madman
Super Moderator
Is fertility-sparing exogenous testosterone therapy a real thing?
It is 2024. Direct-to-consumer testosterone replacement therapy advertisements on social media are pervasive. Academic and private practice men’s health ce
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It is 2024. Direct-to-consumer testosterone replacement therapy advertisements on social media are pervasive. Academic and private practice men’s health centers are abundant. At home semen testing and reproductive health evaluations are commonplace. For many young men, discussing issues such as subfertility and sexual dysfunction has become less taboo. Couples are increasingly recognizing the importance of simultaneous fertility evaluations, and more men are seeing male fertility specialists than ever before. Therein lies a slippery slope of men aiming to optimize their testosterone while maintaining their fertility potential.
It is well known that exogenous testosterone disrupts normal spermatogenesis. By suppressing the hypothalamic pituitary-gonadal axis that is critical for intratesticular testosterone production and spermatogenesis, exogenous testosterone can render men to be severely oligospermic or azoospermic. By the same token, testosterone deficiency is commonly seen in men presenting for infertility evaluation, including men with oligospermia or nonobstructive azoospermia. It is of concern, however, that approximately 25% of urologists who responded to a national survey of American Urological Association members stated that they would treat infertile men with exogenous testosterone while these men actively pursued pregnancy.1
While exogenous testosterone is by no means a treatment for male infertility, at times, testosterone therapy may be necessary, even in men desiring future fertility. For example, a young man who completed local and systemic therapy for advanced malignancy without prior sperm cryopreservation is severely hypogonadal. Despite common alternative testosterone therapies that will be discussed later, he remains hypogonadal with numerous associated symptoms and diminished quality of life. An additional example would be an adolescent male with either hypogonadotropic hypogonadism or hypergonadotropic hypogonadism (ie, Klinefelter syndrome) who presents with delayed puberty and absent secondary sexual characteristics. In these specific cases, exogenous testosterone therapy may be combined with alternative therapies in an effort to maintain spermatogenesis and future fertility.
A hallmark study published by Coviello et al2 in 2005 demonstrated that the addition of low-dose, subcutaneous human chorionic gonadotropin (hCG) every other day in combination with intramuscular testosterone therapy maintains intratesticular testosterone levels necessary for sperm production. In this study, 29 healthy men with an average age of 24 years (range, 18-41 years) were randomized to 125, 250, or 500 IU hCG or saline placebo every other day for 3 weeks, in conjunction with 200 mg intramuscular testosterone enanthate weekly. Men who received 500 IU hCG subcutaneously every other day had the highest intratesticular testosterone level compared with the other groups. Although semen analysis and sperm counts were not assessed in this study, the maintenance of normal intratesticular testosterone might help support spermatogenesis. Thus, the combination of exogenous testosterone and 500 IU hCG 2 or 3 times per week is an emerging, potentially fertility-sparing, exogenous testosterone therapy approach and may be considered in the previously mentioned case scenarios. Additional studies that clarify semen parameter outcomes with this regimen are nonetheless needed.
A second fertility-sparing exogenous testosterone therapy regimen that has been utilized in adolescents with Klinefelter syndrome is the combination of topical testosterone gel and aromatase inhibitors. Mehta et al3 evaluated ten adolescents with Klinefelter syndrome, testosterone deficiency,and a testosterone-to-estradiol ratio <10:1. To facilitate age appropriate pubertal development while maintaining fertility potential, 1 mg of oral anastrozole was added daily to topical testosterone gel. Patients underwent microdissection testicular sperm extraction, and sperm was successfully retrieved in 70% of patients. In other words, spermatogenesis appears to be maintained in the majority of patients based on this small study using a combination of aromatase inhibitors and exogenous topical testosterone. However, at this time there is not enough evidence to support the combination of topical testosterone gel and aromatase inhibitors in men with Klinefelter syndrome prior to microdissection testicular sperm extraction.
More recently, intranasal testosterone monotherapy has been proposed as a fertility-sparing exogenous testosterone therapy. In 2020 investigators conducted a single center, open label, single arm trial4 that demonstrated that more than 90%of men using short-acting nasal testosterone (125 mL per nostril, 11.0 mg testosterone per dose, dosed 3 times per day) for symptomatic hypogonadism had obtained normal testosterone levels and preserved spermatogenesis. Specifically, sperm concentration decreased slightly from baseline; however, this was not found to be statistically significant.
It is important to note that the data surrounding the combination of topical testosterone gel and aromatase inhibitors or short-acting intranasal testosterone monotherapy are not based on level 1 evidence. Both studies mentioned previously lack a control arm, are nonrandomized, non blinded, and thus they should be interpreted in the context of those limitations.
Alternative testosterone therapies may be used to optimize endogenous testosterone production and treat symptomatic hypogonadism while improving reproductive potential. Treatment options include oral selective estrogen receptor modulators (ie, clomiphene citrate), oral aromatase inhibitors (ie, anastrozole), and subcutaneous hCG. These therapies may be used as monotherapy or in combination, and they have considerable differences in pharmacologic properties and mechanisms of action. For these reasons, certain alternative therapies may be more clinically appropriate than others. Importantly, hCG is a luteinizing hormone (LH) analog and is the best option to treat males with hypogonadotropic hypogonadism as opposed to clomiphene citrate, which is not effective in these men. hCG has been approved by the Food and Drug Administration for this indication. Aromatase is found in adipose tissue, and thus aromatase inhibitors are traditionally most appropriate for men with significant adiposity (ie, obesity) and/or testosterone-to-estradiol ratio<10:1. Finally, clomiphene citrate blocks estradiol feedback on the anterior pituitary, resulting in an increase in LH secretion and endogenous testosterone production. If LH levels are significantly elevated at baseline, clomiphene citrate may not provide much of a testicular response.
In our practice, we typically use concurrent lifestyle modifications (weight loss, exercise, etc.) and clomiphene citrate as first steps for men with testosterone deficiency who are interested in preserving their fertility due to its favorable side effect profile, oral route, and cost-effectiveness. We generally reserve hCG monotherapy as a first-line agent for cases of delayed pubertal growth due to congenital or acquired hypogonadotropic hypogonadism or Klinefelter syndrome. If we are unable to achieve symptomatic relief and significant improvement in testosterone levels with serial increases in hCG monotherapy (2000 IU, 2500 IU, or 3000 IU 3 times per week), we sometimes use a combination of exogenous testosterone therapy and 500 IU hCG subcutaneously 2 to 3 times per week. We usually reserve aromatase inhibitors for men with a testosterone-to-estradiol ratio <10:1. Weight loss via glucagon-like-peptide-1 analogs, a new class of therapies for obesity, may also have a role in the management of hypogonadal men with obesity. Data are just now emerging on the potential clinical benefits of these agents on testosterone levels, although this approach is somewhat limited because of the time required to see clinical efficacy.
While we advocate for alternative testosterone therapies for men with symptomatic hypogonadism who are concerned about their fertility potential, we realize that the benefits of exogenous testosterone therapy cannot necessarily be extrapolated to the benefits provided by these alternative therapies. We recognize that select patients may benefit from a fertility sparing exogenous testosterone therapy approach. Further studies are needed to evaluate fertility outcomes in men who are on a combination of exogenous testosterone and low-dose hCG, combination exogenous testosterone and anastrozole, and monotherapy with intranasal testosterone.
