Testosterone replacement therapy (TRT) has long been the standard treatment for men with symptomatic hypogonadism. Current clinical guidelines recommend testosterone supplementation for men who are symptomatic and have low testosterone levels. The benefits of TRT include increased growth of body hair, energy, muscle mass and stamina, overall confidence, and motivation [1]. The diagnosis of hypogonadism and its treatment with TRT has become more common in recent years because of the availability of new forms of supplements, direct-to-consumer advertising, and the successful alleviation of symptoms for many men receiving this treatment. Recent studies have reported that TRT has become one of the largest growing health care markets over the last 5 years [2,3].

Infertility, a serious social issue in many industrialized countries, is commonly associated with sexual dysfunction. Male partners in infertile couples complain more about poor sexual function and satisfaction, and have higher rates of androgen deficiency type complaints than male partners in fertile couples [4]. Thus, these men may also benefit from TRT for their symptoms of hypogonadism. The potential adverse effects of TRT, including cardiovascular disease, prostate cancer, obstructive sleep apnea, and erythrocytosis, have been well reported [5]. The impact of TRT on fertility has only rarely been considered, because traditionally, the candidates for TRT were middle-aged or older men. However, testosterone usage has become increasingly common in young men. Recently, there have been warnings about the potential negative effect of TRT on fertility when used by men of reproductive age due to suppression of the hypothalamic-pituitary-testicular (HPT) axis by a negative feedback mechanism [6,7]. However, this issue is not familiar to all primary care physicians and patients. We investigated the clinical characteristics of TRT-induced hypogonadism in men in infertile couples, and its effect on infertility treatment programs such as assisted reproductive technology (ART).

This retrospective study examined the records of 20 consecutive male patients diagnosed with azoospermia or severe oligozoospermia (< 5 × 10⁶/mL) who visited a single infertility center (CHA Gangnam Medical Center, Seoul, Korea) from January 2008 to July 2018 (Table 1). The study was approved by our Institutional Review Board (IRB No. GCI-19-07). The fertility evaluation consisted of a thorough personal and family history, physical examination (body mass index, testicular volume, palpation of vas deferens, and presence of varicocele), semen analysis (sperm concentration, motility, and morphology), and laboratory tests including reproductive hormone profiles (follicle-stimulating hormone [FSH], luteinizing hormone, testosterone, and prolactin levels). Testis volume was measured using an orchidometer. All patients were treated at a primary clinic for erectile dysfunction or androgen deficiency symptoms combined with low serum testosterone. These men received TRT with multiple injections of testosterone undecanoate Nebido^® (Bayer HealthCare AG, Leverkusen, Germany) or testosterone enanthate Jenasteron^® (EVER Pharma Jena GmbH, Jena, Germany) intramuscularly, in addition to phosphodiesterase 5 inhibitors for sexual dysfunction. Patients older than 50 years or with a chronic medical disease such as diabetes were excluded. None of the patients had a history of genital infection, varicocele, cryptorchidism, or gonadotoxin exposure.

Semen parameters including sperm concentration, motility, and morphology were assessed as previously described [8]. All semen samples were obtained by masturbation into a wide-mouthed plastic container in a separate room after 2 or more days of sexual abstinence, and were allowed to liquefy for at least 20 minutes at 37°C before further analysis. If sperm were not detected through a conventional microscopic Makler chamber evaluation, the semen sample was centrifuged at 1,500 ×g for 10 minutes to detect any viable sperm. Azoospermia was determined by analyzing centrifuged specimen at least two different occasions. IBM SPSS ver. 23.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis. A nonparametric analysis was performed using the Wilcoxon signed-rank test, and p-value less than 0.05 were considered to indicate statistical significance.

The mean age of the patients was 37 years (range, 31–47 years) and the mean duration of infertility was 16.3 ± 11.6 months. Semen analysis at initial presentation indicated that eight patients had azoospermia, nine had cryptozoospermia, and three had severe oligozoospermia (Table 1). None of the patients had any previous history of genital infection, varicocele, cryptorchidism, or gonadotoxin exposure. Physical examinations showed that all patients had normalsized testes (≥14 mL). The serum FSH level was below normal (< 1.0 mIU/mL) in most patients.

An analysis of patients’ histories showed that all 20 patients received TRT at primary clinics because of erectile dysfunction and had low levels of serum testosterone. TRT consisted of multiple injections of testosterone undecanoate (Nebido) or testosterone enanthate (Jenasteron) for a median duration of 8 months (range, 4–12 months). Three ongoing ART programs with female factor infertility were cancelled due to male spermatogenic dysfunction; two of these men had normal semen parameters in the previous ART cycle.

A thorough evaluation of the patients indicated that all 20 patients were suspected to have iatrogenic hypogonadism because of external testosterone supplementation. They were advised to return for subsequent fertility testing, with hormone and semen analysis, after cessation of TRT. After a median duration of 8 months (range, 2–11 months), serum hormone levels and sperm concentrations (≥ 15 × 10⁶/mL) returned to normal range in all 20 patients. There were significant differences in the sperm concentration, sperm motility, and serum FSH levels between the initial presentation and last follow-up (Table 2). The eight patients with azoospermia at the initial presentation also showed a similar recovery pattern (Table 3).

