Clinician’s guide to the management of azoospermia induced by exogenous testosterone or anabolic–androgenic steroids

Abstract

Azoospermia, defined as the absence of sperm in the ejaculate, is a well-documented consequence of exogenous testosterone (ET) and anabolic–androgenic steroid (AAS) use. These agents suppress the hypothalamic–pituitary–gonadal (HPG) axis, leading to reduced intratesticular testosterone levels and impaired spermatogenesis. This review examines the pathophysiological mechanisms underlying azoospermia and outlines therapeutic strategies for recovery. Azoospermia is categorized into pretesticular, testicular, and post-testicular types, with a focus on personalized treatment approaches based on the degree of HPG axis suppression and baseline testicular function. Key strategies include discontinuing ET and monitoring for spontaneous recovery, particularly in patients with shorter durations of ET use. For cases of persistent azoospermia, gonadotropins (human chorionic gonadotropin [hCG] and follicle-stimulating hormone [FSH]) and selective estrogen receptor modulators (SERMs), such as clomiphene citrate, are recommended, either alone or in combination. The global increase in exogenous testosterone use, including testosterone replacement therapy and AAS, underscores the need for improved management of associated azoospermia, which can be temporary or permanent depending on individual factors and the type of testosterone used. Additionally, the manuscript discusses preventive strategies, such as transitioning to short-acting testosterone formulations or incorporating low-dose hCG to preserve fertility during ET therapy. While guidelines for managing testosterone-related azoospermia remain limited, emerging research indicates the potential efficacy of hormonal stimulation therapies. However, there is a notable lack of well-structured, controlled, and long-term studies addressing the management of azoospermia related to exogenous testosterone use, highlighting the need for such studies to inform evidence-based recommendations.

INTRODUCTION

Azoospermia, defined as the absence of sperm in the ejaculate,1 is identified in approximately 1% of all men and in 10%–15% of men presenting for infertility evaluations.2,3 A precise diagnosis of azoospermia and systematic evaluation of the patient to establish the disease etiology are necessary to guide appropriate management options and to determine the expected and realistic outcomes, risks, prognoses, and associated cost benefits for treatment options.4 The categorical classification of azoospermia is either pretesticular (hypothalamic/pituitary dysfunction), testicular (genetics, varicocele, infection, or gonadotoxins and medications), or post-testicular (absence of vasa deferentia, vasal or ejaculatory duct obstruction, or combinations such as Zinner syndrome).5 Many substances or pharmaceutical drugs result in deleterious effects on testicular function either directly, such as chemotherapeutic drugs, or indirectly through inhibitory feedback mechanisms on the hypothalamic–pituitary–gonadal (HPG) axis such as exogenous testosterone (ET), including testosterone replacement therapy (TRT) and androgenic–anabolic steroids (AAS).6

TRT

During the 4^th decade of life, serum testosterone concentrations decline by an average of 0.4%–2% per year, which can result in low testosterone production and, in some cases, impaired spermatogenesis.7 Owing to the widespread expression of androgen receptors in the human body, male hypogonadism (MH) can affect a plethora of cells in different organs. Men suffering from MH may present with different signs and symptoms of androgen deficiency, including low libido, erectile dysfunction, loss of muscle mass, increased visceral adiposity, impaired glucose regulation, increased susceptibility to metabolic syndrome, osteopenia/osteoporosis, as well as cognitive and psychological disturbances.8,9,10,11

The definition of late-onset hypogonadism (LOH) refers to a medical condition that must include a cluster of clinical signs and symptoms as well as two separate low fasting, early morning serum testosterone measurements in men of advanced age.12 LOH is a result of age-related changes in the endocrine system and can impact a man’s overall quality of life and well-being. As men age, the number of Leydig cells in the testes decreases, less testosterone is secreted in the secretory bursts of testosterone, and there is a decline in response to luteinizing hormone (LH).

Untreated testosterone deficiency has deleterious consequences for physical and psychological health.10 TRT aims to restore and maintain optimal testosterone levels within a physiological range, providing symptom relief and benefits in patients with MH. However, it is essential to evaluate the risks and benefits of TRT on an individual basis before starting any treatment.13 There are many modalities for the delivery of TRT, including topical gels, topical patches, subcutaneous pellets, intramuscular injections, buccal formulations, nasal administration, subcutaneous autoinjectors, and new oral formulations.

Indeed, marketing data are reflecting the growing interest in TRT among populations. Data on the global sales of all testosterone products were collected annually between 2000 and 2011 for 41 countries, in which 37 countries out of 41 countries experienced a significant and gradual increase in specific monthly payments for doses per year and per capita. This demonstrated a tripling of total TRT usage.14 Similar results were denoted by Bandari et al.15 in their 2017 published systematic review analyzing TRT prescriptions in the USA over two decades, revealing an increase between 1.8- and 4-fold. Other studies have found that TRT use increased 4-fold in men aged 18–45 years and 3-fold in men >45 years during the investigation period between 2003 and 2013.16,17 Applying the Google Trends analysis search strategy to investigate interest in TRT in the USA population between 2010 and 2019, there was an impressive online search interest in testosterone products, resulting in 5.96-fold (495.76%), 8.47-fold (747.06%), and 5.18-fold (418.42%) increases for search queries for “testosterone pills”, “testosterone pellets”, and “testosterone injection”, respectively.18 To investigate who is the person prescribing TRT products according to growing needs, in 2023, Sellke et al.19 undertook a study demonstrating, on the one hand, an increase among testosterone prescribers by 28.6% between 2016 and 2019 in the USA, resulting in a 52% increase in the testosterone day supply for the same time. Conversely, an analysis by prescriber specialty revealed increases of 18% and 25% among urologists and endocrinologists, respectively. However, the largest increase was observed among nurse practitioners (118%), followed by physician assistants (78%) and family practice physicians (31%).19

Many testosterone users and clinicians are unaware of or underestimate the potential adverse effect of TRT on normal testicular function by significantly suppressing spermatogenesis, which may result in azoospermia and infertility. There is a simultaneous increase in paternal age and in younger men seeking treatment for MH, so the importance of the impact of TRT on spermatogenesis must be considered.20,21 Many men with MH may still desire to maintain their fertility potential.19 A large population-based retrospective study of men in the UK receiving TRT estimated that 7% of those seeking fertility assistance were prescribed TRT.22 In a survey of the American urologists, approximately 25% advocated the use of exogenous TRT to treat low testosterone levels associated with male infertility.23 Similarly, a Canadian study examined the use of TRT in 4400 men presenting for fertility evaluation between 2008 and 2012, reporting that 1.3% remained on exogenous TRT. More notably, 12% of these men were prescribed TRT solely to address infertility, despite explicit warnings in several guidelines.24

