Review – Andrology
Testosterone Replacement Therapy Versus Clomiphene Citrate in the Young Hypogonadal Male

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Abstract

The use of testosterone to treat hypogonadal symptoms has increased during the past decade. Consequently, one clinical challenge that has arisen is how to approach the young and treatment-naïve hypogonadal patient who is still within his reproductive years and may desire children in the future. Testosterone is known to suppress the hypothalamic-pituitary-gonadal axis resulting in suppressed spermatogenesis. There is a concern that, in some men, prolonged testosterone use may result in permanent spermatogenic failure.

Patient summary

In this review, we discuss the risks and benefits of available treatment options for the young hypogonadal patient for whom future fertility is an important consideration. Fortunately, alternatives such as clomiphene citrate and human chorionic gonadotropin have been shown to increase endogenous testosterone production. However, their efficacy as treatments for hypogonadal symptoms is still under debate.

Section snippets

Young men and hypogonadism—What is the issue?

Over the past two decades, there has been a dramatic rise in testosterone prescriptions in the USA. In September 2014, the Food and Drug Administration expressed their concerns for men initiating testosterone replacement therapy (TRT) strictly due to aging alone. They found that 28% of men who initiated TRT did so without having a prior serum testosterone level drawn. In addition, the same study found that 21% of men who initiated TRT did not have a follow-up serum testosterone level after

Guideline statements

Recent guidelines have addressed the issue of preserving fertility in TRT-naïve patients who present with symptomatic hypogonadism. The 2016 European Association of Urology guidelines support the use of human chorionic gonadotropin (hCG) in men with secondary hypogonadism and who desire future fertility [4]. The AUA 2018 guidelines state that men with testosterone deficiency who are interested in fertility should have a reproductive health evaluation and that the long-term impact of exogenous

TRT

TRT suppresses spermatogenesis by decreasing intratesticular testosterone and follicle-stimulating hormone levels through suppression of the hypothalamic-pituitary-gonadal axis [8]. Conflicting evidence exists for the long-term risk to fertility in men undergoing TRT. Data abstracted from trials which sought to utilize TRT as a contraceptive found that sperm concentrations were suppressed to less than 1 × 106 sperm/ml within 3.5 mo. After discontinuation of testosterone, projected time to

Clomiphene citrate

Clomiphene citrate and the single isomer isolate enclomiphene are well-known selective estrogen receptor modulators which have been used alternatively to treat men with hypogonadism [13], [14], [15]. Clomiphene citrate stimulates endogenous testosterone production by inhibiting the negative feedback at the hypothalamus and pituitary, resulting in an increased gonadotropin-releasing hormone and luteinizing hormone (LH) release. In theory, the mechanism of clomiphene citrate is a seemingly

hCG

hCG is an analog of LH and has been used to stimulate testosterone production. Compared with clomiphene citrate, the data supporting the use of hCG is less developed. A study evaluating the use of hCG or clomiphene citrate in hypogonadal men (n = 282) who wished to preserve fertility found that hCG, clomiphene citrate, and combination therapy improved serum testosterone levels by 245 ng/ml, 304 ng/ml, and 305 ng/ml at 3 mo, respectively [19]. Hypogonadal symptoms improved in both the hCG and

Expert summary

It is essential for practitioners to consider the risks to future fertility when considering TRT as a treatment for patients with symptomatic hypogonadism. We recommend first considering alternative therapies, such as clomiphene citrate or hCG, in young men with mildly decreased testosterone. The use of clomiphene citrate or hCG as an alternative to TRT is effective at raising serum testosterone levels. However, the data supporting hypogonadal symptom relief with these agents is still

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