What are the medications available to treat low testosterone? - Peter Attia & Mohit Khera

Beyond Testosterone: The Full Medication Space for Low T Treatment

Most conversations about treating low testosterone begin and end with testosterone itself. Injections, gels, pellets, the usual suspects. But the medication options for addressing hypogonadism are actually broader than most patients realize, and understanding the full space helps you make a more informed decision about which approach makes sense for your specific situation. This conversation between Peter Attia and Dr. Mohit Khera, a urologist and leading researcher in male hypogonadism, covers the complete toolkit available to providers treating low T.

Dr. Khera brings particular credibility to this discussion as a professor of urology at Baylor College of Medicine who has published extensively on testosterone therapy. His combination of clinical practice and research gives him a perspective that balances real-world experience with scientific rigor.

Testosterone Formulations: The Direct Approach

The direct replacement options include injectable testosterone (cypionate and enanthate), topical preparations (gels, creams, and patches), subcutaneous pellets, nasal gel (Natesto), and oral testosterone undecanoate (Jatenzo). Each has a distinct pharmacokinetic profile, and the choice between them involves trade-offs in convenience, cost, stability of blood levels, and side effect profiles.

Injectable testosterone cypionate remains the most commonly used formulation because it is effective, well-studied, inexpensive, and allows precise dose adjustment. The main drawbacks are the need for self-injection and the peaks and troughs inherent to less frequent dosing schedules, both of which can be mitigated with more frequent injection protocols.

Oral testosterone undecanoate (Jatenzo) represents a newer option that avoids the liver toxicity issues that plagued earlier oral testosterone formulations. It uses a lymphatic absorption pathway that bypasses first-pass liver metabolism. The convenience of a pill is obvious, but the formulation requires twice-daily dosing with a fatty meal and produces more variable blood levels than other methods. It is also significantly more expensive than injectable testosterone.

Nasal testosterone (Natesto) is applied inside the nostrils two to three times daily and produces short, pulsatile testosterone peaks that roughly mimic the natural diurnal pattern. An interesting feature of Natesto is that it appears to suppress the HPG axis less than other testosterone formulations, potentially preserving some fertility function. However, the frequent dosing requirement and nasal irritation limit its appeal for many patients.

Clomiphene: The Fertility-Preserving Alternative

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that works by blocking estrogen receptors in the hypothalamus and pituitary. This tricks the brain into thinking estrogen levels are low, which stimulates increased production of LH and FSH, which in turn stimulates the testes to produce more testosterone and sperm. The result is increased testosterone production through your body's own machinery rather than from an external source.

The primary advantage of clomiphene is that it preserves and may even improve fertility while raising testosterone levels. For younger men who want to have children, this is often the preferred first-line treatment. It is also used as a bridge therapy for men who need to come off exogenous testosterone temporarily for fertility purposes.

The limitations of clomiphene are real. Not all men respond well to it. Some experience mood changes, visual disturbances, or headaches. And while it raises total testosterone, the increase does not always translate to proportional symptom improvement. Some men achieve good lab numbers on clomiphene but still feel suboptimal compared to how they feel on exogenous testosterone. The reasons for this are not entirely understood but may involve differences in the testosterone-to-estradiol ratio, the pulsatile versus steady nature of the testosterone production, or effects of elevated LH and FSH themselves.

Enclomiphene: The Next Generation SERM

Enclomiphene is the active isomer of clomiphene citrate. Clomiphene is actually a mixture of two isomers: enclomiphene (which has the desired anti-estrogenic effect at the pituitary) and zuclomiphene (which has estrogenic properties and a long half-life that can accumulate with chronic use). Enclomiphene isolates the beneficial isomer, theoretically providing the testosterone-boosting effect with fewer side effects.

Enclomiphene has been the subject of considerable interest in the TRT community. Clinical trials have shown it can effectively raise testosterone levels while preserving sperm production. However, it is not FDA-approved for the treatment of hypogonadism (as of early 2025), and access has been primarily through compounding pharmacies or research settings. Attia and Khera discuss its potential as a first-line option for appropriate patients, with the caveat that regulatory status and long-term safety data are still evolving.