It is well established that exogenous TRT administration cannot promote or maintain spermatogenesis even though testosterone is the main mediator of LH and has an impact it on spermatogenesis. Exogenous administration severely suppresses intratesticular testosterone (ITT),25 which, under normal physiological circumstances, is 50–120 times higher than the testosterone level in systemic circulation,26,27 and it has been clearly demonstrated that exogenous TRT cannot support spermatogenesis.28

In contrast, exogenous TRT has even been considered a contraceptive modality, and a multicenter study utilizing the most commonly used TRT preparation (testosterone undecanoate) identified it as a contraceptive in more than one thousand patients in China and confirmed its efficacy in establishing azoospermia after 3 months of therapy in 93%–99% of men.29

ANABOLIC-ANDROGENIC STEROIDS

The term “anabolic-androgenic steroids (AAS)” refers to a group of hormones, both natural and synthetic, that have both androgenic and anabolic biological effects. While androgenic refers to the induction and maintenance of male secondary sexual characteristics, anabolic refers to the properties of AAS that help in the development of skeletal muscle. The main endogenous hormone in this class that is produced naturally is testosterone. As a replacement therapy for MH, it is widely used therapeutically, and for prolonged half-life time and stabilization, a variety of esterified forms have been developed. In contrast to the legitimate medical use of TRT, steroids within the AAS category are often abused because of their ability to increase strength and build muscle at dosages far above those used to achieve therapeutic physiologic testosterone levels with medical treatment.

The use of AASs has been a concern in many parts of the world, particularly in the context of their misuse and abuse for nonmedical purposes, such as athletic performance enhancement and bodybuilding.30,31,32 The definition of androgen abuse refers to any use of androgenic substances without a prescription or medical indication. The prevalence of AAS use or abuse varies across different populations and regions. Studies indicate that AAS misuse is particularly prominent among certain subgroups, such as athletes, bodybuilders, and individuals seeking esthetic enhancement.30,33 Prevalence rates range widely, with estimates suggesting that lifetime AAS use may be as low as 1% in the general population but significantly higher (10%–30%) among specific high-risk groups. The overall, global lifetime prevalence rate is estimated to be approximately 6.4% for males and as high as 18.4% for men performing recreational sports.34 Because these estimates are frequently based on self-reported data and because the supply of AASs is illegal and their use is secretive, the prevalence of AAS use is likely understated, particularly in the competitive fields of professional sports. In 2009, a Dutch study found that 8.2% of 718 gym attendees used Image and Performance Enhancement Drugs, which are specific drug clusters of AAS,32 whereas a more recent cross-sectional study conducted in The Netherlands found that 9.0% of 2269 male gym goers (mean ± standard deviation [s.d.]: 24 ± 6 years) used AAS, the majority of whom performed regular strength training (44.6%) and 2.2% trained for Olympic weightlifting.35 In contrast, according to a study by Blouin and Gouldfield,31 44.2% of bodybuilders use AASs regularly. According to a publication from Anawalt,30 the lifetime prevalence of having ever used AASs in men in the general population is approximately 1%–5% worldwide, with a male-to-female ratio of more than 50:1. Although historically, mostly competitive professional athletics have used AASs to increase muscle mass and strength for their performance, according to a recent survey, the use of AAS is increasing among recreational athletes to enhance physical performance and appearance and improve self‐esteem or body image.10,36 Recently, one Australian study investigated the impact of AAS through a social media-recruited, cross-sectional, observational study of 41 current and 31 former AAS users (≥3 months since last use and a median of 300 days since last use) compared with 21 healthy eugonadal nonusers.37 Sperm production per ejaculate was significantly lower in active users than in those who had or had not used them in the past: 4 × 10⁶ (range: 0–39 × 10⁶) versus 210 × 10⁶ (range: 80 × 10⁶–359 × 10⁶) and 203 × 10⁶ (range: 92 × 10⁶–340 × 10⁶) per ejaculate appropriately. Finally, the mean recovery time of having sperm return to the ejaculate after AAS drug discontinuation was 14.1 months, but it was remarkably longer, with 37.6 months for sperm motility recovery. The longer duration of androgen abuse was associated with a delayed improvement in sperm parameters. However, given sufficient time for recovery, the effects of androgen abuse appear to be reversible, provided that the initial semen parameters of former users were comparable to those of the control group.37

The negative effects of AAS on the HPG axis are a unique condition called anabolic steroid-induced hypogonadism (ASIH), which is characterized by functional incompetence of the testes along with subnormal or impaired production of testosterone and/or spermatozoa due to the administration of androgens or anabolic steroids.38

MECHANISM AND PREDICTORS OF AZOOSPERMIA AFTER ET

Both uses of ET, medically prescribed TRT, and AAS can lead to suppression of the HPG axis, with reductions in FSH, LH, and consequently ITT, which are responsible for sperm production and maturation. This suppression results in significant impairment of spermatogenesis in the forms of either oligozoospermia or ET-induced azoospermia, as a form of nonobstructive azoospermia (NOA).39

The suppression of the pulsatile, fine-tuned secretion of gonadotropins leads not only to the suppression of spermatogenesis but also to testicular atrophy by a magnitude of 16.5%–30% due to spermatogenic suppression,40,41,42,43 since seminiferous tubules compromise two-thirds of the testicular volume.44 A study by Rasmussen et al.43 demonstrated that current ASS users exhibited significantly lower testicular volumes, averaging 12.2 (s.d.: 0.7) ml, compared to healthy controls with 22.3 (s.d.: 0.6) ml. Former ASS users had a mean volume of 17.4 (s.d.: 0.8) ml. Moreover, a striking negative association was observed between the cumulative duration of AAS abuse and testis size; the investigators show a clear decline in testicular size with increasing weeks of AAS use for both current and former users, with current users experiencing a more rapid reduction, especially during the first 32 weeks, as indicated by the steeper slope of the spline function compared to former users.43

Often, testicular atrophy in up to 30% and severe oligoasthenozoospermia with induced sperm defects or azoospermia are observed as a consequence of ET.45 An animal study in rats demonstrated that a decrease of 80% in the ITT results in dramatic spermatogenic impairment, resulting in infertility.46

