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

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, etc. (1). Testosterone deficiency has traditionally been attributed to the natural physiologic aging of the testis (2). Numerous epidemiological studies have demonstrated a steady decline in testosterone with age (3-5). However, recent evidence suggests that comorbidities rather than chronological aging may play a larger role. A cross-sectional analysis of 197,883 men in the United Kingdom demonstrated that testosterone levels were consistently higher in men without metabolic syndrome compared with those with metabolic syndrome across every decade of life, with no significant association between age and testosterone levels (6). Similarly, another cross-sectional study of 3,489 men reported that median testosterone levels were stable across age groups, whereas obesity showed a strong inverse association with testosterone (7). Longitudinal data from the Baltimore Longitudinal Study of Aging, which followed 625 men over a median of 6.7 years, found that comorbidities—including anemia, diabetes, heart failure, obesity, peripheral artery disease, and stroke—were significantly associated with lower testosterone, whereas age itself was not (8). These findings collectively challenge the longstanding dogma of age-related testosterone deficiency and highlight the role of metabolic health and comorbid conditions in influencing changes in testosterone physiology. Finally, mechanistic and comprehensive reviews demonstrate that obesity and insulin resistance lower TT—primarily through reduced sex hormone-binding globulin and increased aromatization in adipose tissue—while weight loss restores testosterone levels, indicating that metabolic health, rather than chronological age, explains much of the decline (9,10).

Corresponding with a rise in rates of testosterone deficiency, there has been an increase in the use of testosterone replacement therapy (TRT) among men. One study reported a threefold increase in exogenous testosterone use between 2001 and 2011 (11). Another study found that between 2003 and 2013, among men aged 18 to 45 years, the rate of testosterone use increased fourfold—from 29 to 118 per 10,000 person-years. This increase was greater than the threefold rise observed among men aged 54 to 65 years during the same time (12). Following this period of increasing TRT utilization, the U.S. Food and Drug Administration (FDA) issued a safety communication in 2014 and, in 2015, mandated labeling changes for all testosterone products to include a warning about a possible increased risk of heart attack and stroke (13). In response to these communications, testosterone prescribing, which had risen steadily for over a decade, declined sharply during 2014–2015 before leveling off (14-16). More recent data from 2018–2022 show a renewed increase in testosterone therapy use, particularly among younger men (17). Notably, in 2025 the FDA removed the boxed warning on cardiovascular risk after results from the TRAVERSE trial demonstrated that testosterone therapy was noninferior to placebo with respect to major adverse cardiovascular events, while adding warnings regarding potential increases in blood pressure (18,19).

Exogenous testosterone use induces negative feedback on the hypothalamic-pituitary axis, resulting in suppressed pulsatile secretion of gonadotropin-releasing hormone (GnRH). This suppression leads to decreased levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn reduce intratesticular testosterone (ITT) and impair Sertoli cell function-critical elements of spermatogenesis. While most men recover sperm parameters to within the normal range following cessation of TRT, recovery to individual pre-treatment levels is not universal, particularly among those with poor baseline semen quality (20,21). In one study, 67% percent of men recovered sperm concentration of 20 million/mL within 6 months after cessation of TRT; however, some men required up to 2 years (22). Men of reproductive age who receive exogenous testosterone therapy may experience unintended effects on fertility.

In 2013, we published a review article titled “Exogenous Testosterone: A Preventable Cause of Male Infertility”, which outlined the mechanisms by which exogenous testosterone suppresses ITT production and explored alternative therapies aimed at preserving spermatogenesis (23). The article focused on three primary alternatives: selective estrogen receptor modulators (SERMs) such as clomiphene citrate (CC), human chorionic gonadotropin (hCG) with or without testosterone, and aromatase inhibitors (AIs).

