Testosterone replacement therapy (TRT) is evolving rapidly. Historically, TRT was limited to intramuscular injections and a handful of topical gels or patches. However, as research into male hypogonadism has expanded, so too has the range of treatments available. Hypogonadism—characterized by abnormally low testosterone levels and symptoms such as decreased libido, fatigue and loss of muscle mass—affects a large portion of the population. MenMD notes that nearly 40 % of men aged 45 and older exhibit some degree of hypogonadism. Greater public awareness has increased diagnosis rates, yet many men remain hesitant to pursue treatment due to concerns about older delivery methods. Innovations in 2025 address these concerns, offering more personalized, effective and safer therapies. This article explores the latest TRT methods—from novel injection protocols and oral formulations to selective estrogen receptor modulators (SERMs), gene therapy research and updated regulatory guidance—helping individuals and clinicians navigate the changing landscape.
Understanding Testosterone Deficiency and Traditional TRT
Low testosterone (commonly referred to as “Low‑T”) arises when the body’s production of testosterone falls below normal. According to the Cleveland Clinic, hypogonadism may result from damage to the testicles, pituitary gland or hypothalamus. Before initiating therapy, physicians typically perform morning testosterone tests, hemoglobin and hematocrit measurements, liver function testing, luteinizing hormone (LH), PSA and prolactin levels. These assessments ensure that low testosterone is accurately diagnosed and that TRT can be administered safely.
Historically, TRT consisted of:
- Intramuscular injections — long‑acting testosterone cypionate or enanthate injected into muscle every one to two weeks.
- Subcutaneous injections — smaller volumes injected weekly under the skin.
- Topical gels and patches — daily application of testosterone gel or patch to the skin.
- Pellet implants — pellets placed under the skin every three to six months releasing testosterone steadily.
- Buccal tablets — sticky tablets applied to gums twice daily.
- Nasal gels — gel applied into each nostril three times per day.
- Oral capsules — twice‑daily pills.
These options improved symptoms of hypogonadism, such as sexual function, lean body mass, mood and energy. Yet they also carried drawbacks: injections caused peaks and troughs in serum levels leading to mood swings; gels risked transfer to partners; patches caused skin irritation; oral formulations had low bioavailability and potential liver toxicity; and all exogenous testosterone suppressed fertility by inhibiting LH and follicle stimulating hormone (FSH).
New Injection Formulations: Microdosing and Subcutaneous Delivery
One major trend in 2025 is the shift from large, infrequent intramuscular injections to subcutaneous injection protocols and microdosing. MenMD highlights that modern injection strategies include subcutaneous formulations that patients can administer at home. Microdosing protocols—where smaller doses are injected more frequently—help maintain steadier serum testosterone levels and reduce the drastic peaks and troughs seen with traditional weekly or bi‑weekly shots. These protocols can minimize side effects like mood swings and polycythemia (elevated red blood cell count) because serum concentrations remain within physiological ranges. Extended‑release formulations are another innovation; by releasing testosterone more slowly, they require less frequent injections and simplify treatment adherence.
Innovations in Transdermal Systems
Gels and patches have been mainstays of TRT, but innovations aim to reduce transfer risk and skin irritation. New gel formulations boast improved absorption characteristics and novel application sites. These formulations are less likely to rub off on partners, reducing the chance of inadvertently exposing family members to testosterone. Enhanced patch technologies distribute the hormone more evenly and use materials that cause less skin irritation. For patients who disliked injections, these improvements make topical therapy more appealing.
Improved Pellet Implants
Implantable pellets remain popular for men who prefer infrequent dosing. Recent advances focus on smaller pellet size, which improves comfort during implantation. Modified release kinetics provide more consistent hormone levels over the implant’s lifespan, and improved insertion techniques minimize complications like infection or pellet extrusion. Some companies are researching bioabsorbable pellets that gradually dissolve, eliminating the need for surgical removal. Pellets provide a steady release of testosterone and avoid daily or weekly administration but require minor surgery and careful dose selection.