The primary cause of ET-induced azoospermia is the inhibition of the HPG axis via negative feedback on the hypothalamus and pituitary gland due to elevated exogenous testosterone levels. This testosterone exerts a suppressive effect on the gonadotropin-releasing hormone (GnRH) pulse generator at concentrations just below normal physiological levels, with additional mechanisms potentially contributing to further suppression. One of these mechanisms is associated with increased estradiol (E2) levels due to a pronounced increased peripheral conversion by aromatase activity of excessive testosterone. E2 is able to decrease the GnRH pulse frequency and thus act on LH secretion, which is in line with previous studies showing that E2 suppression results in a significant increase in LH pulse frequency. This is notable, on a molar basis, since estradiol itself exerts a 200-fold more potent suppressive effect than testosterone does.47 Testicular suppression in ET may also occur through progesterone-like effects. Although not all AAS elevate progesterone levels, nandrolone—a commonly used preparation—exerts significant activation of progesterone receptors, mimicking the effects of progesterone.48 Many studies of AAS abusers suggest that AAS-induced hypogonadism is an underestimated problem, and a full recovery is not always expected. Recovery may take long periods of time, and many medical stimulating therapies may be needed to enhance the recovery of the HPG axis. This delayed and complex recovery is not related to HPG axis suppression alone, but the simultaneous use of different types of AAS at high doses and for a prolonged period may also be associated with testicular failure which may lead to cases, in which recovery is not possible.49 Experimental studies in animal models have reported AAS-induced Leydig cell alterations, cellular morphology anomalies, specific end-stage spermatogenesis impairment, and a lack of advanced forms of spermatids. After AAS discontinuation, Leydig cells tend to proliferate but remain below regular counts, even after longer periods. In addition, there was a significant increase in the rate of apoptosis of spermatogenic cells, and sex chromosomes XY and chromosomes 1 and 9 disomies, suggesting anomalies in the meiotic process and genetic damage among AAS users.50,51 All these facts could explain the persistence of abnormal semen analysis and azoospermia in some users, even for long durations after the discontinuation of AAS use.

The factors associated with the persistence of azoospermia or longer recovery time after ET courses include a longer duration and higher dose of ET, Asian ethnicity, older age at initiation or cessation, and baseline subfertility or poor testicular function prior to ET use.33,37,52

According to the health risks of anabolic androgenic steroid use by male amateur athletes (HAARLEM) study, in AAS users with previously normal endocrine profiles and normal spermatogenesis, there will be a 90% testosterone level recovery within 3 months after AAS cessation and approximately 100% testosterone level recover after 12 months of discontinuation of AAS use, but in some cases, persistent testicular failure remains after AAS-induced hypogonadism.40 Some clinicians found that a return of testosterone after ceasing androgen intake is to be expected between 7 months and 18 months.37 Notably, a recent meta-analysis concluded that secondary hypogonadism after AAS abuse might be expected, representing a serious and underrated problem.53 Aside from anticonceptive hormonal studies in men,28 which have shown a median recovery time for a sperm concentration of 20 × 10⁶ ml⁻¹ after testosterone intake is stopped in 67%, 90%, 96%, and 100% of men at 6 months, 12 months, 16 months, and 24 months, respectively,29,54 specific and detailed data on the return of spermatogenesis after discontinuation of AAS are scarce. However, case reports suggest that recovery is possible within 4–12 months, although some patients may require 24–30 months to return to spermatozoa concentrations >20 × 10⁶ ml⁻¹.52,55

CLINICAL AND LABORATORY EVALUATION

Patients with ET-induced azoospermia are characterized by many clinical findings and hormonal abnormalities. At least two semen analyses are needed to confirm the diagnosis of azoospermia. The normalization of sperm counts lags behind the normalization of endocrine parameters such as plasma testosterone levels after cessation of ET or AAS. Therefore, the wait-and-see attitude is generally often proposed first, meaning that semen analysis should not be performed within the first 3 months after the cessation of anabolic steroids unless there is an urgency or other specific necessity. In the case of short-term ET (mean ± s.d.: 9.45 ± 4.0 months) and previously normal testicular function, sperm recovery is estimated at approximately 67% for a sperm concentration over 20 × 10⁶ ml⁻¹ within 6 months after ET cessation.54 In the case of prolonged exposure to ET or other esterified compounds in ASS users, the rate of sperm recovery is reduced because of multiple effects and thus requires meticulous therapeutic planning to regain normal endocrine and reproductive function.

The levels of LH and FSH are usually reduced to very low levels, often undetectably low, owing to severe inhibitory effects of high doses of ET on the HPG axis.

Measuring total testosterone in the early morning is essential for accurately assessing endogenous testosterone levels, as these levels follow a natural circadian rhythm, peaking between 7 a.m. and 11 a.m.56 Ideally, the patient should fast overnight for at least 8 h, as serum testosterone levels can decrease by up to 39% following a glucose load and by 56% after a typical mixed meal.11,57,58 Usually, serum testosterone levels are higher than normal during the course of ET and significantly lower than normal soon after the discontinuation of ET. In unclear cases, repeated, confirmatory testosterone measurements should be advised. The best and most accurate assay for measuring serum testosterone levels is liquid chromatography-tandem mass spectrometry (LC-MS/MS); however, immunoassays demonstrate a good correlation with LC-MS/MS.59

Sex hormone-binding globulin (SHBG) is usually significantly reduced during supraphysiological dosages of testosterone with saturation of the SHBG/testosterone (SHBG/T) binding capacity.60 Interestingly, SHBG has a very low affinity for different AASs.61 Therefore, to estimate the bioavailable testosterone (BT) and free testosterone (FT) levels, the free online testosterone calculation formula is utilized (https://www.issam.ch/freetesto.htm). Such calculation will sometimes be more accurate in evaluating free testosterone levels, as assays of FT based on analog displacement immunoassays give unpredictable results and are not universally recommended. Additionally, this online formula provides the value of BT, which can easily be dissociated into FT.

Estradiol may increase during the course of ET due to peripherally increased aromatization of excessive testosterone, which largely takes place in the endoplasmic reticulum of peripheral tissues such as adipose tissue, where a higher content of the catalytic aromatase cytochrome P450 enzyme (P450arom, encoded by the cytochrome P450 family 19 subfamily A member 1 [CYP19A1] gene on chromosome 15) is found.62 In different male organs, such as the testis (mainly in Sertoli cells), epididymis, prostate, and seminal vesicles, the enzymatic conversion of testosterone to estradiol takes place; this results in a surprisingly high concentration of intratesticular estradiol with levels of 11 000–58 000 pmol l⁻¹.27,63 As a result of this enzymatic activity, the testis-to-serum ratio for estradiol is considerably higher by a factor of 407 than that for testosterone, which is approximately 120.27 The estrogenic role is well recognized in the testes; spermatogenesis is modulated at every level by estrogen, starting with the HPG axis, followed by the Leydig, Sertoli, and germ cells and concludes with the ductal epithelium, epididymis, and mature sperm. However, steroids other than testosterone used in AAS regimens are not aromatized similarly to 17β-estradiol to the same extent; thus, a meticulous understanding of the formulation of AAS used is imperative when evaluating estradiol measurements.