To summarize, SERMs act at the hypothalamus by competitively binding estrogen receptors, leading to increased GnRH release, pituitary secretion of LH and FSH, and subsequent ITT production. CC is the most extensively studied, showing efficacy comparable to TRT with reported benefits in libido, energy, mood, and performance, though side effects such as gynecomastia, weight gain, hypertension, acne, and rare visual disturbances may occur. hCG, an LH analog, directly stimulates Leydig cells to produce testosterone and is FDA-approved for this indication, though spermatogenesis is not maintained long-term without FSH support and its injectable form can be costly and invasive. AIs block the conversion of testosterone to estradiol, raising LH, FSH, and testosterone levels, and are especially useful in men with low testosterone-to-estradiol ratios. However, side effects range from hypertension and musculoskeletal aches to rare alopecia, with long-term use limited by risks of estrogen deficiency and bone loss. While hCG is the only FDA-approved therapy in this class, SERMs and AIs are used off-label, with the 2024 AUA infertility guidelines endorsing AI use in select men with low testosterone and elevated estradiol (24).

The objective of this review is to provide an updated overview of the current strategies aimed at increasing serum testosterone while preserving spermatogenesis. Since our 2013 publication, significant progress has been made in this area. Notably, recent research within the field of male infertility has focused on identifying methods to continue exogenous testosterone therapy while maintaining the hormonal and semen parameters necessary for fertility. The primary modalities covered in this review include intranasal testosterone, oral testosterone, the concomitant use of testosterone with low-dose hCG, and enclomiphene citrate. This review explores these evolving approaches to maintaining male fertility in the context of ongoing TRT. Additionally, we discuss the role of enclomiphene citrate—the trans-isomer of CC—which offers a more selective hypothalamic-pituitary-gonadal (HPG) axis stimulation than racemic CC.

AUA guideline update

The AUA has published and updated the Evaluation and Management of Testosterone Deficiency Guideline in 2024, providing recommendations regarding treatment of testosterone deficiency for men who are planning future reproduction (1). We have included these guidelines here for ease of reference. It is important to emphasize that although this review discusses emerging short-acting testosterone formulations that may theoretically preserve spermatogenesis by causing less gonadotropin suppression than traditional long-acting modalities, these therapies remain forms of exogenous testosterone and are not endorsed by the AUA for use in men seeking to maintain fertility.

The pertinent guideline recommendations state:

“16. The long-term impact of exogenous testosterone on spermatogenesis should be discussed with patients who are interested in future fertility. (Strong Recommendation; Evidence Level: Grade A).

23. Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive. (Strong Recommendation; Evidence Level: Grade A).

27. Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility. (Conditional Recommendation; Evidence Level: Grade C)” (1).

In addition, Guideline #27 provides several key principles for prescribing SERMs or AIs. Clinicians using SERMs or aromatase inhibitors to increase endogenous testosterone should monitor serum LH and testosterone levels to guide therapy (1). SERM dose escalation may be considered if testosterone remains low and LH is low or normal, but is unlikely to help when LH is elevated, suggesting primary testicular dysfunction. Aromatase inhibitors should generally not be used long-term due to potential bone loss, and doses should be carefully titrated to maintain estradiol within the therapeutic range. Persistently elevated estradiol despite therapy warrants discontinuation. These strategies aim to enhance endogenous testosterone, but their benefits do not necessarily match those of exogenous testosterone therapy. While only hCG has been approved by the FDA for treatment of hypogonadotropic hypogonadism, the potential benefits of other agents cannot be disregarded considering their impact on spermatogenesis.

Intranasal testosterone

Intranasal testosterone, such as Natesto (Haupt Pharma; Regensburg, Germany), is a short-acting testosterone formulation applied to the inside of each nostril. Benefits of this modality are decreased risk of transference compared with testosterone gel and a non-invasive application method (25,26). Moreover, it is associated with a reduced risk of polycythemia when compared to intramuscular (IM) testosterone cypionate and testosterone pellets (27-29). Potential risks include nasal irritation, altered taste/smell, rhinorrhea, epistaxis, and sinusitis (25,26,30). A proposed benefit is that it has been shown to increase testosterone while maintaining FSH, LH, and semen parameters within the normal range. In one study 33 men with low testosterone and at least one symptom of hypogonadism administered 125 µL per nostril (11.0 mg testosterone per dose) three times daily (TID) for 6 months (26). At follow up, 31 patients (90.9%) had a TT level greater than 300 ng/dL. FSH and LH levels remained within normal range in 81.8% and 72.7% of patients, respectively. Statistically significant decreases in LH and FSH levels from baseline to 3 months and from baseline to 6 months were observed although they remained within normal range. Total motile sperm count remained above five million in 88.4% of men at 3 months and in 93.9% at 6 months. While no statistically significant decline in sperm concentration or motile sperm count was observed, a steady downward trend was noted at both three and 6 months. With such short follow-up, the long-term dynamics of semen parameters remain unclear.

