel 4.5%) received FDA approval in 2014 and offers three-times-daily intranasal dosing. Its rapid absorption and clearance produce a pulsatile testosterone profile that more closely mimics natural circadian secretion than gels or injections 16. One retrospective study of 90 men using Natesto for 6 months showed maintained sperm concentration in 96.7% of subjects, suggesting less HPG axis suppression than other TRT routes 17.

On the opposite end of the pharmacokinetic spectrum, subcutaneous testosterone pellets (Testopel) provide stable levels for 3-5 months per insertion. Newer pellet formulations with modified excipients are in development to extend duration to 6 months and reduce the extrusion rate, which runs approximately 8-12% with current products.

Long-acting injectable testosterone undecanoate (Aveed) provides stable testosterone levels over 10-week dosing intervals after the loading phase. However, its FDA label carries a Risk Evaluation and Mitigation Strategy (REMS) for pulmonary oil microembolism and anaphylaxis, limiting its use to certified healthcare settings 18.

Diagnostic Advances: Refining Who Needs Treatment

The diagnosis of male hypogonadism still rests on two morning total testosterone measurements below 300 ng/dL (Endocrine Society threshold) plus consistent symptoms 2. But emerging research is refining this binary threshold.

The Harmonized Reference Ranges for Serum Testosterone study, using mass spectrometry in a healthy non-obese population of men aged 19-39, established a lower limit of 264 ng/dL for the 2.5th percentile, now adopted by the CDC 19. This has prompted debate about whether the traditional 300 ng/dL cutoff overtreats some men.

Free testosterone measurement is gaining attention. The Endocrine Society recommends calculating free testosterone using equilibrium dialysis or the Vermeulen equation when total testosterone is borderline (200-400 ng/dL) and SHBG may be altered by obesity, aging, or hepatic disease 2. Automated immunoassays for free testosterone are unreliable, and LC-MS/MS-based methods are becoming the recommended standard.

Genetic testing is also advancing the understanding of hypogonadism subtypes. Whole-exome sequencing has identified rare variants in KISS1, KISS1R, TAC3, TACR3, and GnRH receptor genes in patients with congenital hypogonadotropic hypogonadism, enabling precise etiologic diagnosis rather than empiric classification 20.

Trials Actively Recruiting or Reporting

Several ongoing trials merit close monitoring. The Testosterone TRIALS Extension (TTrials-X) is tracking long-term outcomes in men who participated in the original TTrials, which showed benefits for anemia, bone density, and sexual function over 12 months 21. The REACT trial (Randomized Evaluation of Anastrozole versus Clomiphene Treatment) is comparing aromatase inhibition to clomiphene for secondary hypogonadism. Multiple phase II programs evaluating novel SARMs for age-related muscle loss and functional decline in hypogonadal men are registered on ClinicalTrials.gov.

The European Male Ageing Study (EMAS) continues to publish longitudinal data on the natural history of late-onset hypogonadism, emphasizing that obesity and metabolic syndrome account for a large proportion of testosterone decline previously attributed to aging alone 22. These data reinforce that weight loss itself can raise testosterone by 50-100 ng/dL in obese men, a finding supported by post-bariatric surgery cohorts 23.

What This Means for Patients Considering Treatment

The field is moving toward precision. A man with secondary hypogonadism and fertility goals now has viable pharmacologic options (enclomiphene, clomiphene, kisspeptin analogs) that did not exist in clinical pipelines a decade ago. Oral testosterone removes the injection barrier. SARMs may one day offer tissue-selective anabolism without prostate risk.

But none of these newer agents should replace standard evaluation. The Endocrine Society recommends confirming the diagnosis with two morning samples, investigating reversible causes (opioids, obesity, obstructive sleep apnea, hyperprolactinemia), and initiating TRT only when symptoms persist after addressing modifiable factors 2.

Serum hematocrit should be checked at baseline, 3-6 months, and annually on TRT, with dose reduction or phlebotomy if hematocrit exceeds 54% 2.