In addition, it is important to measure the testosterone to estradiol (T/E) ratio to determine treatment options, especially in obese patients who present with gynecomastia, to keep the T/E ratio within the optimum of more than 10:1.

The detection of testicular atrophy in men using ET is crucial, as it is an indication of reduced spermatogenesis and size of seminiferous tubules. Testicular size should be measured either clinically with an orchidometer, supplemented by ultrasound as per European Association of Urology (EAU) guidelines (Section 4.3),64 or preferably, directly via scrotal ultrasound according to the European Academy of Andrology (EAA) recommendations.65,66

Gynecomastia, which is defined as a palpable, uni- and/or bilateral, benign enlargement of the glandular breast tissue, typically results from either an alteration in estrogen-to-androgen balance or by the absolute excess of estrogens induced by ET or as a result of AAS use with excessive peripheral aromatization. Since high doses of AAS are administered during an AAS cycle, the development of gynecomastia is not the result of an absolute or relative lack of androgenic activity but is due to estradiol increases. Estradiol levels increase in a dose-dependent manner following the administration of testosterone or testosterone-like substances. However, the increase in estradiol is proportionally smaller with increasing doses of testosterone, indicating saturation of aromatase activity. These findings suggest that there is an absolute excess of estrogenic action responsible for gynecomastia development during AAS use. The EAA clinical practice guidelines on gynecomastia evaluation and management recommend a set of hormonal assessments for the identification of gynecomastia (Recommendation 9).66

In the HAARLEM study, intramuscular injection of 200 mg of testosterone enanthate weekly therapy for more than 6 months resulted in 3% of the participants developing gynecomastia, whereas in the AAS users, the development of gynecomastia was 12%67 and up to 39.19% in a more recent study.68 It is widely indicated that the development of gynecomastia in AAS users may be related to progestin actions or to prolactin elevation since estrogen itself can stimulate prolactin release. Since AAS users are often multidrug users and take additional nutritional supplements containing prohibited and not declared AAS,69 the net-endocrine response to such administrations often remains unclear.

Acne vulgaris, folliculitis, and hair loss are well-recognized frequently observed side effects of ET and are mostly related to the role played by dihydrotestosterone and testosterone in regulating sebum production and the direct role of dihydrotestosterone on hair follicles.70 There is an increased bacterial population with Propionibacterium acnes and Staphylococcus aureus.71,72 Generally, however, acne induced by AAS is reversible and disappears after discontinuation of the substance.

AAS use results in increased free fat and reduced fat mass. Higher low-density lipoprotein (LDL)-cholesterol and lower high-density lipoprotein (HDL)-cholesterol levels, resulting in dyslipidemia, were reported in up to 17% of AAS abusers.73 Conversely, no differences in total cholesterol, triglycerides, or glucose levels were observed.74,75

The estimation of liver enzymes is important and expected to be higher than normal levels, especially with the use of oral 17α-alkylated agents,76 whereas for short-term ASS, there might be a lower risk.67

However, the EAU guidelines for TRT recommend prostate-specific antigen (PSA) controls at 3 months, 6 months, and 12 months in the 1^st year and then annually.64 The American Urological Association (AUA) guidelines for the Evaluation and Management of Testosterone Deficiency recommend measuring PSA in men over 40 years before starting TRT, and in cases of elevated PSA, a second PSA test is recommended to assess any prostate cancer risk, whereas there are no strict PSA control intervals in the follow-up for men receiving TRT therapy (Recommendation 12).77 Remarkably, it should be noted that even supraphysiologic dosages of testosterone, at least up to 600 mg of testosterone enanthate, did not affect serum prostate-specific antigen levels in eugonadal young individuals (18–35 years) treated with different dosages of testosterone enanthate intramuscularly weekly.60 In ET-induced azoospermia, serum hormone tests evaluating the HPG axis should be performed at intervals to assess the return of HPG axis function.

One study investigated which blood test variables are useful discriminators for optimal distinction in the first presentation between current and previous AAS users and found that using 5 variables, namely serum LH, anti-Müllerian hormone (AMH), hematocrit, FSH, and total inhibin, yielded a good discrimination factor in 96% of the tested men (68 out of 71).37 The ability to distinguish between the individual components is expressed as normalized canonical factors for LH, AMH, FSH, total inhibin, and hematocrit of 0.60, 0.42, 0.38, 0.27, and 0.24, respectively. Restriction of predictor variables to only three available blood tests (serum LH, FSH, and hematocrit) lowers the correct classification to 91.5%, while the addition of AMH serum increases it to 94%. On the other hand, adding other blood test variables (serum SHBG, hemoglobin, urea, and creatinine), clinical variables such as acne or gynecomastia or sperm count did not further improve discrimination accuracy for distinction between current and past ASS users.37 According to this study, this implies for the clinician that by analyzing these five specific variables collectively, it is possible to achieve good overall discriminative power with high accuracy to distinguish between current and previous AAS users. This implies that these variables, when considered together, can be valuable in identifying individuals who may have used AAS in the past or are currently using them.

TREATMENT OF EXOGENOUS TESTOSTERONE-INDUCED AZOOSPERMIA

In several guidelines and position statements, the importance of normal serum testosterone levels to maintain regular spermatogenesis is highlighted, and congruently, most of the guidelines, except for the International Society for Sexual Medicine (ISSM),78 stress the negative role of any TRT regardless of its clinical indications in men desiring fertility.11,58,64,79,80,81 There are no specific guidelines or known society recommendations for the treatment of ET-induced azoospermia. Most of the treatment regimens used by medical specialists are based on the management of contraceptive testosterone-induced azoospermia and some clinical trials of the treatment of AAS-associated azoospermia.73,82

Several approaches exist for restoring HPG axis function and spermatogenesis in men undergoing testosterone therapy or using AAS. These include discontinuing testosterone to allow natural recovery, initiating treatment with hCG, FSH, and SERMs such as clomiphene citrate (CC) or tamoxifen, or using aromatase inhibitors such as letrozole, anastrozole, or the nonselective testolactone. These options for treatment, either used as monotherapy or in combination, can restore spermatogenesis in most cases.83,84 Even if the underlying pathophysiological process is by no means fully understood, there seems to be a difference between a long-acting and a short-acting testosterone preparation. Indeed, the conversion from a long-acting form of TRT to the short-acting intranasal form of TRT, which is less suppressive to the HPG axis, has been shown to allow for faster resumption of spermatogenesis in some men.85

SPONTANEOUS RECOVERY OF SPERMATOGENESIS

All ET suppresses the secretion of the gonadotropins LH and FSH by the anterior pituitary gland, resulting in insufficient ITT production by Leydig cells. Due to the suppression of ITT, exogenous testosterone in the serum cannot maintain spermatogenesis in the testis. The regular pulsatile secretion of gonadotropins, along with adequate high ITT levels, is essential for spermatogenesis.