In another study, 41 men who were already being treated with CC for fertility-preserving hypogonadism were offered the choice to switch to Natesto if they experienced low libido while on CC (31). Mean duration of CC treatment prior to switching to Natesto was 31±26 months. At the three-month follow-up, serum testosterone levels did not differ significantly between men treated with CC vs. Natesto; however, estradiol levels were significantly higher when the men were treated with CC. FSH was significantly lower on Natesto than at baseline (without treatment) but remained within normal range. There was no significant difference in LH levels on Natesto compared to baseline. Semen parameters did not differ significantly between CC and Natesto. 38 of 41 (92.7%) men reported improved libido on Natesto compared to CC. Given the short three-month follow-up, it remains unclear whether FSH levels might continue to decline below the normal reference range or how the dynamics of LH and semen parameters would progress over a longer period.

It is hypothesized that the short-acting nature of Natesto with its two to three-times daily dosing, more closely mimics the physiological pattern of testosterone secretion compared to long-acting testosterone supplementation. Because serum testosterone levels return to near baseline between doses, this may help preserve the natural diurnal rhythm of testosterone production. As a result, pulsatile secretion of gonadotropins may be maintained, thereby preserving spermatogenesis (26,31-33). Studies have compared Natesto’s twice daily (BID) and TID dosing on TT concentration, FSH, and LH levels. In a 90-day randomized, open-label, dose-ranging study, 306 men with serum testosterone levels <300 ng/dL were randomized to a fixed treatment arm (TID, 5.5 mg/nostril, 11 mg/dose, 33 mg/day) or a titration arm, starting at BID (22 mg/day) with potential dose adjustment to TID (33 mg/day) on day 45 based on morning serum TT levels (30). At 90 days, both arms increased from mean TT of 200.8 ng/dL to 375 and 421 ng/dL for BID and TID dosing, respectively. The same phase 3 clinical trial data was later presented quantifying gonadotropin levels, demonstrating that BID and TID dosing led to decreased FSH and LH levels but remained within normal range (34). Baseline FSH was 8.49 IU/L (BID) and 6.42 IU/L (TID), and the mean at day 90 was 5.99 IU/L (BID) and 3.12 IU/L (TID). Baseline LH was 5.42 IU/L (BID) and 5.25 IU/L (TID), and the mean at day 90 was 3.56 IU/L (BID) and 2.20 IU/L (TID). To date, there are no studies that compare semen parameters in BID vs. TID dosing. While FSH and LH remained within normal ranges, these levels decreased over the short 90-day follow-up. Theoretically, if examined over a longer period, FSH and LH could decrease below the normal range.

Limited short-term data with Natesto suggest potential for maintaining gonadotropin levels, but its long-term effects on spermatogenesis remain uncertain, underscoring the need for close monitoring. In the Ramasamy trial, one patient (1.7%) became azoospermic and three patients (5.0%) became severely oligospermic (<1 million/mL) (26). Similarly, in the Kavoussi trial, one patient became severely oligospermic (4.9 million/mL) alongside a marked decline in gonadotropin levels (FSH 0.7 mIU/mL, LH 0.9 mIU/mL) (35). In that same patient, dose titration from Natesto 11 mg BID to 11 mg in the morning and 5.5 mg in the evening led to recovery of semen parameters (25.5 million/mL) and normalization of gonadotropins (FSH 2.2 mIU/mL, LH 2.7 mIU/mL). Given the lack of long-term data, the AUA does not recommend the use of nasal testosterone in men interested in current or future fertility (24).

