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Emerging Trends in Testosterone Replacement Therapy (TRT) in 2025
Written by a menMD Expert
1177 Words. 5 minute read.
Testosterone replacement therapy (TRT) has undergone significant evolution in recent years, with innovations in delivery systems providing clinicians with more options to personalize treatment approaches.
As the clinical landscape evolves and continues to grow, staying informed about these advancements may help optimize patient outcomes while minimizing adverse effects.
This article examines the most recent trends in TRT, with particular focus on novel delivery methods that are transforming the standard of care.
Rising awareness and diagnosis rates
The prevalence of male hypogonadism continues to increase, partly due to greater awareness among both patients and providers which in turn increases diagnoses.
According to recent data, hypogonadism affects just under 40% of men aged 45 and older, with prevalence rates increasing with age.
Educational initiatives targeting both practitioners and patients have contributed significantly to improved diagnosis rates yet treatment initiation rates remain relatively low.
There are several theories as to why. First off, there are patient and physician concerns about limitations of older delivery methods.
Older formulations ran the risk of liver strain and potential toxicity as exogenous testosterone injections had been found to elevate liver enzymes and which could cause damage with long-term use. Moreover, due to where it was being processed, the liver would metabolize much of the testosterone before it could enter the bloodstream, requiring higher doses which then raises the risk of liver damage.
Many eligible patients decline therapy due to concerns about injection discomfort, gel transfer risks, or inconvenient administration protocols. Similarly, some clinicians may hesitate to prescribe TRT when considering the potential drawbacks of available options and patient preferences.
These barriers to treatment highlight the importance of innovations in delivery systems that address these concerns.
Evolution of delivery methods in TRT
The TRT landscape has expanded dramatically from its originally limited options.
Let’s cover a few of them.
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Newer formulations of injections
While intramuscular injections of testosterone cypionate and enanthate remain common, advances include:
- Development of subcutaneous formulations allowing for easier self-administration
- Microdosing protocols providing more stable testosterone levels and reducing peak/trough fluctuations
- Extended-release formulations requiring less frequent administration
-
Transdermal Systems
Topical formulations have evolved to address past limitations:
- Newer gel formulations with improved absorption characteristics
- Development of transdermal systems with reduced transfer risk
- Novel application sites to minimize skin irritation
-
Implantable Pellets
Subcutaneous implants continue to improve with:
- Reduced pellet size improving patient comfort
- Modified release kinetics providing more consistent hormone levels
- Improved insertion techniques minimizing complication rates
-
Buccal and nasal systems
Additional innovative delivery methods include:
- Buccal adhesive systems applied to the gum line
- Nasal gels providing rapid absorption through highly vascularized nasal mucosa
- Novel mucoadhesive technologies improving residence time and absorption
-
Oral testosterone
Perhaps the most significant recent advancement has been the reemergence of oral testosterone as a viable option.
Previous oral formulations faced substantial limitations due to hepatotoxicity concerns and poor bioavailability. There are two in question that we would like to highlight.
Kyzatrex (testosterone undecanoate)
Testosterone undecanoate, patented under the brand name Kyzatrex, represents one such shift in oral testosterone delivery. This FDA-approved formulation employs a novel lymphatic absorption pathway that fundamentally changes how oral testosterone is processed:
- Intestinal vs. Hepatic Processing: Unlike previous oral formulations that underwent extensive first-pass metabolism in the liver, Kyzatrex is primarily processed in the intestines
- Lymphatic System Delivery: The medication enters the lymphatic system directly, largely bypassing hepatic filtration
- Reduced Hepatotoxicity Risk: By avoiding first-pass metabolism, liver enzyme elevations are significantly reduced
- Improved Bioavailability: Direct lymphatic absorption results in approximately 90% bioavailability compared to 3-5% with older oral formulations
- Consistent Serum Levels: Proper dosing establishes stable testosterone concentrations without the peaks and troughs common with injectable therapies
Clinical data demonstrates Kyzatrex maintains serum testosterone within the normal physiologic range (300-1000 ng/dL) in over 87% of treated patients, with minimal hepatic impact even after extended treatment periods.
Clomiphene citrate/Enclomiphene
This treatment modality actually doesn’t involve exogenous testosterone at all. Instead, these drugs are classed as Selective Estrogen Receptor Modulator (SERM). What that means is they stimulate the body’s testosterone production by interacting with excess estrogen in the bloodstream.
This innovative approach offers several significant advantages:
- Preserved fertility: By maintaining or even improving sperm production rather than suppressing it
- Natural production: Stimulates your body’s own testosterone rather than replacing it
- Testicular protection: Avoids the testicular atrophy common with external testosterone
- Effective symptom relief: Addresses low testosterone symptoms without compromising reproductive function
The results confirm efficacy with one study for clomiphene citrate seeing that 88% of men treated for more than three years achieved the proper levels of testosterone with only 8% experiencing side effects.
Clinical Implications of these new delivery systems
These advances in delivery technology directly impact clinical decision-making in several important ways:
Personalization of therapy
Previously, TRT treatment came down to injections of testosterone enanthate. As you’ve read above, the significantly expanded array of delivery options enables more tailored approaches based on:
- Patient preference and lifestyle considerations
- Comorbidities that may contraindicate specific delivery methods
- Need for fertility preservation in younger men
- Likelihood of compliance based on administration complexity
Side effect management
Different delivery systems present distinct side effect profiles:
- Polycythemia Management: Injectable formulations typically produce higher peak levels associated with increased red blood cell production, potentially necessitating therapeutic phlebotomy. Formulations like Kyzatrex can prevent this issue in almost all cases.
- Skin Irritation: Transdermal systems may cause application site reactions in 7-10% of patients
- Transfer Risk: Gels carry risk of testosterone transfer to partners or children through skin contact
- Fluctuating Levels: Injectables often create more pronounced mood and energy fluctuations compared to newer oral or transdermal options
Regulatory Considerations
The FDA continues to emphasize that TRT should only be prescribed for medical conditions causing hypogonadism confirmed by laboratory tests, not for age-related testosterone decline or non-specific symptoms of aging.
Guidelines also reinforce the need for regular monitoring of hematocrit, PSA, and lipid profiles during treatment.
These changes aim to enhance patient safety and ensure appropriate TRT use.
Selecting the optimal delivery method
When determining the most appropriate delivery system, clinicians might consider:
- Patient Preference: Administration frequency, complexity, and lifestyle integration
- Comorbidities: Cardiovascular status, polycythemia risk, and liver function
- Compliance Likelihood: Simplified regimens typically yield better adherence
- Cost Considerations: Insurance coverage varies substantially across delivery systems
- Monitoring Requirements: Different formulations necessitate distinct monitoring protocols
Conclusion
The reemergence of oral testosterone formulations like Kyzatrex, clomiphene citrate, enclomiphene represents a particularly important advancement in treating Low-T, potentially offering improved treatment adherence and reduced side effect profiles.
That said, there are still more innovations on the horizon.
There are new technologies in development, including smart delivery systems with programmable release patterns, biodegradable long-term implants requiring only annual replacement, and combination formulations addressing multiple aspects of male hormonal health.
As with all therapeutic decisions, an individualized approach based on patient factors could lead to optimal outcomes.
Staying informed about these advances in TRT delivery systems may help clinicians mitigate potential risks for patients as they undergo treatment.
Looking to learn more? Click here to access our provider webinar covering KYZATREX, presented by Dr. John Mulhall.
Remember, the menMD support teams are here to streamline your practice by handling patient education, basic questions, and medication troubleshooting, freeing you to focus on delivering exceptional care.