With extrapolation from previous TRT studies, some experts in the field believe that even for AAS users, there is a need for a washout period of approximately 4 months due to the esterification of some steroids with a prolonged biological half-life.84,86 Other studies failed to demonstrate any definitive duration for the expected recovery of spermatogenesis.83,84,87

Other predictors of the duration of recovery of spermatogenesis following the discontinuation of AAS include age, fertility status, or testicular function estimated by the testicular volume before AAS or ET initiation, which are considered relevant parameters for predicting spermatogenic and hormonal recovery.33,37,52,88,89,90 In individuals with durations of less than 1 year of AAS or ET use, the probability of recovery is greater than that in long-term users over many years.30,43 Increased age at the time of ET cessation was found to limit recovery more than the duration of TRT use.90 A recent survey performed by Al Hashimi et al.91 of 171 practitioners on the treatment of AAS adverse effects showed that 32.5% would advise for no treatment but only waiting for spontaneous recovery.

One study suggested monitoring hormones and semen analyses after a 6-month washout period to allow for spontaneous recovery of the HPG axis, and every 3 months thereafter, with most men expected to recover in approximately 6–12 months.34

Another study advised solely discontinuing ET and noted that following ET discontinuation, serum gonadotropin levels gradually returned to baseline values within 13–24 weeks, whereas serum testosterone levels remained reduced at 16 weeks following discontinuation.87

Rasmussen et al.43 evaluated former AAS users who discontinued use for more than 2.5 years and used serum inhibin B and AMH levels as markers of Sertoli cell function and spermatogenesis. The authors concluded that 27.2% of former AAS abusers exhibited plasma total testosterone levels below the lower reference limit, gonadotropins were significantly suppressed, and inhibin B and AMH were significantly decreased below the limit of impaired spermatogenesis, indicating the need for prolonged durations for spermatogenic recovery.43 Kanayama et al.75 similarly reported that former users of AAS had significantly smaller testicular volumes and lower total testosterone levels than nonusers did, which persisted despite abstinence from the AAS for up to 26 months in some patients (estimated change in testicular volume per year of AAS use: −0.5 [−0.1, −0.9] ml; P = 0.029).

A large meta-analysis assessed the spontaneous recovery of spermatogenesis in azoospermic patients due to ET used as a form of male contraception. Liu et al.54 followed 1549 patients with azoospermia after discontinuation of testosterone use for no longer than 18 months and found that the median time for sperm to recover to thresholds of 20 × 10⁶ ml⁻¹, 10 × 10⁶ ml⁻¹, and 3 × 10⁶ ml⁻¹ was 3.4 months, 3.0 months, and 2.5 months, respectively. The typical probability of recovery to 20 × 10⁶ ml⁻¹ was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months.54 However, the authors emphasized that in view of the treatment period for hormonal male contraception of 18 months or less, these results should not be extrapolated to longer treatment durations until more data are available relating the time to recovery to the duration of treatment with identical regimens. Shankara-Narayana et al.37 demonstrated that the recovery of the sperm concentration after ceasing AAS took a mean of 14.1 months. It is worth noting that after the discontinuation of an AAS, there is an earlier rise and recovery for LH (269 days), AMH (219 days), and testosterone, whereas FSH recovery and normalization can take a longer time (562 days).

Despite the above data showing high percentages of spontaneous recovery of spermatogenesis after ET or ASS cessation, contrary findings were reported by Al Hashimi87 who followed 463 AAS abusers for 1 year after stopping their AAS use. He found abnormal semen analysis parameters in 411 patients (79%) and azoospermia in 33 patients (7%). Oligospermic men opting for spontaneous recovery had a significantly lower rate of sperm parameter normalization than men in the intervention group did. Strikingly, 32% of all men suffering from azoospermia due to ET or AAS remain infertile with proven azoospermia even after 1 year of treatment.87

The predictors of recovery are mostly related to the duration of ET or AAS use, the preparation, and doses of the used ET. Higher rates of recovery are demonstrated with shorter treatment durations, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of LH at baseline.37,54,87 For men who are infertile and have a recent history of using high dosages of AAS for greater than 1 year, the time to recovery of normal serum gonadotropins and testosterone and the even longer lag time for recovery of normal spermatogenesis might be excessive. This could be an indication to initiate treatment, while for those with less than 1 year of ET or AAS use, spontaneous recovery could still be an option.30

These data demonstrate that stopping ET and waiting for spontaneous recovery of the HPG axis and spermatogenesis is a valid option for the treatment of many ET-induced azoospermic patients in whom there is no rush to restore spermatogenesis either because of the short duration of use or lack of a plan for conception in the near future. The female partner’s age and ovarian reserve status must also be considered when considering the aggressiveness of treatment options for recovery of spermatogenesis following ET use.

TREATMENT WITH GONADOTROPINS

The role of hCG injections in inducing and/or maintaining spermatogenesis alone or in combination with FSH/recombinant FSH (rFSH) in patients with hypogonadotropic hypogonadism (HH) is acknowledged by some clinical guidelines.11,64 This role has been investigated in many clinical trials treating male infertility secondary to pathology at the level of the hypothalamus or pituitary gland as seen in patients with Kallman syndrome, Prader–Willi syndrome, panhypopituitarism from prolactinomas, pituitary tumors, infection or radiation, or idiopathic causes. All of these etiologies are categorized as secondary HH, many of which present with azoospermia, and the role of gonadotropins in their treatment represents a valuable model for the treatment of ET-induced HH and related azoospermia.11 While GnRH can be effective in treating Kallmann syndrome, characterized by defective GnRH release, its use is generally discouraged for former ET/AAS users due to its high cost, limited availability, and sometimes impracticality, as it requires a pulsatile GnRH-releasing pump.52

Essentially, hCG has the same alpha subunit as LH and has been shown to act as an agonist of LH receptors. Thus, hCG increases ITT and in turn promotes spermatogenesis, exhibiting effective therapeutic potency in former ET/ASS users with secondary infertility similar to men with HH. The hCG application route can be either intramuscular or subcutaneous, and it is typically administered two to three times per week, either alone or in combination with FSH/rFSH.92