TRT has long been the standard treatment for men with symptomatic hypogonadism. The well-known benefits of TRT include increased growth of body hair, energy, muscle mass and stamina, overall confidence, and motivation. Testosterone usage is increasing secondary to new forms of supplementation, partly due to consumer advertising and symptomatic improvement for many men receiving this treatment in recent years [1,2]. Our study showed that TRT aggravated male fertility in infertile couples and had a clear negative impact on infertility treatment programs. Three ongoing ART programs with female factor infertility were cancelled due to the husband’s spermatogenic dysfunction. Two patients among our cases had normal semen parameters in the previous cycle. ART refers to treatments used to help an infertile couple achieve pregnancy by manipulation of eggs, sperm, and/or embryos outside the body. It includes procedures such as in vitro fertilization (IVF) and intracytoplasmic sperm injection. Because an ART program does not always lead to successful pregnancy, an infertile couple may require multiple ART cycles to achieve pregnancy. In each IVF cycle, the female partner usually receives a high-dose hormonal supplement to stimulate ovulation, and an invasive oocyte aspiration procedure under anesthesia. IVF programs are expensive, and also have the potential to cause ovarian hyperstimulation syndrome [9,10].

When an IVF cycle fails, infertile couples may try to conceive naturally through timed intercourse during the ovulation period before another IVF cycle. We previously reported that many male partners in infertile couples report significantly greater stress, including erectile dysfunction, during fertile periods [11]. It is not uncommon for young men undergoing a fertility evaluation to have a low or borderline serum testosterone levels. Therefore, the possibility exists that the male partner might be treated with exogenous testosterone to improve his sexual function. However, the fertility issues associated with TRT in men have been rarely mentioned because traditionally, the candidates for TRT were middle-aged or older men [5]. All patients in this study received injections of testosterone undecanoate (Nebido) or testosterone enanthate (Jenasteron) due to poor sexual function or low libido while trying to conceive a baby. However, none of the patients were informed that TRT could reduce fertility, and all 20 men experienced spermatogenic dysfunction, although it was reversible. The authors previously reported a similar finding for TRT with testosterone undecanoate (Nebido) only [12]. These results highlight the need for more proper education of urologists and primary care clinicians who care for patients with hypogonadal symptoms.

Testosterone plays essential roles in the development and maturation of the male reproductive system and in spermatogenesis. However, administration of exogenous high-dose testosterone can cause infertility due to suppression of the HPT axis and decreased production of FSH, leading to decreased spermatogenesis [6]. In fact, because of this effect, some researchers consider testosterone to be a potentially promising contraceptive [13]. Despite the deleterious effect of TRT on male fertility, more men of reproductive age appear to be taking testosterone in recent years, either because of a lack of knowledge regarding its contraceptive effects or because of a misconception that it may increase male fertility. This misconception is not limited to non-urologists. A survey of the American Urological Association found that as many as 25% of respondents had used testosterone as an empirical treatment for male infertility [14].

Previous studies have described the recovery pattern of spermatogenesis after discontinuation of TRT. Our study patients experienced recovery to normal serum hormone levels and sperm concentrations (≥ 15 × 10⁶/mL) at 7.9 ± 2.1 months after cessation of TRT (Table 2). A previous study reported recovery of 67% at 6 months, 90% at 12 months, 96% at 16 months, and 100% at 24 months [15]. Insufficient recovery has also been reported. Kohn et al. [16] studied the recovery of spermatogenesis in 66 men who received TRT and reported that 30% of them were unable to achieve a total motile sperm count of more than 5 million after 12 months. They suggested that failure of recovery had positive correlations with patients’ age and TRT duration. In most cases, gonadotropin replacement therapy is not required for the recovery of TRT-induced hypogonadism. However, if a patient wants to accelerate the recovery, gonadotropin agents similar to those used for patients with hypogonadotropic hypogonadism may be helpful [17].

The major limitation of this study is its small number of subjects, with the possibility of substantial selection bias. Nevertheless, our results clearly show that male infertility must be considered as a serious side effect of TRT. Use of TRT by men with hypogonadal symptoms is generally safe, but numerous reports have documented other adverse effects of TRT, such as cardiovascular disease, prostate cancer, obstructive sleep apnea, and erythrocytosis [18-20]. However, only a few recent studies have documented the deleterious effect of TRT on male fertility [6,7]. Considering the current widespread use and easy availability of TRT, this negative effect on male fertility should be stressed as a potentially serious side effect of TRT. Clinicians should be more informed of this adverse effect, and should use caution when initiating TRT in men of reproductive age. TRT with high-dose testosterone is definitely contraindicated for couples attempting to conceive.

TRT with high-dose testosterone can cause spermatogenic dysfunction due to suppression of the HPT axis, adversely affecting infertility treatment programs. TRT is therefore contraindicated for infertile couples attempting to conceive, and the patient’s desire for fertility must be considered before initiation of TRT in a hypogonadal man.