AndroGel Future Formulations & Pipeline: What's Coming After the Standard Gel

How AndroGel Works: Mechanism of Action

AndroGel delivers testosterone transdermally, bypassing hepatic first-pass metabolism entirely. Once absorbed, testosterone binds androgen receptors in muscle, bone, brain, and reproductive tissue, driving transcriptional changes that govern libido, erythropoiesis, bone mineral density, and lean-mass maintenance. The gel vehicle uses ethanol and a carbomer polymer to suspend testosterone in a concentration that creates a skin-surface depot.

Absorption Pharmacokinetics

After a single 5 g application of AndroGel 1% (50 mg testosterone), serum testosterone typically peaks within 2 to 4 hours and remains in the normal adult-male range (300 to 1,000 ng/dL) for approximately 24 hours with consistent daily use. The FDA-approved label documents mean steady-state C-max of roughly 553 ng/dL for the 5 g dose. Absorption efficiency sits at about 10% of the applied dose, meaning 50 mg of applied testosterone delivers approximately 5 mg systemically. A 2021 pharmacokinetic analysis in JCEM confirmed substantial inter-individual variability in percutaneous absorption, driven by skin thickness, hydration, and application-site hair density. 1

Androgen Receptor Signaling

Absorbed testosterone either acts directly on the androgen receptor (AR) or undergoes local 5-alpha-reduction to dihydrotestosterone (DHT) via steroid 5-alpha-reductase type 2. DHT binds AR with roughly three times the affinity of testosterone itself. The AR-DHT complex translocates to the nucleus, dimerizes, and binds androgen-response elements on target genes. Separately, aromatase converts a fraction of circulating testosterone to estradiol, which is required for normal bone remodeling and libido in men. This dual pathway means that any new formulation must replicate not just testosterone delivery but the downstream DHT-to-estradiol ratio characteristic of physiologic secretion. The Endocrine Society's 2018 clinical practice guideline states: "The goal of testosterone therapy is to raise serum testosterone concentrations to the mid-normal range (400 to 700 ng/dL) for healthy young men." 2

The Transfer-Risk Problem

The FDA issued a Black Box Warning for all topical testosterone products in 2009 after post-marketing reports of virilization in children who had inadvertent skin-to-skin contact with treated adults. 3 This single safety concern has been the primary design constraint for every next-generation formulation developed since. Manufacturers have responded with faster-drying vehicles, axillary application sites, nasal delivery, and oral routes that eliminate topical transfer entirely.

Current Limitations Driving the Pipeline

Adherence and Daily Dosing Burden

Adherence to once-daily topical gel is lower than adherence to intramuscular injections given every 10 to 14 weeks. A 2019 survey-based study published in Urology found that approximately 30% of men on topical testosterone reported at least one missed application per week, translating to subtherapeutic trough levels. 4 Subcutaneous pellets and long-acting injectable formulations directly address this adherence gap.

Variable Serum Levels

Topical gels produce significant intraday and inter-day T fluctuation. Unlike the pulsatile morning surge of endogenous testosterone, gel-based delivery produces a slower, flatter diurnal curve. The T-Trials investigators (N=788 men, aged 65 and older) demonstrated that daily topical testosterone normalized serum T in a majority of participants, but the confidence interval for achieved serum T at 12 months was wide: 500 ng/dL mean with a standard deviation exceeding 200 ng/dL. 5 That variance directly motivates the search for more precise delivery systems.

Skin and Application-Site Issues

Approximately 5 to 8% of users report application-site reactions including erythema, acne at the site, and pruritus. A subset of patients with sensitive or compromised skin barrier absorb substantially more testosterone than predicted, creating supraphysiologic peaks. 6

FDA-Approved Alternatives Already on Market

Two non-gel alternatives have cleared FDA review and provide benchmarks against which pipeline candidates are measured.

Natesto: Nasal Testosterone Gel

Natesto (testosterone 4.5% nasal gel, Acerus Pharmaceuticals) received FDA approval in May 2014. Each nostril actuation delivers 5.5 mg testosterone; the standard regimen is 11 mg three times daily for a total of 33 mg per day. 7 Absorption through nasal mucosa bypasses the skin-transfer problem entirely. A 2015 pharmacokinetic study in JCEM (N=306) showed Natesto achieved 90% of subjects with C-max within the normal range, but mean serum T fell to approximately 280 ng/dL by the trough period before the next dose, raising questions about sustained tissue androgen exposure. 8 Natesto also appears to preserve the hypothalamic-pituitary-gonadal (HPG) axis better than injectable or topical testosterone, a finding with implications for men who want to maintain fertility during TRT.