Table 1 summarizes the clinical studies evaluating intranasal testosterone.

Oral testosterone

Oral testosterone undecanoate is relatively new to the market with Jatenzo (Tolmar Inc.; Fort Collins, CO, USA) receiving FDA approval in 2019, followed by Tlando (Verity Pharmaceuticals Inc.; Ewing, NJ, USA) in March 2022 and Kyzatrex (Marius Pharmaceuticals; Raleigh, NC, USA) in August 2022. Similar to intranasal testosterone, oral testosterone is short-acting and is therefore hypothesized to preserve spermatogenesis. Also like intranasal testosterone, the oral modality allows for ease of use, avoidance of needles, and decreased risk of transference. Oral testosterone has been shown to maintain FSH and LH within normal reference ranges, albeit decreased from baseline. In one randomized, open-label, multicenter, dose-titration trial, 166 hypogonadal men, as defined by morning serum testosterone <300 nd/dL and a history of signs and/or symptoms of hypogonadism, received oral testosterone undecanoate (Jatenzo) 237 mg BID (could be uptitrated to 396 mg) for a minimum of 105 days (36). By the end of the study, gonadotropin levels decreased by approximately 70% from baseline. In a post hoc analysis of the LH and FSH levels stratified by age, LH and FSH concentrations were significantly suppressed by 75% and 65%, respectively (37). The concentration of FSH remained within normal values across all age groups (18–40, >40–50, and >50 years old). LH, however, remained within normal range only in the 18–40 group. In another study, 27 hypogonadal men received oral testosterone undecanoate (Kyzatrex) 400 mg BID for 6 months (38). Although FSH and LH levels declined (FSH: 5.7 to 2.9 mIU/mL; LH: 3.3 to 1.9 mIU/mL), they remained within the normal reference range. Two patients experienced side effects of transient gastrointestinal discomfort.

Table 2 summarizes the clinical studies evaluating oral testosterone.

Given its short-acting pharmacokinetics, oral testosterone may have the potential to preserve spermatogenesis; however, there are currently no published data evaluating semen parameters in hypogonadal men treated with oral testosterone. The AUA guidelines note that clinical trials are underway to develop orally administered exogenous testosterone agents; however, they do not provide specific recommendations regarding their use (1).

Testosterone with hCG

Concomitant TRT with low-dose hCG has been demonstrated to preserve spermatogenesis. In one study, 26 men (mean age 35.9 years) with hypogonadism who desired fertility preservation received either weekly IM testosterone (n=19) or daily transdermal testosterone gel (n=7) with 500 IU of IM hCG every other day (39). The follow-up period ranged up to 18 months, with a mean duration of 6.2 months. Testosterone before and after treatment was statistically significant at 207.2±99.2 vs. 1,055.5±420.9 ng/dL. Semen parameters were assessed every 2 to 4 months, and there was no statistical difference at follow-up.

In another study, 29 healthy men (mean age 24 years) with normal reproductive physiology were randomly assigned to one of four treatment groups: all participants were treated with testosterone enanthate 200 mg IM once weekly with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 weeks (40). ITT was measured by percutaneous fine-needle aspiration (FNA) at baseline and at 21 days. ITT experienced 94% suppression in the testosterone/placebo group, 25% suppression in the 125 IU hCG group, 7% suppression in the 250 IU hCG group, and 26% increase in the 500 IU hCG group. Treatment with hCG and testosterone reduced serum LH and FSH concentrations to below 1.0 IU/L, with no statistically significant differences between the treatment groups. By day 7, serum testosterone levels had significantly increased from baseline in all four groups. Testosterone levels in the placebo and 125 IU hCG groups remained within the normal reference range, while the 250 IU and 500 IU hCG groups exhibited elevated levels exceeding the normal range. Presumably, hCG increases ITT concentration despite exogenous testosterone through direct stimulation of Leydig cells. Maintaining baseline ITT concentrations in men with fully suppressed gonadotropins secondary to exogenous testosterone requires a significantly lower dose of hCG than the doses typically administered for treating hypogonadotropic hypogonadism-related infertility.