HCG and Other Supportive Medications

Human chorionic gonadotropin (HCG) mimics LH and directly stimulates the Leydig cells in the testes to produce testosterone. It is commonly used alongside exogenous testosterone to maintain testicular size and function, preserve intratesticular testosterone (which is important for sperm production), and maintain fertility potential. The typical dose is 500 to 1000 IU two to three times per week, injected subcutaneously.

HCG availability has become more complicated since the FDA reclassified it as a biologic in 2020, which removed it from compounding pharmacy production. Brand-name HCG is available but significantly more expensive. Some providers have shifted to using gonadorelin (a GnRH analog) as an alternative, though the evidence for its effectiveness as an HCG substitute is limited and debated.

Aromatase inhibitors (anastrozole, exemestane) are sometimes used to manage elevated estradiol on TRT, though their routine use has fallen out of favor. Other medications like tamoxifen (another SERM) and kisspeptin (a neuropeptide that stimulates GnRH release) exist in the toolkit but are used less commonly and mostly in specialized clinical settings.

Choosing the Right Approach

The decision tree for low testosterone treatment is more nuanced than "do I want TRT or not." The first branch point is fertility. If preserving fertility is important, clomiphene, enclomiphene, or HCG-based protocols should be considered before exogenous testosterone. If fertility is not a concern, exogenous testosterone in the delivery method that best fits your lifestyle, preferences, and clinical profile is typically the most effective option.

Age, symptom severity, and the underlying cause of hypogonadism also influence the choice. Secondary hypogonadism (where the problem is at the pituitary level rather than the testes) may respond well to SERMs since the testes are capable of producing testosterone when properly stimulated. Primary hypogonadism (where the testes themselves are the problem) generally requires exogenous testosterone because the testes cannot respond adequately to increased stimulation.

Who Should Watch This

This video is essential for anyone at the decision-making stage of low testosterone treatment. If you have been diagnosed with low T and are trying to understand your options beyond just "start testosterone injections," this conversation lays out the full space in a clinically informed way. It is particularly important for men under 40, men planning to have children, and men whose providers have not discussed alternatives to exogenous testosterone. It is also a valuable resource for anyone who wants to understand why their provider recommended a specific medication and what the alternatives would have been.

Building Your Treatment Decision Framework

The breadth of options presented in this conversation can feel overwhelming, but a simple framework helps organize the decision process. Start by answering two questions. First: is fertility preservation important to me now or in the foreseeable future? If yes, start with clomiphene, enclomiphene, or a testosterone protocol that includes HCG for testicular function preservation. If no, exogenous testosterone in the delivery method that best fits your lifestyle is typically the most effective option.

Second: what delivery method matches my lifestyle and preferences? If you value precise dose control and low cost, injectable testosterone is hard to beat. If you prefer daily application without needles, topical options (gel or cream) offer that convenience. If you want the least frequent dosing possible, pellets or testosterone undecanoate (Aveed) minimize the number of times you need to think about your TRT. If you want an oral option, Jatenzo exists but with meaningful trade-offs in cost and dietary requirements.

No option is perfect for everyone. The best medication is the one that you will use consistently, that produces adequate and stable blood levels, that fits within your budget, and that your provider can monitor and adjust effectively. This video gives you the knowledge to have a detailed conversation about all of these factors with your provider rather than simply accepting whatever default protocol they happen to offer.

The Future of Low Testosterone Treatment

The treatment space for low testosterone continues to evolve. New formulations, new delivery technologies, and new approaches to stimulating endogenous production are all in various stages of development and clinical testing. Oral SERM therapies like enclomiphene may eventually receive FDA approval specifically for hypogonadism, providing a validated fertility-preserving option. Novel testosterone formulations with improved pharmacokinetics are in development. Gene therapy approaches to restore testicular function are in preclinical stages.

Staying informed about emerging options through channels like the Attia podcast and conversations with forward-thinking providers ensures that you can take advantage of advances as they become available rather than being locked into a protocol that becomes outdated. The men who achieve the best long-term outcomes with testosterone management are the ones who treat it as an ongoing relationship with evolving science rather than a static prescription to be filled indefinitely without review.