Depenbusch et al.93 found that hCG alone (500–2500 IU twice weekly, adjusted based on testosterone levels) can preserve spermatogenesis in men with HH and azoospermia who initially received combined hCG/FSH therapy for spermatogenesis induction. However, for optimal sperm concentration, the combination of hCG and FSH is preferred.93 Subcutaneous hCG monotherapy stimulates testosterone production and spermatogenesis in most men with HH as long as testicular size of ≥6 ml. For comparison, in the EAA ultrasound study (EAAUS) study, the lower limits for the right and left testes were 12 ml and 11 ml, respectively, which are considered normal ranges; therefore, lower testicular sizes are considered “testicular hypotrophy”.65 Similar to dosing for HH, in men being treated after cessation of ET, the typical dose of hCG administered is 1000–2000 IU subcutaneously 2–3 times weekly. The dosage is adjusted accordingly until serum total testosterone level is within normal range and continues at least until sperm recovery for conception.28,94 Sometimes, after an induction phase, a lower dosage therapy of 500–750 IU is reasonable. An increase in the sperm concentration usually lasts 4–6 months with hCG monotherapy, and if the sperm concentration remains below 10 × 10⁶ ml⁻¹ and fertilization has not occurred, treatment with FSH is added. FSH can be administered as recombinant human FSH (rhFSH) or human menopausal gonadotropin. The usual starting dose is 75 IU subcutaneously every other day. The FSH dose can be doubled if conception has not occurred, and the sperm count remains <20 × 10⁶ ml⁻¹ within 6 months of starting FSH combination therapy.

A multicenter group of men previously treated with TRT with secondary azoospermia or severe oligospermia (≤1 × 10⁶ ml⁻¹) investigated the outcomes after treatment with 3000 IU hCG every other day supplemented with either FSH, CC, tamoxifen, or anastrozole. This series demonstrated a mean recovery of spermatogenesis to a concentration of 22 × 10⁶ ml⁻¹ in 4 months.95 In a study of healthy men with normal reproductive potential treated with TRT and randomized to receive concurrent administration of placebo or low-dose hCG (125 IU, 150 IU, or 500 IU) every other day, intratesticular testosterone levels were maintained in all hCG-treated groups with levels closest to those at baseline and with normal ITT in the 250 IU and 500 IU dose groups, thereby suggesting preservation of spermatogenesis.28

For the treatment of AAS-related azoospermia, Al Hashimi et al.91 found that the combination of hCG and CC enabled 50% of azoospermic patients to recover sperm in their ejaculate at 12 months following treatment. However, all of them continued to have severe oligospermia and infertility at the end of the study, and further follow-up was recommended.91

According to the results of Kohn et al.,90 age at discontinuation of TRT use and duration of testosterone use predict the time to recovery of spermatogenesis after TRT use. Restoration of spermatogenesis was defined as a sperm concentration greater than 5 × 10⁶ motile sperm per ml. Seventy percent of the men achieved this level of spermatogenesis within 12 months of discontinuation of TRT. Approximately 65% of men who developed azoospermia during TRT recovered, whereas the more favorable subgroup with secondary cryptozoospermia showed a better outcome within 12 months after discontinuation of TRT and initiation of high-dose hCG and SERM therapy by more than 90%, achieving normalized sperm total motility.

Conversely, after discontinuation of ET, Ramasamy et al.96 recommended a combination strategy by administration of 3000 IU of hCG every other day with the aromatase inhibitor anastrozole or SERMs (tamoxifen or CC) for 3 or more months. The authors found the successful return of sperm to the ejaculate in most of the patients after 4–6 months, which is faster than that observed in other studies.96 Campbell et al.97 reiterates that FSH in combination with hCG may be considered a better alternative to a combination of hCG and CC in the treatment of testosterone-induced azoospermia. FSH and hCG dual therapy resulted in a more rapid recovery of sperm, which was nearly three times faster in the FSH group (5.5 months vs 14.8 months) than that in the CC group. Additionally, patients who have failed dual therapy with hCG and clomiphene should be considered for subsequent FSH.97

In summary, there is no globally accepted therapeutic algorithm. Indeed, a few case reports indicate that hCG alone at variable doses (2000 IU 3 times per week to 10 000 IU once weekly) for 3 months39 or both hCG (10 000 IU weekly) and FSH (75 IU daily) in combination98 can restore spermatogenesis, leading to spontaneous conception in some cases.

At least for HH cases, two large studies with a total of 162 men reported that combination therapy with hCG and rFSH resulted in successful spermatogenesis in approximately 90% of patients, which justifies the assumption that such a therapy should also be used for men with previous ET/AAS use.88,89

Collectively, these conclusions are a clue for the role of gonadotropins (alone or in combination) in the restoration and maintenance of spermatogenesis in patients with ET-induced azoospermia.

SERMS

SERMs include the centrally acting CC and tamoxifen, which exhibit both central and peripheral effects. Classified as nonsteroidal SERMs, they can increase serum gonadotropins and thus testosterone concentrations by competitively binding to estrogen receptors in the anterior pituitary and hypothalamus.99 Through antagonizing action, the inhibitory effect of estradiol is abolished, resulting in gonadotropin release within 2–4 weeks in men with intact pituitary function. Furthermore, some estrogen-dependent genes downregulation in the testis and apoptosis induction actions can thus be attenuated in this way.100,101,102 In many studies, SERMs have been found to be useful in the treatment of HH and maintenance of spermatogenesis and fertility either as a monotherapy or in combination with hCG.102,103

Despite the lack of the USA Food and Drug Administration (FDA) or European Medicine Agency (EMA) approval for male infertility treatment, CC is one of the most widely prescribed drugs to improve sperm parameters.83 A published systematic review and meta-analysis including both interventional and observational studies by Huijben et al.104 revealed a significant positive effect of CCs on sperm concentration (95% confidence interval [CI]: 5.17–11.59; P < 0.00001; I² = 87%) and sperm motility (95% CI: 3.83–12.45; P < 0.00001; I² = 76%) but not on sperm morphology (Z = 1.42, I² = 42%) in men with idiopathic infertility. Testosterone levels and both gonadotropins LH and FSH increased after CC therapy.104 Nevertheless, the exact role of CC use in restoring spermatogenesis in azoospermic men after ET is limited to small studies. A small retrospective case series examined three men: two with idiopathic acquired HH and oligospermia or azoospermia, and one with AAS-induced azoospermia. All were treated with 50 mg of CC three times per week. Within three months, 100% of the men experienced full recovery of serum gonadotropins, testosterone, and spermatogenesis, with a pregnancy rate of 66% achieved in the study.105 Case reports of CC use at higher doses (100 mg daily) in young men with ASIH resulted in normalization of the HPG axis within 2–3 months.106

Similarly, a series of hypogonadal men on TRT seeking vasectomy reversal underwent testicular salvage medical therapy with CC with or without hCG for a median of 2.8 months. Thirty-three percent of men with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Additionally, there was a higher rate of normalization of HPG parameters and successful vasectomy reversal, in addition to higher spontaneous pregnancy (50%) during the follow-up period.107