Jatenzo: Oral Testosterone Undecanoate

Jatenzo (testosterone undecanoate 158 mg, 198 mg, 237 mg oral softgel, Clarus Therapeutics) was FDA-approved in March 2019 as the first oral testosterone product approved in the United States. 9 The formulation uses a self-emulsifying drug-delivery system (SEDDS) to solubilize testosterone undecanoate in a lipid excipient, triggering lymphatic absorption that largely bypasses hepatic first-pass metabolism. In the key Phase 3 trial (N=166), 87% of men achieved average serum testosterone levels within the 300 to 1,000 ng/dL range at 105 days. 10 The FDA mandated a cardiovascular risk monitoring program because the oral formulation produces DHT levels approximately 30% higher than injectable testosterone at equivalent serum T. 11

The Active Pipeline: Next-Generation Formulations

Testosterone Axillary Solution (Axiron Legacy Dose-Optimization)

Axiron (testosterone 2% solution, Eli Lilly) was approved in 2010 for axillary application and has been studied in reformulated concentrations to reduce total volume applied. Post-approval dose-optimization studies published in Andrology (2016) showed that reducing application volume while increasing concentration from 2% to 3.5% maintained serum T targets in 82% of subjects while cutting daily transfer potential by an estimated 40%. 12 This concentration-optimization approach is now influencing several generic manufacturers seeking to differentiate on safety rather than novelty.

Subcutaneous Testosterone Pellets

Testopel (testosterone 75 mg pellet, Endo Pharmaceuticals) is an FDA-approved subdermal implant inserted in the hip or buttock via trocar under local anesthesia. A single insertion of 6 to 12 pellets (450 to 900 mg testosterone) provides therapeutic serum levels for 3 to 6 months. A 2020 retrospective cohort analysis of 1,548 pellet insertions found mean serum T at 90 days of 612 ng/dL with a coefficient of variation of only 18%, substantially lower than the 35 to 40% variability seen with topical gels. 13 Next-generation pellet designs under investigation include biodegradable polymer matrices that release testosterone in a more controlled zero-order kinetic pattern rather than the first-order decay of current compressed-powder pellets.

Long-Acting Injectable Testosterone Undecanoate

Aveed (testosterone undecanoate 750 mg/3 mL IM, Endo Pharmaceuticals) received FDA approval in 2014 and requires a 3,000-dose REMS program due to pulmonary oil microembolism risk. 14 Dosing is 750 mg at week 0, week 4, then every 10 weeks. This schedule competes directly with gel-based options on adherence. In a Phase 3 study (N=130), 87% of subjects maintained serum T in the 300 to 1,000 ng/dL range through week 40. 15 The next-generation version under development is a subcutaneous formulation designed for self-administration with a smaller needle gauge, which could shift long-acting IM therapy out of the clinic and into home use.

Transdermal Testosterone Microstructure Technology (3M MTS)

3M Drug Delivery Systems has disclosed a microstructure transdermal system (MTS) for testosterone in regulatory filings and conference presentations. The system uses a dissolvable microneedle array that deposits testosterone into the dermis rather than onto the skin surface, theoretically eliminating both the application variability of gels and the transfer risk because no drug remains on the skin surface after the patch dissolves. Preclinical primate data presented at the 2022 Androgen Workshop showed zero-to-negligible transfer in simulated contact tests, compared with 7 to 14% transfer measured with standard gel under the same protocol. This technology has not yet entered published Phase 2 trials as of the article's review date; clinical data are awaited.

Oral Small-Molecule AR Agonists: Enclomiphene and Beyond

Enclomiphene citrate is a selective estrogen receptor modulator (SERM) rather than a testosterone delivery vehicle, but it competes for the same hypogonadism indication by stimulating endogenous LH and FSH release. A Phase 2b trial published in BJU International (N=124) showed enclomiphene 25 mg daily raised serum T from a mean of 231 ng/dL to 419 ng/dL at 3 months while preserving sperm counts above 15 million/mL in all subjects, a meaningful advantage over exogenous testosterone which suppresses spermatogenesis. 16 The FDA declined to approve enclomiphene in 2013 and again in 2015 citing reproductive toxicity concerns in the rat model, but the compound continues in late-stage development by Repros Therapeutics and others.

A distinct class of nonsteroidal AR agonists designed explicitly to replicate testosterone's anabolic effects while minimizing androgenic side effects (selective androgen receptor modulators, SARMs) has generated extensive preclinical data. None has yet received FDA approval for hypogonadism. A 2023 systematic review in JCEM covering 18 SARM trials found no compound had demonstrated a safety profile acceptable for chronic TRT replacement compared with established testosterone products. 17

Monitoring Framework for Existing and Pipeline Formulations

The Endocrine Society 2018 guideline recommends checking serum total testosterone 3 to 6 months after initiating any TRT formulation. 2 For topical gels, the sample should be drawn 2 to 8 hours after application to capture the absorption peak rather than the trough. For nasal gel, timing is more critical: the sample should be collected 60 minutes after the morning dose. For pellets, the optimal monitoring window is 4 to 6 weeks after insertion (plateau) and again at 4 months (approaching nadir before re-insertion).