Buccal and Nasal Delivery Systems
Less commonly used but gaining attention are buccal adhesive systems and nasal gels. These methods deliver testosterone via the richly vascularized mucosa of the mouth or nose, resulting in rapid absorption. MenMD notes that buccal tablets and nasal gels utilize mucoadhesive technologies that improve residence time and absorption. Nasal gels deliver testosterone into the bloodstream through the nasal epithelium, bypassing first‑pass metabolism and offering convenience to men who dislike injections or skin applications.
Oral Testosterone: The Resurgence of Testosterone Undecanoate (Kyzatrex)
Perhaps the most significant development is the return of oral testosterone as a viable option. Earlier oral formulations were limited by poor bioavailability and hepatotoxicity because testosterone underwent extensive first‑pass metabolism in the liver. Newer formulations, notably Kyzatrex (testosterone undecanoate), use a lymphatic absorption pathway that largely bypasses hepatic metabolism. By processing the drug primarily in the intestines, Kyzatrex reduces the risk of liver enzyme elevations and achieves roughly 90 % bioavailability compared with 3–5 % in older oral preparations. Clinical data show that Kyzatrex maintains serum testosterone within the normal range (300–1 000 ng/dL) in over 87 % of treated patients, with minimal hepatic impact even after extended use. Unlike traditional pills, Kyzatrex uses a fatty acid‑based capsule that enters the lymphatic system, resulting in more consistent serum levels. For men worried about injections, patches or gels, oral testosterone now offers a convenient alternative with a safety profile comparable to other delivery methods.
Selective Estrogen Receptor Modulators (SERMs): Clomiphene and Enclomiphene
Rather than providing exogenous testosterone, SERMs stimulate the body’s own production of testosterone by blocking estrogen receptors. Two major SERMs—clomiphene citrate and its isomer enclomiphene—have gained popularity in 2025. These agents are particularly useful for younger men or those desiring fertility preservation because they do not suppress LH or FSH and therefore do not lower sperm counts. Enclomiphene has several advantages over clomiphene: it acts primarily as an estrogen antagonist (the zuclomiphene isomer acts as an agonist), leading to a more predictable hormonal response. A 2024 retrospective study of 66 men transitioning from clomiphene to enclomiphene demonstrated that enclomiphene produced a median testosterone increase of 166 ng/dL, compared with 98 ng/dL on clomiphene. More importantly, estradiol levels decreased on enclomiphene (–5.92 pg/mL) versus an increase on clomiphene (17.50 pg/mL). Adverse effects such as decreased libido, reduced energy and mood changes were significantly less frequent with enclomiphene; regression analysis found lower odds of adverse events (OR 0.18). These findings support enclomiphene as a viable alternative for hypogonadal men, particularly those concerned about estrogenic side effects or fertility.
Emerging Gene Therapies
One of the most exciting research areas is gene therapy for Leydig cell failure and male hypogonadism. Although still preclinical, the field took a significant step forward in 2024 when researchers used an adeno‑associated virus (AAV) vector to restore testosterone production in mice with Leydig cell failure. Traditional AAV8 gene therapy improved testosterone production but failed to restore natural fertility, as sperm counts and hormonal levels remained insufficient. Scientists screened a panel of AAV serotypes and discovered that AAVDJ, an engineered vector, more efficiently transduces Leydig cell progenitors. Intratesticular injection of AAVDJ‑Lhcgr produced significant recovery of testosterone levels, improved sexual development, and restored natural fertility in Lhcgr‑deficient mice. The therapy also improved adipose, muscle and bone function in treated animals. These findings suggest gene therapy could provide long‑lasting or even permanent correction of certain forms of hypogonadism. While human trials have not yet begun, this research underscores the potential of gene editing or gene replacement strategies as future solutions for Low‑T, particularly for genetic conditions.
Personalization: Microdosing, Extended‑Release and Patient‑Centered Decisions
Personalized care is central to emerging TRT strategies. New delivery systems allow physicians to tailor therapy to a patient’s lifestyle, comorbidities and preferences. Microdosing protocols deliver smaller doses more frequently, which mimic natural diurnal testosterone patterns and reduce peaks and troughs. Men who prefer fewer injections may opt for extended‑release formulations requiring administration every few weeks. Some may choose transdermal gels because they are simple to apply but must consider transfer risk and skin sensitivity. Men seeking infrequent dosing and steady levels can choose pellet implants. Buccal and nasal options provide fast absorption for those uncomfortable with injections or skin application. Clinicians must weigh multiple factors when selecting a delivery system: patient preference, comorbidities (e.g., heart disease, sleep apnea), need for fertility preservation, likelihood of adherence and cost. This patient‑centered approach ensures that TRT remains a long‑term, sustainable therapy tailored to individual needs.
