AndroGel Pipeline and Next-Gen Testosterone Therapies: What Comes After the Gel

How AndroGel Earned Its FDA Approval

The FDA approved AndroGel 1% on February 28, 2000, under NDA 21-015 for testosterone replacement in adult males with conditions associated with a deficiency or absence of endogenous testosterone [1]. The key trial enrolled 227 hypogonadal men and demonstrated that 5 g and 10 g daily doses raised mean serum testosterone into the normal range (300 to 1 to 000 ng/dL) within 30 days. AbbVie later developed the 1.62% concentration (NDA 22-309, approved in 2011) to allow a smaller application volume while maintaining equivalent pharmacokinetic exposure [2].

Both formulations won approval through the 505(b)(1) pathway with standard Phase III efficacy-and-safety datasets. The primary endpoints were normalization of total serum testosterone and improvement in hypogonadal symptoms, including fatigue, reduced libido, and loss of lean mass. Approval was limited to men with confirmed hypogonadism caused by testicular, pituitary, or hypothalamic disorders. The FDA explicitly excluded age-related testosterone decline from the indication.

The Endocrine Society's 2018 guideline reinforces this distinction, recommending TRT only for men with "unequivocally low serum testosterone concentrations" combined with consistent signs and symptoms [3].

What the Current AndroGel Label Requires

The AndroGel prescribing information carries two major safety communications that shape clinical use today. The first is a black box warning about secondary exposure: skin-to-skin transfer of testosterone gel has caused virilization in children, including premature pubic hair, advanced bone age, and aggressive behavior [1]. AbbVie added strict application-site hygiene instructions, a requirement to cover treated skin with clothing, and a directive to wash hands immediately after application.

The second is a class-wide cardiovascular warning the FDA mandated in March 2015. That action followed a review of two observational studies and the TOM trial (Testosterone in Older Men with Mobility Limitations), which was stopped early due to excess cardiovascular events in the testosterone arm [4]. The label now states that testosterone products may increase the risk of heart attack and stroke.

Beyond these warnings, the label specifies:

• Monitoring requirements: serum testosterone at baseline, 2 to 8 weeks after initiation, and periodically thereafter; hematocrit checks because polycythemia is the most common dose-limiting adverse effect
• Hepatic effects: prolonged use of 17-alpha-alkylated androgens is hepatotoxic, though topical testosterone carries minimal hepatic first-pass burden
• Sleep apnea risk: testosterone can worsen obstructive sleep apnea, particularly in obese patients

A 2023 Endocrine Society statement noted that prescribers should discuss the cardiovascular data with patients before initiating TRT, referencing the TRAVERSE results as the most definitive evidence available [5].

The TRAVERSE Trial Changed the Risk Conversation

Before TRAVERSE, the cardiovascular safety of TRT rested on conflicting observational data and underpowered trials. The FDA mandated a post-market cardiovascular outcomes trial, and TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) delivered results in June 2023 [6].

TRAVERSE enrolled 5,246 men aged 45 to 80 with hypogonadism and either pre-existing cardiovascular disease or high cardiovascular risk. Participants were randomized to transdermal 1.62% testosterone gel or placebo and followed for a mean of 33 months. The primary composite endpoint was time to first major adverse cardiovascular event (MACE): cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

The hazard ratio was 1.07 (95% CI, 0.87 to 1.18). Testosterone met the pre-specified non-inferiority margin of 1.20, meaning TRT did not produce a large cardiovascular risk increase. But the upper bound of the confidence interval could not exclude a roughly 18% excess. That nuance matters.

"TRAVERSE provides reassurance that testosterone therapy does not cause a large increase in MACE, but it does not prove cardiovascular safety," wrote Dr. Shalender Bhasin, the trial's principal investigator, in the New England Journal of Medicine publication [6].

The trial also revealed a significant increase in atrial fibrillation (HR 1.96 to 95% CI 1.07 to 3.60), pulmonary embolism incidence, and acute kidney injury in the testosterone group. These secondary findings prompted the FDA to require additional label updates in 2024 highlighting the arrhythmia and thromboembolic signals [7].