CC was investigated in a multicenter study on 400 men with hypogonadism receiving long-term treatment, 280 received CC for 3 years or less (mean±s.d.: 12.75 ± 9.52 months), and 120 received CC for more than 3 years (mean ± s.d.: 51.93 ± 10.52 months), resulting in normal testosterone values in 88.8%, even in the long-treatment arm. The results did not significantly differ between patients treated for more than 3 years and 3 or fewer years. Regarding reported side effects during therapy, the authors concluded that CC is safe and effective with few side effects.108

There have been 3 published cases of CC therapy in oligozoospermic men who developed azoospermia even after a short treatment period of 4.5 months. After stopping the CC regimen, all three men regained sperm in their ejaculate.109 It was speculated that such a paradoxical effect might be attributable to the racemic mixture of two isomers in CC, namely enclomiphene (EC) and zuclomiphene. Enclomiphene is the trans isomer of CC with pure antiestrogenic effects and a shorter half-life (10.5 h) than CC.110 Some recent studies have shown promising conclusions on its use to treat ET-induced azoospermia.108,111 A clinical trial followed men previously treated with TRT for >6 months who had HH with oligospermia or azoospermia; they were randomized to receive 25 mg of EC daily versus topical testosterone gel for 6 months. The study demonstrated equivalent responses in terms of serum testosterone levels in both arms and statistically significant improvements in semen parameters in the EC group.112 Another study assessed the use of EC in men with secondary hypogonadism and demonstrated consistently increased total serum testosterone in the normal range and increased LH and FSH above the normal range within 2 weeks of treatment with EC, which persisted for at least 1 week after stopping treatment.113

Another study evaluated 73 men with HH and normal spermatogenesis who were treated with EC at 12.5 mg or 25 mg daily, topical TRT, or placebo. There were significant elevations in LH, FSH, and total testosterone in men taking EC, accompanied by positive effects on sperm counts. TRT-treated men presented increased oligospermia and azoospermia, whereas spermatogenesis was preserved in the EC and placebo groups.108 Therefore, EC may represent an interesting future option for the restoration and maintenance of spermatogenesis in hypogonadal men, although FDA approval is still lacking, aside from the nominated use in compounding under Section 503A for the USA.

Therefore, the combination of SERMs, either alone or in combination with hCG, can be considered an important modality for the treatment of ET-induced azoospermia.

AROMATASE INHIBITORS (AIS)

AIs, including highly selective nonsteroidal agents such as anastrozole and letrozole, have been used in male infertility treatment, although they have not received specific FDA approval for male reproductive purposes. They function through reversible inhibition of the aromatase enzyme, thus blocking the conversion of testosterone to estrogen in different organs, such as the testes, liver, kidney, brain, and adipose tissue.114 Estrogen is an indirect mediator of testosterone feedback inhibition of the HPG axis; therefore, aromatase inhibition in men can result in decreased estrogen levels, stimulate gonadotropin production, and enhance spermatogenesis.115 The rationale for this use may not entirely be to reverse the inhibitory effects of ET on FSH and LH, but it may stop the rise in estradiol via peripheral conversion of exogenous testosterone, which is known to occur in men supplemented with ET. Estradiol may have direct effects on the testis to suppress spermatogenesis, in addition to a central effect of inhibiting FSH and LH release.116

AIs have been widely used to restore or improve male fertility in cases of idiopathic male infertility or hypogonadism, but data on their use in relation to previous ET or AAS users are very limited.

When evaluating the effectiveness of AIs in treating male infertility, the key factor to consider is the T/E2 ratio. Studies indicate that men with a T/E2 ratio below 10:1 (with testosterone measured in ng dl⁻¹ and estradiol in pg ml⁻¹) show the greatest improvement in semen quality when AIs are used. Importantly, AIs are typically employed as an adjunctive treatment alongside hCG, rather than as standalone therapy, for better outcomes. Based on this, their use is particularly beneficial in obese men or in those with a serum T/E2 ratio <10, where improvements of approximately 77% of patients have been observed.117,118 Some investigators described the beneficial effect of AIs as an additive therapeutic treatment to 3000 IU hCG subcutaneously administered every other day as primary therapy in 49 men with azoospermia or severe oligospermia (<1 × 10⁶ ml⁻¹) after cessation of ET after long-term use (52.4 months) in different formulations.95 In this study, 20.4% of the men were prescribed additionally anastrozole, whereas the others received different additive combinations, such as CC in 71.4% or tamoxifen in 57.1% of the men. Although this study might not be powered adequately for investigating AI benefits when added to hCG therapy, the authors did not find any inferiority between these types of supplemental therapy used for sperm recovery, observed after therapy after a mean of 4.6 months.95

Another study investigated the effect of letrozole on the treatment of 27 patients with male infertility associated with decreased T/E2 ratios. The results demonstrated an increase in the T/E ratio, ejaculate volume, sperm count, and sperm motility. Twenty percent of oligospermic men achieved spontaneous pregnancy, and 24% of azoospermic patients achieved spermatozoa recovery in the ejaculate.119

A prospective nonplacebo-controlled randomized study compared the efficacy of AIs and CC, with each being used as monotherapy for improving semen parameters in hypogonadal men. While serum testosterone levels were significantly higher in the CC group and T/E2 ratio was higher in the AIs group, there was no significant improvement in the sperm concentration in either group or any difference in semen parameters between the groups.120

The recently published meta-analysis by Guo et al.121 showed beneficial effects for both AIs investigated in 666 men suffering from infertility, but in the study protocol, baseline azoospermia was considered an exclusion criterion, and no additional data about the previous history of ET/AAS were provided. Nevertheless, it appears that both anastrozole and letrozole exhibit positive effects on different sperm parameters.121

AIs may result in a positive influence on the HPG axis after ET-induced azoospermia but are limited to patients who have abnormally low T/E ratios. To gain a deeper understanding of the efficacy of AIs, genetic analyses investigating the relationship between aromatase polymorphisms, specifically single nucleotide polymorphisms (SNPs) and the tetranucleotide (TTTA) repeat polymorphisms, and male fertility are required.122

PREVENTION OF AZOOSPERMIA DURING TESTOSTERONE OR AAS USE

Although the mainstay to maintain normal spermatogenesis in a patient with ET is to avoid or immediately stop ET itself, some studies recommend medications to maintain normal ITT levels, which are necessary to maintain spermatogenesis during the course of ET treatment.

