Human chorionic gonadotropin treatment: a viable option for management of secondary hypogonadism and male infertility (2020) Julius Fink, Brad J. Schoenfeld, Anthony C. Hackney, Takahiro Maekawa & Shigeo Horie Abstract Introduction: Low testosterone and its symptoms is a condition affecting...
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5.1 Effects on intratesticular testosterone
Exogenous testosterone administration suppresses intratesticular testosterone (ITT), which is crucial for the production of sperm [24]. In such patients, ITT has been shown to be suppressed by 94%. However, with every other day injections of HCG at dosages of 125IU, ITT was only 25% less than baseline, with 250IU 7% less, and with 500IU 26% greater than the baseline [25]. In another study, 37 normal men were treated with GnRH antagonist acyline and attributed to one of the following low dose HCG groups: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 days. In order to measure ITT, testicular fluid was retrieved via percutaneous aspiration at baseline and after 10 days of treatment. The median baseline ITT was 2508 nmol/liter. ITT improved in a dose-dependent manner: 15 IU HCG group reached an ITT of 136 nmol, 60 IU HCG group reached an ITT of 319 nmol, 125 IU HCG group reached an ITT of 987 nmol/liter. Serum HCG significantly correlated with both ITT and serum testosterone [24,26].
These studies indicate that HCG can significantly increase ITT in a dose-dependent manner and that dosages between 250 and 500 IU might be optimal to restore physiological ITT levels.
5.2 Effects on serum testosterone
A weekly dosage of 4500IU spread over 3 weekly injections has shown to lead to normal testosterone levels in isolated HH men [27]. Another study showed that single injections of 400IU, 2000IU, and 4000IU of HCG led to significant serum testosterone concentrations in hypogonadal as well as eugonadal males without differences among the groups after administration [28].
In hypogonadal men, 400IU, 2000IU, and 4000IU of HCG increased testosterone from about 200 to 400 ng/dl. In eugonadal men, 400IU, 2000IU, and 4000IU of HCG led to an increase from about 450 to 700 ng/dl in testosterone [28]. Interestingly, higher doses of HCG did not lead to greater testosterone level increases [28]. Another study showed similar results, with no differences in serum testosterone after single injections of 1500, 3000, or 4500IU of HCG, with testosterone increasing 24 hours post-injection and peaking 3-4 days later [29]. Serum testosterone peaked 3 days after injection [28].
From the above information, it can be suggested that low dose HCG (~500IU) injected 3 times per week can restore healthy serum and intratesticular testosterone levels in HH patients. The higher dosages used in infertility treatment to trigger sperm production might not be necessary if the goal is to increase serum testosterone levels. That is, combined treatment with HCG followed by rFSH might also be potent in order to induce fertility [21].
Indeed, HCG dosages used in the treatment of infertility can range from 3,000 to 10,000 IU 2-3 times per week [30]. One study showed that 3-6 months (1000 IU 3 times/week or 2000IU 2 times/week) of HCG treatment in 100 males with hypogonadotropic hypogonadism leads to normal serum testosterone concentrations despite the fact that 81 patients remained azoospermic [31].
These data show that low dose HCG treatment is very effective in restoring normal serum testosterone levels, however, spermatogenesis might require higher dosages of HCG. The exact mechanism by which HCG affects sperm production besides testosterone increase is not completely understood yet and needs further investigation. We summarized studies involving HCG treatment on testosterone and/or fertility parameters in Table 1.
10. Conclusion
HCG therapy is an effective treatment for patients suffering from infertility, often restoring healthy sperm production. However, HCG also increases serum and intratesticular testosterone levels, making it a prime candidate to treat patients with secondary hypogonadism. Even though the cost and injection frequency might be slightly higher as compared to TRT, HCG alone or used with TRT might be the best option for patients who desire to have children in the future. Depending on the response to HCG alone, concomitant TRT might be necessary to bring serum testosterone levels to the desired levels.
Responses of serum testosterone levels seem to be independent of the dose of HCG and to peak 3 days post-injection. Therefore, low doses of ~400 IU HCG injected every 3 days intramuscularly or subcutaneously might lead to a significant increase of serum and intratesticular testosterone with few daily fluctuations in levels. Indeed, high dosages commonly seen in the treatment of male infertility going as high as 5000 IU several times per week might be unnecessary if the goal is not to increase sperm production but rather to increase testosterone only.
In summary, HCG might be a safe, affordable, and effective method to restore healthy testosterone levels in males suffering from secondary hypogonadism. Nonetheless, further clinical trials should be carried out to demonstrate and elucidate the benefits of HCG therapy.
11. Expert opinion
*The HPG axis seems responsive HCG in a similar fashion as LH and self-regulates the testosterone production within the testes in an amount independent manner. Doses of HCG as low as 400 IU seem to significantly increase serum testosterone levels and even with dosages, 10 times that amount (4000 IU), the serum testosterone elevations seem similar to that of a 400 IU dosage (i.e., remaining within the physiological range). Rather than sensing the amount of HCG and accordingly producing testosterone, even small amounts of HCG seem to maximize the response for testosterone production within the testes probably due to receptor sensitivity.