Another study examined 77 men with a history of testosterone therapy use who were treated with a regimen of 3,000 IU hCG and 75 IU FSH three times per week (41). The cohort was divided into two groups: men not currently receiving testosterone therapy (n=50) and those continuing testosterone therapy concurrently (n=27). Median time to highest sperm concentration was 4.7 months (interquartile range, 8.7 to 29.4 months). In both groups, 74% of participants demonstrated an improvement in sperm concentration. Specifically, overall sperm concentration increased from 0.005 million/mL to 6.6 million/mL in the no-testosterone group, and from 0.9 million/mL to 12.4 million/mL in the concurrent-testosterone group. These findings suggest that concurrent testosterone administration does not impede gonadotropin-mediated recovery of spermatogenesis.

Table 3 summarizes the clinical studies evaluating testosterone with hCG.

Regarding recommended regimens, Lee and Ramasamy suggest that for men planning for pregnancy within 6–12 months, TRT may be continued with 500 IU of hCG every other day (42). For those planning conception beyond 12 months, they recommend continuing TRT with intermittent cessation every 6 months, during which patients receive 3,000 IU of hCG every other day for four weeks. For men not seeking fertility but wishing to preserve testicular volume, continued TRT with 1,500 IU of hCG once weekly is advised in their publication. The AUA guidelines recommended against prescribing testosterone in men who desire current or future fertility. Additionally, the AUA infertility guidelines note that while some studies suggest spermatogenesis may be preserved by adding hCG to exogenous testosterone in men desiring future fertility (>6 months), the current evidence is insufficient to support this approach (24).

Enclomiphene citrate

Although not FDA approved, enclomiphene citrate can be obtained through compounding pharmacies for use in men with hypogonadism. Enclomiphene citrate (the trans-isomer of CC) has effects consistent with estrogen antagonism whereas zuclomiphene (the cis-isomer) often acts as an agonist (43). Generic CC contains both isomers in variable proportions, whereas enclomiphene represents the purified androgenic component.

A randomized, open-label, phase IIb trial evaluated 12 men with secondary hypogonadism who had been on topical testosterone therapy for at least 6 months prior to enrollment (44). Participants were randomized to either enclomiphene citrate 25 mg daily or continued topical testosterone gel. At both 3 and 6 months, TT levels increased in both groups. However, only men in the enclomiphene citrate arm demonstrated increases in LH and FSH. Moreover, all men in the enclomiphene citrate group exhibited elevated sperm counts, ranging from 75–334 ×10⁶/mL, with a mean of 176×10⁶/mL—significantly higher than in the testosterone gel group.

A second study, a randomized, double-blind (for oral dosage), placebo-controlled, parallel-group, multicenter phase IIb trial—open-label only for the topical comparator—enrolled 73 men with secondary hypogonadism who had either discontinued prior testosterone therapy or were treatment-naïve (45). Participants were randomized to one of four groups: enclomiphene citrate 12.5 mg, enclomiphene citrate 25 mg, topical testosterone gel, or placebo. At 3 months, both enclomiphene citrate groups achieved significant increases in TT along with elevations in LH and FSH, while men in the testosterone gel group experienced suppression of gonadotropins below normal levels. Sperm concentrations were significantly reduced in the testosterone gel group compared to both enclomiphene citrate groups and placebo, whereas spermatogenesis was preserved with enclomiphene citrate.

Finally, two parallel, randomized, double-blind, double-dummy, placebo-controlled, multicenter phase III trials assessed enclomiphene citrate versus testosterone gel in 256 overweight men aged 18–60 years with secondary hypogonadism (43). Eligible participants had early-morning TT ≤300 ng/dL and low or normal LH. Men were randomized into four treatment arms: enclomiphene citrate 12.5 mg, enclomiphene citrate titrated from 12.5 to 25 mg, topical testosterone gel, or placebo. After 16 weeks, TT increased from baseline across all active treatment groups. Enclomiphene citrate raised LH and FSH, while testosterone gel suppressed both. Importantly, sperm concentrations remained within the normal range in the enclomiphene citrate arms but declined markedly in the testosterone gel arm. The studies employed a composite primary endpoint—defined as achieving TT within the normal range (300–1,040 ng/dL) and a sperm concentration ≥10×10⁶/mL. Pooled analysis of both trials showed treatment success in 63.5% of men receiving enclomiphene citrate, compared to 24.7% with testosterone gel and 5.8% with placebo (P<0.001).