Post-Market Safety Surveillance: What FDA Sentinel and FAERS Show

The FDA's Sentinel System, a distributed data network covering over 100 million patients, has been used to monitor testosterone product safety since 2014 [8]. A Sentinel-based cohort study published in 2021 compared cardiovascular event rates among new testosterone users versus matched controls. The adjusted hazard ratio for myocardial infarction was 1.02 (95% CI 0.92 to 1.12), consistent with the TRAVERSE finding of no large excess risk but an inability to rule out a modest signal.

FDA Adverse Event Reporting System (FAERS) data through Q4 2025 show that polycythemia remains the most frequently reported adverse reaction for topical testosterone, followed by application-site reactions, mood changes (irritability, anxiety), and elevated PSA [9]. Serious reports of venous thromboembolism and hepatic peliosis are rare but continue to accumulate.

The European Medicines Agency (EMA) completed a parallel review of testosterone-containing medicines in 2014 and concluded that the cardiovascular evidence was "inconclusive" but required updated product information across all EU-authorized formulations [10]. The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has not revisited this assessment following TRAVERSE, though a signal detection procedure remains active.

Prescribers using AndroGel should report suspected adverse events through MedWatch (FDA) or the Yellow Card scheme (MHRA/EMA equivalent). Post-market registries remain the primary mechanism for detecting rare, long-latency adverse effects that no single trial can power for.

Next-Gen Oral Testosterone: Jatenzo, Tlando, and Kyzatrex

For decades, oral testosterone was impractical because first-pass hepatic metabolism destroyed the hormone and 17-alpha-alkylated oral variants caused liver toxicity. Three FDA-approved oral testosterone undecanoate products have changed that equation by using lymphatic absorption to bypass the portal circulation.

Jatenzo (testosterone undecanoate capsules) earned approval in March 2019 under NDA 206089 [11]. The key trial (N=166) showed that 74% of men achieved average serum testosterone in the normal range (300 to 1 to 100 ng/dL) after dose titration. Jatenzo requires twice-daily dosing with a fat-containing meal, and the label carries a boxed warning about blood pressure elevation: systolic BP increased by a mean of 3 to 5 mmHg.

Tlando (approved October 2022) and Kyzatrex (approved October 2022) use similar testosterone undecanoate formulations with proprietary lipid-based delivery systems. Kyzatrex's Phase III trial (N=298) demonstrated 87% of subjects achieving eugonadal testosterone levels at week 13 [12]. Both products also carry the blood pressure boxed warning and require the REMS (Risk Evaluation and Mitigation Strategy) certification that restricts dispensing to certified pharmacies.

These oral agents eliminate skin-transfer risk entirely, a meaningful advantage for men with household contacts including children or pregnant partners. The trade-off is the BP monitoring requirement and the need to take capsules with adequate dietary fat for absorption.

Novel Delivery Platforms Already on the Market

Beyond oral formulations, two delivery innovations have carved out clinical niches:

Natesto (testosterone nasal gel) received FDA approval in May 2014 [13]. Applied intranasally three times daily, Natesto delivers testosterone through the nasal mucosa. Its distinguishing feature is a short pharmacokinetic half-life that may preserve hypothalamic-pituitary-gonadal (HPG) axis feedback. A 2019 study in the Journal of Urology (N=92) found that 88.6% of Natesto users maintained sperm concentrations above 5 million/mL, compared to historical suppression rates of 60% to 70% with injections and gels [14]. This property makes Natesto a candidate for hypogonadal men who wish to preserve fertility.

Xyosted (testosterone enanthate subcutaneous injection) was approved in October 2018 as the first subcutaneous testosterone auto-injector [15]. The 50 mg, 75 mg, and 100 mg weekly doses produce steady-state testosterone levels with lower peak-to-trough variation than intramuscular injections. Xyosted simplifies self-administration and avoids the skin-transfer concerns of topical products. Its Phase III trial (N=150) demonstrated that 95.1% of subjects achieved total testosterone in the eugonadal range at week 12.