Kavoussi et al.85 conducted an intriguing study aimed at preserving spermatogenesis while utilizing different approaches for TRT. The study involved switching patients from long-acting TRT to Natesto, a short-acting intranasal form of TRT, which allowed the maintenance of normal FSH and LH levels. This adjustment enabled the continued support of spermatogenesis without a washout period after the long-acting TRT. The mean duration of treatment with Natesto was approximately 24.3 (s.d.: 19) months, highlighting its potential for sustaining fertility while on TRT. Interestingly, under Natesto therapy, 27 men with prior hypogonadism by a mean testosterone level of 234.2 (s.d.: 53) ng dl⁻¹ resulted in a mean testosterone level of 643.9 (s.d.: 170) ng dl⁻¹. But, 10 out of 27 patients with proven azoospermia after long-acting TRT showed a normal sperm concentration of 41.0 × 10⁶ (s.d.: 27.4 × 10⁶) ml⁻¹ resulting in resumption of spermatogenesis after 3 months of Natesto therapy. Notably, men treated with Natesto not only experienced normalization of their HPG axis, with normalized levels of testosterone, LH, and FSH but also exhibited significantly lower E2 concentrations. Therefore, for well-selected men requiring TRT and who are concerned about fertility, the option of Natesto, as opposed to other long-acting TRT, should be discussed with patients.85

An important study concluded that low doses of hCG (500 IU every other day) can maintain baseline levels of ITT in men with gonadotropin withdrawal from ET administration.28 Another similar study evaluating higher doses of hCG given as monotherapy (500–2500 IU twice weekly) or low-dose hCG (500 IU every other day) in combination with TRT demonstrated satisfactory results for maintaining spermatogenesis. No patient became azoospermic during concomitant testosterone replacement and hCG therapy in this small study. Nine of 26 men contributed to pregnancy with their partner during follow-up.123

Chen et al.124 investigated patients on oral testosterone undecanoate (TU) supplementation for the treatment of adolescents with HH and added hCG injections to maintain spermatogenesis compared with hCG alone. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated HH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.124

There is no definite medical regimen that can guarantee normal spermatogenesis during ET use, as it depends on many variables related to the status of spermatogenesis before ET treatment as well as the dose, duration, and testosterone preparations used. Many studies suggest replacing low testosterone with modalities other than ET to maintain testosterone and preserve spermatogenesis, such as synthetic gonadotropins, SERMs, and AIs.102,104,125 Although such medications are being used off-label to raise serum and intratesticular testosterone levels while preserving fertility, they may have unintended side effects, including a decrease in semen quality and consequences for bone mineral density and libido due to changes in estrogen levels. Thus, there is a need to develop different approaches to restoring testosterone levels in patients who can both reduce negative side effects and preserve the HPG axis and fertility.126,127

The future of TRT in men desiring to preserve fertility is moving toward the stimulation of endogenous testosterone production by manipulating Leydig cells. Novel therapeutic approaches for transplanting Leydig cells in various animal model testes have shown great promise in this endeavor. A promising study in 2019 was the first study of its kind to show successful Leydig cell differentiation, increased testosterone production, and preservation of the HPG axis with subcutaneous autografts of Leydig cells in hypogonadal mice.128 Furthermore, in vivo studies are needed to assess the efficacy, safety, and clinical applicability of Leydig stem cell transplantation in practice.129

AAS ABUSERS’ WILLINGNESS TO SEEK MEDICAL HELP

Regardless of the therapeutic possibilities after AAS use, there remains a need to understand the behaviors and decisions of individuals regarding seeking medical therapy. Seeking help can often be complex and challenging, especially in cases where there might be social stigma or legal concerns involved. However, various studies have explored related topics, such as the motivations behind AAS use, the prevalence of misuse, and the associated health risks. The length of time men wait for medical help after starting ET or AAS can vary on the basis of individual factors, circumstances, and awareness about potential health risks. These studies often provide insights into the factors that influence individuals’ decisions about seeking medical care. Bonnecaze et al.130 reported in their global, web-based survey assessing the experiences of 2385 males using the AAS that most respondents did not disclose their AAS use to their healthcare providers (n = 1338, 56.1%), and of those who did, 55.30% (n = 579) said they felt discriminated against because of their use.

In a 2022 published systematic review and meta-analysis by Amaral et al.131 investigating the overall prevalence of help-seeking behaviors for medical assistance in 10 101 AAS users from 36 studies, only 37.12% (95% CI: 27.71%–44.52%) of all AAS users were seeking support from physicians, with the lowest adherence among adolescent AAS users of 17.27% (95% CI: 4.80%–29.74%). To overcome such barriers, various professional societies and organizations are now striving to implement special programs with comprehensive educational efforts. For guidance on harm minimization strategies for patients using non-prescribed AAS and other performance and image-enhancing drugs, a comprehensive resource is available in the GP Guide by the Sydney North Health Network (https://www.snhn.net/steroid-harm-minimisation/).

CONCLUSIONS

Exogenous testosterone exerts a significant negative impact on the HPG axis. This inhibitory effect varies based on several factors, including the patient’s gonadal status prior to initiating exogenous testosterone therapy, as well as the dose, duration, and type of testosterone preparation used. ET-induced azoospermia is a well-recognized sequela, and all patients should be informed of its occurrence and the possibility of it being a permanent complication before ET is administered, regardless of the indication.

Although there is no definitive evidence supporting a specific treatment for ET-induced azoospermia, several therapeutic options have proven effective in various clinical scenarios. Men desiring maintenance of fertility potential should avoid ET; otherwise, immediate discontinuation should be advised. While spontaneous recovery of spermatogenesis can occur following ET cessation, this approach is most successful in patients with a shorter duration of ET use, those using short-acting testosterone preparations, and younger patients with normal baseline gonadal function. Indicators of slower recovery of spermatogenesis include previously hypogonadal men with poor baseline testicular function, a long history of ET use, and older age at the time of ET cessation.

Gonadotropins, particularly hCG injections either alone or in combination with other medications, such as rFSH, CC, or AIs, have shown considerable improvement in spermatogenesis and reversal of ET-induced azoospermia. Alternatively, SERMs such as CC and tamoxifen, either as a monotherapy or in combination with hCG, can be used. AIs, such as anastrozole and letrozole, are reserved for men with abnormally low T/E ratios. While these agents are employed on a theoretical basis, their use in this context remains empirical and off-label. While some studies have shown an increase in testosterone and improvement in several semen parameters,132,133 considering the importance of E2 for spermatogenesis and the influence of ET on E2, the prolonged or uncontrolled use of aromatase inhibitors with drastic lowering of the E2 concentration might nevertheless be critical.

There is an urgent need for prospective, randomized, placebo-controlled trials to clarify the role of these medications in the recovery of spermatogenesis following ET and to determine the optimal treatment combinations, dosages, and durations. More research is needed for novel therapeutic approaches to provide endogenous testosterone with preservation of spermatogenesis, such as Leydig stem cell transplant.

AUTHOR CONTRIBUTIONS

AA and RS contributed to the conceptualization. MAH and GMP contributed to the methodology and prepared the original draft. MAH, GMP, AA, and RS reviewed the manuscript. AA supervised the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.