Regulatory Changes and Safety Considerations in 2025
Safety remains a paramount concern. Testosterone therapy has been scrutinized for potential cardiovascular risks. In February 2025 the U.S. Food and Drug Administration (FDA) issued class‑wide labeling changes for all testosterone products following the TRAVERSE trial and ambulatory blood pressure monitoring (ABPM) studies. The TRAVERSE trial found that in men with hypogonadism and high cardiovascular risk, TRT was non‑inferior to placebo regarding major adverse cardiac events (MACE: 7.0 % on TRT vs. 7.3 % on placebo; hazard ratio 0.96). The FDA’s updated labeling therefore removes language suggesting a heightened risk of heart attacks and strokes. However, ABPM studies revealed that testosterone therapy can increase blood pressure. As a result, the FDA’s label now adds warnings about elevated blood pressure, retaining limitations of use for age‑related hypogonadism. The labels also incorporate TRAVERSE data and remove the boxed cardiovascular warning. Healthcare providers must continue to monitor hematocrit, PSA and lipid profiles regularly. The Cleveland Clinic emphasizes routine follow‑up testing once therapy begins to ensure that TRT is not causing harm.
Benefits and Risks: A Balanced Perspective
TRT can significantly improve quality of life by boosting sexual function, increasing lean muscle mass, strengthening bones and elevating mood and energy. However, side effects are not trivial. The Cleveland Clinic lists potential adverse effects such as acne, fluid retention, stimulation of the prostate, breast enlargement, worsening sleep apnea, reduced sperm count and infertility. Laboratory abnormalities may include increased PSA and red blood cell counts. Oral formulations like Kyzatrex minimize liver toxicity, but all exogenous testosterone suppresses the hypothalamic‑pituitary‑gonadal axis and requires ongoing therapy. SERMs preserve fertility but can produce side effects including headaches or visual disturbances; enclomiphene has fewer adverse events than clomiphene. Gene therapy offers hope for permanent cures but remains experimental. Patients must weigh benefits against risks and work closely with healthcare providers to select appropriate therapies.
Guidelines and Patient Selection
To guide clinicians, the American Urological Association (AUA) updated its guidelines in 2024 for diagnosing, treating and monitoring testosterone deficiency. The guidelines recommend confirming low testosterone with two morning measurements and evaluating symptoms before initiating therapy. TRT is approved by the FDA only for men with low testosterone due to an underlying medical condition, not for age‑related decline alone. The AUA also addresses off‑label treatments like clomiphene citrate and enclomiphene for men who wish to preserve fertility. Women or transgender individuals using testosterone should be monitored by specialists due to unique physiologic effects, and children or adolescents require pediatric endocrinology oversight. Patients with certain conditions—such as untreated heart failure, recent heart attack or stroke, elevated red blood cell counts or prostate cancer—should not use TRT. Counseling should emphasize that TRT is a long‑term therapy; if therapy stops, testosterone levels will return to baseline.
Future Technologies: Smart Delivery and Combination Therapies
Looking beyond 2025, research is exploring smart delivery systems, biodegradable long‑term implants and combination formulations. MenMD hints at programmable release patterns and implants requiring only annual replacement. Advances in biomaterials may allow testosterone pellets to biodegrade safely over extended periods, reducing surgical interventions. Combination therapies could pair testosterone with agents that support other aspects of male hormonal health, such as selective aromatase inhibitors or estradiol modulators, to maintain hormonal balance. Artificial intelligence might optimize dosing schedules based on real‑time biomarker monitoring. Although these technologies are in early development, they illustrate a trend toward more precise, patient‑specific hormone modulation.