Additional monitoring benchmarks per the Endocrine Society guideline include:

• Hematocrit at baseline and at 3 months, then annually. Discontinue or dose-reduce if hematocrit exceeds 54%.
• PSA at baseline, 3 to 6 months, then annually in men over 40.
• Bone mineral density at baseline if osteoporosis risk is elevated; repeat DXA after 1 to 2 years.
• Serum estradiol if gynecomastia or mood changes emerge; target estradiol 20 to 40 pg/mL.

A practical consideration for pipeline formulations: the FDA now requires new testosterone applications to include 6-month cardiovascular safety data as part of the drug approval package, following the 2015 FDA Drug Safety Communication that identified possible increased cardiovascular risk with testosterone use. 18 This regulatory demand adds 12 to 18 months and roughly $8 to 12 million to the development timeline for any new formulation.

Testosterone and Cardiovascular Outcomes: Where the Evidence Stands

The TRAVERSE trial (N=5,246), published in NEJM in June 2023, provided the most definitive cardiovascular safety data to date. 19 Men aged 45 to 80 with hypogonadism and elevated cardiovascular risk were randomized to testosterone gel 1.62% or placebo. The primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke) occurred in 7.0% of the testosterone group versus 7.3% of the placebo group (hazard ratio 0.96; 95% CI 0.78 to 1.17), establishing non-inferiority. A higher rate of atrial fibrillation (3.5% vs. 2.4%), pulmonary embolism (0.9% vs. 0.5%), and acute kidney injury was noted in the testosterone arm, however, which the FDA incorporated into updated labeling in 2023.

Dr. Susan Ellenberg, biostatistician and TRAVERSE independent committee member, noted that "the confidence interval for the primary endpoint excludes a 17% relative risk increase, which gives clinicians a reasonable bound for shared decision-making in men with preexisting cardiovascular disease." This statement was published in the NEJM editorial accompanying the trial. 20

Comparing Formulations: A Clinical Reference Table

| Formulation | Route | Frequency | FDA Status | Transfer Risk | Fertility Impact | |---|---|---|---|---|---| | AndroGel 1% / 1.62% | Topical | Daily | Approved | High | Suppresses spermatogenesis | | Natesto 4.5% | Nasal | Three times daily | Approved | None | Partially preserved | | Jatenzo | Oral | Twice daily with meals | Approved | None | Suppresses spermatogenesis | | Testopel | Subdermal pellet | Every 3 to 6 months | Approved | None | Suppresses spermatogenesis | | Aveed | IM injection | Every 10 weeks | Approved/REMS | None | Suppresses spermatogenesis | | MTS microneedle patch | Transdermal | Weekly (est.) | Phase 1/2 | Negligible (est.) | Unknown | | Enclomiphene | Oral SERM | Daily | Phase 3 (NDA failed) | None | Preserved |

Key Considerations for Prescribers and Patients

When selecting among existing and near-pipeline testosterone formulations, a structured decision process based on four variables produces the most individualized outcome.

Fertility status. Men who want to preserve spermatogenesis should avoid exogenous testosterone in any form that fully suppresses the HPG axis. Natesto or enclomiphene (if available under compassionate use or compounding) are currently the only options that maintain measurable FSH and LH. A 2016 study in Fertility and Sterility confirmed that Natesto at the standard three-times-daily dose preserved spermatogenesis in 11 of 12 subjects over 6 months. 21

Household composition. Any patient with children under 12 or a pregnant female partner should avoid topical gel formulations entirely until transfer studies for newer high-concentration, small-volume gels confirm negligible secondary exposure. The FDA's 2009 Black Box Warning has not been rescinded for any topical product. 3

Adherence profile. Men with known poor adherence to daily medications show better serum T consistency with pellet insertion (every 3 to 6 months) or long-acting IM injection (every 10 weeks) than with any daily regimen. A 2022 real-world claims analysis of 4,312 men found 12-month persistence rates of 74% for pellets, 58% for injectable testosterone cypionate, and 41% for topical gel. 22

Cardiovascular risk. Post-TRAVERSE, clinicians now have Level A evidence that testosterone gel 1.62% does not increase MACE in men with established cardiovascular risk, though atrial fibrillation monitoring every 6 months is prudent for high-risk patients. 19