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

Sep 30, 2026

Uploaded by Logic

The rising prevalence of testosterone deficiency has increased demand for exogenous testosterone therapy, including in men who want to preserve fertility. Conventional TRT restores serum testosterone but suppresses gonadotropins, impairing spermatogenesis. Newer strategies aim to maintain testosterone within physiologic targets while protecting fertility potential through approaches such as intranasal delivery, oral testosterone undecanoate, low-dose hCG support, and enclomiphene citrate stimulation of the HPG axis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Abstract

Introduction

Preserving spermatogenesis in testosterone deficiency: innovations in replacement and stimulatory therapies Gabrielle Hochu1^, Isabella Geyer-Kim2^, Edward Kim1^ 1Department of Urology, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 2University of Southern California, Los Angeles, CA, USA Contributions: (I) Conception and design: E Kim; (II) Administrative support: G Hochu, E Kim; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: G Hochu, E Kim; (V) Data analysis and interpretation: G Hochu, E Kim; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Edward Kim, MD. Department of Urology, University of Tennessee Graduate School of Medicine, 1928 Alcoa Highway, Suite 222, Knoxville, TN 37920, USA. Email: [ekim@utmck.edu](ekim@utmck.edu). Abstract: 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 FSHand 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 ofclomiphene, 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. Keywords: Testosterone replacement therapy (TRT); enclomiphene citrate, spermatogenesis; male fertility; semen parameters Submitted Jul 08, 2025. Accepted for publication Nov 21, 2025. Published online Dec 18, 2025. doi: 10.21037/tau-2025-480 View this article at: [https://dx.doi.org/10.21037/tau-2025-480](https://dx.doi.org/10.21037/tau-2025-480) Introduction Testosterone deficiency, as defined by the American Urological Association (AUA), is total testosterone (TT) level below 300 ng/dL combined with symptoms and/or signs of hypogonadism-reduced energy, fatigue, diminished lean muscle mass, cognitive dysfunction, decreased libido, ^ ORCID: Gabrielle Hochu, 0000-0003-3185-7405; Isabella Geyer-Kim, 0009-0007-0962-8186; Edward Kim, 0009-0008-0538-4484. © AME Publishing Company. Transl Androl Urol 2025;14(12):3975-3987 | [https://dx.doi.org/10.21037/tau-2025-480](https://dx.doi.org/10.21037/tau-2025-480) 3976 Hochu et al. Preserving spermatogenesis in testosterone deficiency etc. (1) . Testosterone deficiency has traditionally been attributed to the natural physiologic aging of the testis (2) . Numerous epidemiological studies have demonstrated a steady declin

FAQs

Why can conventional testosterone replacement therapy impair spermatogenesis?

Conventional TRT restores serum testosterone but suppresses gonadotropins, which impairs spermatogenesis.

How does intranasal testosterone help support fertility in testosterone deficiency?

Intranasal testosterone provides short-acting, pulsatile delivery that mimics physiologic diurnal variation, with studies showing maintained FSH and LH within reference ranges.

What roles do low-dose hCG and enclomiphene citrate play?

Low-dose hCG combined with exogenous testosterone sustains intratesticular testosterone and sperm production despite gonadotropin suppression. Enclomiphene citrate stimulates the HPG axis to increase endogenous testosterone while maintaining spermatogenesis.

Sep 30, 2026

Uploaded by Logic