Conclusion
Testosterone replacement therapy has transformed from a limited set of injections and gels into a diverse landscape of treatments in 2025. New subcutaneous injections and microdosing protocols offer more stable serum levels and reduced side effects. Transdermal systems continue to evolve with better absorption and less transfer risk, while pellet implants deliver steady hormones with increasing convenience. Oral testosterone has returned in the form of Kyzatrex, achieving high bioavailability and minimal liver toxicity. SERMs like clomiphene and especially enclomiphene provide alternatives that maintain fertility and have favorable safety profiles. Cutting‑edge gene therapy experiments hint at future curative treatments. At the same time, regulatory authorities have updated labeling to reflect modern trial data and emphasize blood pressure monitoring. As new methods emerge, individualized patient care—balancing benefits with risks and aligning therapy with personal goals—remains paramount. The future of TRT promises ever more sophisticated, safe and effective ways to restore hormonal balance and improve quality of life.
Frequently Asked Questions (FAQs)
What makes Kyzatrex different from older oral testosterone pills?
Kyzatrex (testosterone undecanoate) uses a lymphatic absorption pathway rather than being processed through the liver. It is mainly absorbed in the intestines and enters the lymphatic system, significantly reducing hepatotoxicity. This results in approximately 90 % bioavailability, compared with the 3–5 % seen in previous oral formulations. Clinical data show it maintains normal testosterone levels in over 87 % of patients with minimal impact on liver enzymes.
How does enclomiphene differ from clomiphene?
Clomiphene citrate is a mixture of two isomers: enclomiphene (trans) and zuclomiphene (cis). Enclomiphene acts as an estrogen antagonist, stimulating LH and FSH secretion and promoting endogenous testosterone production without significantly raising estradiol levels, while zuclomiphene has estrogenic effects. A 2024 study found that enclomiphene increased testosterone more than clomiphene (median increase of 166 ng/dL vs. 98 ng/dL) and produced far fewer adverse effects. Clinicians may consider enclomiphene when fertility preservation is important or when patients experience estrogenic side effects on clomiphene.
Are oral testosterone capsules safe for long‑term use?
New oral formulations like Kyzatrex are designed to minimize liver toxicity by bypassing first‑pass metabolism. They provide stable serum levels comparable to injections and gels. However, like all exogenous testosterone, they suppress the body’s natural production and require ongoing therapy. Patients must be monitored regularly for hematocrit, lipid profiles, PSA and blood pressure. Individuals with certain conditions (heart failure, prostate cancer, recent heart attack or stroke) should avoid oral testosterone.
What is micro dosing, and why is it popular in 2025?
Microdosing involves administering smaller doses of testosterone more frequently, usually via subcutaneous injections. This approach mimics the body’s natural diurnal testosterone secretion, reduces fluctuations and lowers the risk of side effects such as mood swings and polycythemia. Patients may find microdosing more comfortable and physiologically balanced than large, infrequent doses.
Is gene therapy available for testosterone deficiency?
Currently, gene therapy for TRT remains in the research phase. A 2024 animal study used an AAVDJ vector to deliver the Lhcgr gene to Leydig cell progenitors, restoring testosterone production and natural fertility in mice. While promising, these techniques have not yet been tested in humans. Clinical application will require rigorous trials to confirm safety and efficacy.
What are the main risks of testosterone replacement therapy?
TRT can cause side effects, including acne, fluid retention, prostate stimulation, gynecomastia, sleep apnea, smaller testicles and reduced sperm count. Laboratory abnormalities can include increased PSA levels and elevated red blood cell counts. Recent findings suggest TRT does not increase major adverse cardiac events but may raise blood pressure. Regular monitoring and individualized care are essential.
How do the FDA’s 2025 labeling changes affect testosterone therapy?
After reviewing results from the TRAVERSE trial and ABPM studies, the FDA updated labels for all testosterone products. The new labels clarify that TRT does not increase major adverse cardiac events but highlight that it can raise blood pressure. They remove the boxed warning for cardiovascular risk while maintaining limitations for age‑related hypogonadism. This means clinicians must monitor blood pressure and continue using TRT only in medically indicated cases.
Can testosterone therapy be stopped once started?
Yes. TRT is not a lifetime mandate. Men may discontinue therapy if side effects become bothersome, if symptoms fail to improve after several months, or if new health conditions make TRT unsafe. After stopping TRT, the body may take time to resume its natural testosterone production. Men who wish to maintain fertility or avoid long‑term dependence may consider alternatives like enclomiphene.
