Does testosterone pellet therapy cause a negative feedback loop that shuts down natural testosterone production via the hypothalamic-pituitary-gonadal (HPG) axis?

Testosterone Pellets and Suppression of Natural Testosterone Production

Yes, testosterone pellets absolutely cause negative feedback that shuts down natural testosterone production through the hypothalamic-pituitary-gonadal (HPG) axis, just like all forms of exogenous testosterone therapy. 1, 2

Mechanism of Suppression

Exogenous testosterone administration—regardless of delivery method (pellets, injections, gels, or patches)—provides negative feedback to the hypothalamus and pituitary gland, resulting in inhibition of gonadotropin secretion. 1 This is a fundamental physiological response that cannot be avoided with any form of testosterone replacement therapy. 3

The FDA drug label for testosterone explicitly states: "During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH)." 2

The Feedback Loop Works as Follows:

• Testosterone pellets release exogenous testosterone into the bloodstream 1
• The hypothalamus detects elevated testosterone levels and reduces GnRH secretion 4, 5
• Reduced GnRH leads to decreased pituitary secretion of LH and FSH 1, 2
• Without LH stimulation, the Leydig cells in the testes stop producing endogenous testosterone 1, 4
• Without FSH stimulation, spermatogenesis decreases or ceases altogether, potentially causing oligospermia or azoospermia 1

Research confirms that this negative feedback mechanism remains intact even in men with hypogonadotropic hypogonadism, demonstrating that the pituitary-testicular hormonal axis maintains its physiological negative feedback between testosterone and gonadotropins regardless of the underlying condition. 6

Critical Fertility Implications

For any male interested in current or future fertility, clinicians should NOT prescribe exogenous testosterone therapy in any form, including pellets. 1 This is an absolute contraindication according to the 2024 AUA/ASRM guidelines and 2025 European Association of Urology guidelines. 1

Recovery Timeline After Cessation:

• Although recovery of sperm to the ejaculate occurs in most azoospermic males after cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years. 1
• Therefore, exogenous testosterone therapy should be avoided in males pursuing or planning to pursue family building in the near future. 1
• In those who may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient MUST be counseled about testosterone's inhibitory effects on spermatogenesis and the time course required for resumption of spermatogenesis after cessation. 1

No Difference Between Testosterone Formulations

All forms of exogenous testosterone—whether pellets, injections, gels, or patches—suppress natural testosterone production through the same negative feedback mechanism. 1, 2, 3 The delivery method does not change this fundamental physiological response. 3, 5

The 2017 Gastroenterology guidelines note that "implantable testosterone pellets offer a longer-term alternative, but require a procedure for implantation," without suggesting any difference in their suppressive effects compared to other formulations. 1

Alternative Approaches for Fertility Preservation

For men with secondary hypogonadism who desire fertility preservation, gonadotropin therapy (hCG with or without FSH) is the standard treatment, NOT testosterone replacement in any form. 1

• Human chorionic gonadotropin (hCG) injections (500-2500 IU, 2-3 times weekly) stimulate the testes to produce endogenous testosterone while maintaining spermatogenesis 1
• FSH injections may be added after testosterone levels normalize on hCG 1
• Combined hCG and FSH therapy provides optimal outcomes for fertility preservation 1, 7

Other Fertility-Preserving Options:

• Selective estrogen receptor modulators (SERMs) like clomiphene block estrogen receptors at the hypothalamus, stimulating GnRH secretion and increasing pituitary gonadotropin release 1
• Aromatase inhibitors decrease estrogen production, reducing negative feedback and increasing FSH production 1
• These agents increase endogenous testosterone production without suppressing the HPG axis 3, 5

Common Pitfalls to Avoid

• Never prescribe testosterone pellets (or any testosterone formulation) to men who desire fertility without explicit counseling about irreversible or prolonged suppression of spermatogenesis 1
• Do not assume that "low-dose" testosterone or any particular formulation will avoid HPG axis suppression—all exogenous testosterone suppresses natural production 2, 3
• Avoid starting testosterone therapy without first measuring LH and FSH to distinguish primary from secondary hypogonadism, as this determines whether fertility-preserving alternatives are appropriate 1, 8
• Do not fail to counsel patients that recovery of spermatogenesis after stopping testosterone can take months to years, and may not occur at all in some cases 1

Partial Mediation by Estradiol

The direct pituitary effect of testosterone to inhibit gonadotropin secretion is partially mediated by aromatization to estradiol. 9 Research demonstrates that both testosterone and estradiol administration decrease biologically and immunologically active LH and FSH, while DHT administration does not alter gonadotropin secretion. 9 This means that testosterone's suppressive effects occur both directly and through conversion to estradiol, making the feedback inhibition even more robust. 9