Oral Native Testosterone Does Not Suppress HPTA Function: Evidence from Clinical Practice

Traditional testosterone replacement therapy (TRT) suppresses the hypothalamic-pituitary-testicular axis (HPTA), leading to impaired gonadotropin release and potential loss of fertility. The HPTA is the central hormonal feedback loop that regulates testosterone production. The hypothalamus releases GnRH, which stimulates the pituitary to secrete LH and FSH. These gonadotropins act on the testes to produce testosterone and support spermatogenesis. Exogenous testosterone disrupts this loop by signaling to the brain that levels are sufficient, shutting down natural production.1 While effective at increasing serum testosterone, injectable and transdermal formulations often reduce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to undetectable levels. As shown in prior studies, even modest doses of exogenous testosterone are associated with marked suppression of gonadotropins.2

Oral native testosterone (unesterified and absorbed via the lymphatic system) offers a potential alternative. Like testosterone undecanoate, it bypasses hepatic first-pass metabolism through lymphatic absorption. However, its native (non-esterified) form likely allows for more rapid absorption and systemic availability, as it does not require enzymatic cleavage before becoming active.

This retrospective analysis aimed to determine whether oral native testosterone monotherapy could improve testosterone levels while preserving gonadotropin production. We focused on whether patients maintained LH and FSH levels within normal ranges after treatment, which would indicate preserved HPTA function.

We reviewed clinical data from 34 male patients treated with oral native testosterone monotherapy. All patients had paired hormone panels before and after treatment. Inclusion required both symptomatic hypogonadism, based on a combination of testosterone levels and low qADAM scores.3 Patients using enclomiphene or other hormonal agents were excluded.

Patients took 600 mg of native oral testosterone daily with a minimum of 30 g dietary fat to ensure lymphatic absorption. Lymphatic absorption refers to the transport of lipophilic compounds through intestinal lymph vessels instead of blood capillaries. This route bypasses the liver initially, allowing compounds like testosterone to enter systemic circulation directly. Dietary fat stimulates this process by triggering chylomicron formation, which packages and transports the testosterone through the lymphatic system.4 This dosing protocol aimed to balance patient compliance with optimal pharmacokinetic performance, as dietary fat significantly influences testosterone absorption.5

Hormone panels included total testosterone, calculated free testosterone (via the Vermeulen equation), LH, FSH, SHBG, and estradiol. Paired t-tests were used to assess changes, with significance defined as p < 0.05.

All 34 patients maintained LH and FSH levels above 2.0 mIU/mL following oral native testosterone monotherapy. This threshold is commonly accepted as sufficient for fertility. The average post-treatment LH was 7.9 ± 4.6 mIU/mL and FSH was 6.7 ± 3.1 mIU/mL, demonstrating preserved gonadotropin production across the cohort. No patients experienced suppression below any clinical cutoffs, including those who reached supraphysiologic testosterone levels.

Free testosterone rose from 86.0 ± 40.4 pg/mL to 197.6 ± 96.5 pg/mL, a 129.8% increase (p < 0.001). SHBG declined significantly by 24% (p < 0.001), contributing to the enhanced bioavailability of free testosterone. LH and FSH showed small nonsignificant decreases but remained within physiological ranges. Total testosterone also increased from 453.9 ± 178.0 ng/dL to 790.1 ± 313.8 ng/dL, a 74% increase (p < 0.001).

"No patients experienced suppression below any clinical cutoffs, including those who reached supraphysiologic testosterone levels."

When benchmarked against NHANES reference data for lean, healthy, non-smoking men aged 19 to 40, patients shifted from the 26th to the 87th percentile in total testosterone, and from the 11th to the 95th percentile in free testosterone.6

Further analysis showed that 62 percent of patients had lower estradiol at follow-up despite increased testosterone levels, and 76 percent experienced a reduction in SHBG. There was no meaningful correlation between the magnitude of testosterone increase and change in estradiol levels (p=0.65).

Patients also reported substantial improvements in quality of life, based on the validated qADAM questionnaire. 94% of participants experienced an increase in their overall composite score. These improvements reached statistical significance across every domain. Physical symptoms such as energy, strength, and athletic performance improved in more than 90% of participants. Sexual function, including libido and erectile quality, improved in over 97%. Measures of mental well-being such as happiness and life enjoyment showed similar gains, with the majority of patients reaching scores consistent with normal function. Improvements in daily function were also notable. All patients reported a reduction in excessive sleepiness after dinner, and more than 94% reported enhanced work performance. These changes were statistically significant across all symptom categories, with p-values ranging from < 0.001 to < 0.05.