Preserving spermatogenesis in testosterone deficiency: innovations in replacement and stimulatory therapies

The rising prevalence of testosterone deficiency has led to increased use of exogenous testosterone therapy, including among men desiring fertility. Conventional testosterone replacement therapies (TRT) restore serum testosterone but suppress gonadotropins, resulting in impaired spermatogenesis. Consequently, newer approaches aim to normalize testosterone levels while preserving fertility potential. Intranasal testosterone provides short-acting, pulsatile testosterone delivery that mimics physiologic diurnal variation. Studies demonstrate normalization of serum testosterone while maintaining follicle-stimulating hormone (FSH) and luteinizing hormone (LH) within reference ranges, supporting the potential for preserved spermatogenesis. Similarly, oral testosterone undecanoate formulations offer noninvasive administration and short-acting pharmacokinetics. Clinical data show maintenance of FSH and LH within normal limits, albeit reduced from baseline, suggesting possible fertility preservation-though data on semen parameters remain limited. Concomitant administration of low-dose human chorionic gonadotropin (hCG) with exogenous testosterone has been shown to sustain intratesticular testosterone (ITT) and spermatogenesis. Multiple studies demonstrate that hCG maintains sperm production even with full gonadotropin suppression from TRT. Finally, enclomiphene citrate, a purified trans-isomer of clomiphene, stimulates the hypothalamic-pituitary-gonadal (HPG) axis, increasing endogenous testosterone while maintaining spermatogenesis. This paper provides an updated overview of these evolving modalities and advances since our 2013 publication, highlighting short-acting testosterone delivery, concomitant gonadotropin support, and selective estrogen receptor modulation. Continued research with larger, long-term studies is essential to confirm their safety, efficacy, and fertility outcomes.