Assessment of Quality of Life During Gonadotrophin Treatment for Male Hypogonadotrophic Hypogonadism

Koji Shiraishi; Shintaro Okal Hideyasu Matsuyama


Clin Endocrinol. 2014;81(2):259-265. 

In This Article


In men with MHH, the scores on all of the SF-36 domains, except for BP, were much lower than the national norms, indicating that MHH patients exhibit decreased HRQOL. Gonadotrophin treatment for MHH was shown to be effective and safe in our series. Different from testosterone treatment, treatment with hCG/rhFSH was associated with significant improvements in GH, VT, RE and MH domains, irrespective of the cause of MHH. The presence of sperm in the ejaculate was shown to be associated with these improvements.

A distinct difference of this study from studies investigating the HRQOL of men with Klinefelter syndrome[11] and MHH[10] was that we included the patients with gonadotrophin treatment. Testosterone replacement results in negative effects on testicular volume and spermatogenesis, whereas gonadotrophin treatment stimulates both spermatogenesis and testosterone production. Although gonadotrophin treatment is usually reserved for spermatogenesis induction after marriage, all MHH patients should be recommended to undergo gonadotrophin treatment and semen examination to determine whether they possess the ability to produce sperm after appropriate treatment. A majority of MHH patients suffer significant anxiety concerning future reproductive function, and anxiety has been shown to be a strong predictor of decreased overall health, physical ability and mental ability.[12] If sperm cannot be found in the ejaculate, then there is potential of retrieving sperm by testicular sperm extraction. Fahmy et al.[13] reported that sperm were retrievable from the testicular tissue of 73% of MHH men unresponsive to gonadotrophin treatment, and those sperm could be used for ICSI. This counselling could also have encouraging effects on the HRQOL of such patients.

The psychosocial impact of small testes, penile length and the density of pubic hair can be considerable, particularly if the patient becomes sexually active.[5] We expected that the development of external genitalia would positively impact HRQOL; however, neither pubic hair nor genital stage was associated with any of the SF-36 domains (Table 3). It is possible that the patients were unaware of their gradual changes and were satisfied with stage 3 development. We also expected that there would be differences in the baseline and improvements in SF-36 domains between the primary and secondary MHH groups because the degree of prior sexual development was completely different between the groups, varying from the complete absence of sexual maturation to partial puberty to near normal testicular volume with developed genitalia. The SF-36 was unable to detect a difference in HRQOL with regard to genital development and anxiety/depression.[10]

The appropriate serum testosterone concentration to manage MHH patients remains controversial. We adjusted the hCG dose to maintain serum testosterone levels of approximately 500–600 ng/dl. In LOH syndrome, several reports, including Japanese literature,[14,15] have indicated the usefulness of testosterone replacement in HRQOL using the SF-36[16,17] and have shown that VT, SF RE and MH are likely to improve. Lower levels of testosterone in young men were associated with an increase in the occurrence of depression-spectrum disorders,[18] although testosterone replacement had minimal effects on behavioural problems or mood in adolescents.[19] In our study, there was no association between serum testosterone level and improvements in the SF-36 domains (Table 3).

Infertility often leads to emotional stress, depression, anxiety, relationship problems with partner/family/friends, loss of self-esteem and security and an increased sense of self-blame and guilt in women,[20] and men experience a similar response to infertility. It is likely that knowing that sperm exists in the ejaculate has a substantial effect on the improvement of psychological QOL, and our results support this relationship with the patients' psychological backgrounds. The results of gonadotrophin treatment for MHH using the current regimen per se have been excellent for testicular growth and spermatogenesis in 80–95% of patients;[1–4] however, it is necessary to more efficiently improve the results. Dwyer et al.[21] reported the effectiveness of pretreatment with rhFSH, which enhances the number of Sertoli cells and spermatogonia. In this study, the average time to observe sperm in the ejaculate was 16·3 months, and the total sperm count per ejaculate increased steadily throughout the 24-month period because we added rhFSH 6 months after the beginning of hCG treatment. In cases of patients with small testes or in primary cases, the sperm count tended to increase at a slower rate, which is consistent with previous reports.[22,23] In addition to increased patient HRQOL, secondary to the presence of sperms in the ejaculate, gonadotrophin stimulation at a proper age (pre-adolescent to adolescent) also beneficially affects the final testicular volume and spermatogenesis. Recently, Zacharin et al.[24] reported that the treatment of adolescent males with exogenous hCG, alone or in combination with rhFSH, for the induction of puberty could result in testicular growth and, hence, improvement in potential fertility, compared with treatment with testosterone. Early induction of spermatogenesis could reduce the time required for the appearance of sperm and increase the final testicular volume.

Although questionnaires regarding sexual function are inappropriate in MHH patients because they have never experienced any type of sexual activity, there was a close association between sexual dysfunction and vitality on the SF-36 in adults.[25] Another major finding in patients with hypogonadism is sexual dysfunction, including loss of libido and erectile and ejaculatory dysfunction. Miyagawa et al.[23] reported that ejaculatory dysfunction was more common than erectile dysfunction (ED). Patients who could not ejaculate before treatment exhibited significant improvement in the VT domain and apparent but not significant improvement in the GH and MH domains (Table 3). A difficult problem is the management of patients without any libido or sexual desire. Seven patients refused the semen examination itself because of no libido.

Several potential limitations of the study must be discussed. First, as a limitation of the clinical study, there were no age-matched men as a control arm, including MHH patients not receiving treatment or a placebo-treated group. Because the normal population-based value is already set in the SF-36 and because the main purpose of this study was to examine individual HRQOL changes and the factors that resulted in these changes, our conclusions were not affected by the absence of a control group. Second, the patients' backgrounds were heterogeneous (i.e. age, primary or secondary, coexisting endocrinological disorders), leading to the stratification of some of the results and small sample sizes, which limited the statistical stability of some of our effect estimates. All of the patients were appropriately treated endocrinologically, and there were no differences in SF-36 improvement between isolated gonadotrophin-deficient cases and cases with coexisting endocrinological disorders. Third, disease-specific tools to assess HRQOL are necessary to understand and evaluate better QOL in MHH. By establishing an MHH-specific questionnaire, we will be able to use another parameter to manage MHH patients in the same manner that we currently use serum testosterone value, genital stage and semen analysis.