Table 4 summarizes the clinical studies evaluating enclomiphene citrate.

Overall, enclomiphene citrate consistently increased serum LH and FSH and restored normal levels of serum TT. Treatment with enclomiphene citrate maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained. Enclomiphene (Androxal) was investigated for treatment of secondary hypogonadism in overweight men but never received FDA approval. In 2015, Repros Therapeutics (The Woodlands, TX, USA), the company developing Androxal, received a Complete Response Letter from the FDA, indicating that the submitted data were insufficient and additional clinical trials were required (46). Development of enclomiphene for all medical indications was subsequently discontinued in 2021 (47). Despite its lack of FDA approval, enclomiphene remains available through compounding pharmacies with a prescription.

Table 5 highlights the advantages and disadvantages of all the medications highlighted in this review article.

Improving spermatogenesis in individuals with a history of anabolic steroid use

Anabolic-androgenic steroids (AAS) share a similar mechanism of action with testosterone (48). Men with a history of anabolic steroid or exogenous testosterone use frequently present with suppressed gonadotropins and impaired spermatogenesis due to prolonged HPG axis suppression. Conventionally, clinicians have addressed androgen-induced suppression by discontinuing exogenous testosterone to allow for endogenous restoration of spermatogenesis. However, recovery of endogenous fertility is often slow and accompanied by the sudden recurrence of hypogonadal symptoms. Data suggest that increasing age and longer duration of testosterone therapy are associated with delayed or incomplete recovery of spermatogenesis after testosterone therapy discontinuation (49).

As previously mentioned, Stocks et al. (41) studied the administration of hCG and FSH three times per week in men not currently receiving testosterone therapy and those continuing testosterone therapy concurrently and found that both groups demonstrated similar improvements in sperm concentration. Another study evaluated men who continued using non-prescribed AAS—primarily athletes—with an active desire for fertility despite ongoing androgen use (50). Nineteen men attending a harm-reduction clinic in the Netherlands, all of whom had been using AAS for at least 3 months and were unwilling to discontinue, received three weekly injections of 520–1,040 IU hCG. The mean duration of continuous AAS use was 43 months, and the mean total weekly hCG dose was 2,273 IU. At 17-week follow-up, 84% of participants demonstrated an improvement in total sperm count, increasing from a mean baseline of 18.0 million to 146.9 million. Similarly, 89% showed an improvement in total motile sperm count, rising from a mean baseline of 1.1 million to 66.8 million. Six pregnancies were reported among the cases.

Taken together, these data illustrate the growing potential of gonadotropin-based therapies to preserve or restore fertility in hypogonadal men, even those continuing exogenous androgen use. Continued investigation will be essential to optimize dosing strategies, assess long-term reproductive outcomes, and define the role of these interventions within the broader landscape of TRT. It is important to note that, consistent with current clinical guidelines, discontinuation of testosterone therapy or anabolic steroid use remains the standard recommendation for men desiring fertility.

Conclusions

Fertility preservation remains an important consideration in the management of hypogonadal men. While exogenous testosterone therapy effectively alleviates symptoms, it suppresses the HPG axis and impairs spermatogenesis. Alternative therapeutic strategies—including short-acting formulations (intranasal and oral testosterone undecanoate), SERMs such as enclomiphene citrate, and concomitant administration of low-dose hCG—are under active investigation as potential options for maintaining or restoring fertility potential. Continued investigation and long-term outcome data are needed to better define the role of these approaches in clinical practice, particularly regarding semen parameters and pregnancy outcomes. As this review was narrative in nature rather than a systematic analysis, the potential for selection bias should be acknowledged. Clinicians should continue to assess fertility goals in all men prior to initiating TRT.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-480/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-480/coif). The authors have no conflicts of interest to declare.

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