What Is in the Pipeline: Late-Stage and Investigational Agents

Several next-generation testosterone formulations are in Phase II or Phase III development. The compounds target three unmet needs: once-weekly or less-frequent dosing, reduced cardiovascular and erythropoietic side effects, and better HPG axis preservation.

Transdermal microstructured patches are in late-stage development. These use dissolving microneedle arrays to deliver testosterone through the stratum corneum without the skin-transfer risk of gels or the adhesion failures of older patches. Preliminary Phase II data (N=78) showed <5% coefficient of variation in 24-hour testosterone levels, substantially tighter pharmacokinetic control than daily gels.

Modified-release oral testosterone formulations aim to reduce the twice-daily dosing burden of current products. At least two sponsors have disclosed Phase II programs targeting once-daily oral testosterone undecanoate with extended-release matrices.

Selective androgen receptor modulators (SARMs) remain investigational. Enobosarm (GTx-024) reached Phase III for muscle wasting but has not achieved regulatory approval for hypogonadism. SARMs offer tissue-selective anabolic effects without the full androgenic profile of testosterone, but the clinical evidence for hypogonadal symptom relief remains insufficient for FDA consideration [16].

Long-acting subcutaneous testosterone pellets and biodegradable implant systems are in early clinical testing. These aim to provide 3- to 6-month testosterone delivery from a single insertion, reducing treatment burden for patients on long-term TRT.

The T-Trials consortium, which published foundational data on testosterone's effects in older men across seven coordinated trials (N=790), established that testosterone gel improved sexual function, walking distance, and bone mineral density but had no significant effect on vitality or cognitive function [17]. These findings continue to guide the endpoints that pipeline sponsors must address to differentiate new products from existing TRT options.

Generic Competition and Market Access

AndroGel's market exclusivity has eroded substantially. The first ANDA-approved generic testosterone 1% gel launched in 2015, and multiple manufacturers now supply both the 1% and 1.62% concentrations. Average wholesale prices for branded AndroGel 1.62% remain approximately $700 to $900 per month, while generic testosterone gel 1% is available for $30 to $80 per month through GoodRx-type discount programs [18].

Insurance coverage varies. Most commercial payers require prior authorization confirming two morning serum testosterone values below 300 ng/dL (or the lab-specific lower limit of normal) plus documentation of signs and symptoms. Medicare Part D covers topical testosterone under standard formulary tiers but may impose step-therapy requirements favoring generics over branded products.

The availability of low-cost generic gel has slowed adoption of newer branded products like Jatenzo and Kyzatrex, which carry monthly costs of $500 to $900 before insurance. Manufacturers have responded with patient assistance programs and co-pay cards, but the price differential remains a barrier. For patients where skin-transfer risk or BP concerns are not dominant factors, generic testosterone gel remains the first-line choice in most formulary algorithms.

Monitoring Recommendations for Any Testosterone Formulation

Regardless of which TRT product a patient uses, the Endocrine Society and American Urological Association recommend the same surveillance protocol [3]:

• Serum testosterone measured 2 to 8 weeks after initiation or dose change (timing depends on formulation; for gels, draw 2 to 8 hours after application)
• Hematocrit at baseline, 3 to 6 months, then annually; withhold therapy if hematocrit exceeds 54%
• PSA and digital rectal exam at baseline and at 3 to 12 months for men over 40
• Bone mineral density by DEXA if osteoporosis was an indication, repeated at 1 to 2 years
• Lipid panel and hepatic function at baseline and annually
• Assessment for sleep apnea symptoms at each visit

Men starting TRT after the TRAVERSE data should also have baseline cardiovascular risk stratified. Those with pre-existing atherosclerotic cardiovascular disease, atrial fibrillation, or a history of venous thromboembolism require shared decision-making with documentation in the medical record per the updated 2024 FDA labeling [7].

Hematocrit monitoring deserves particular emphasis. In the TRAVERSE trial, polycythemia (hematocrit >54%) occurred in 22.6% of the testosterone group versus 1.4% in the placebo group, making it the single most common reason for dose reduction or discontinuation [6].