Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study

A meta-analysis was performed to systematically analyse the results of gonadotropin and GnRH therapy in inducing spermatogenesis in subjects with hypogonadotropic hypogonadism (HHG) and azoospermia. An extensive Medline and Embase search was performed including the following words: 'gonadotropins' or 'GnRH', 'infertility', 'hypogonadotropic', 'hypogonadism' and limited to studies in male humans. Overall, 44 and 16 studies were retrieved for gonadotropin and GnRH therapy, respectively. Of those, 43 and 16 considered the appearance of at least one spermatozoa in semen, whereas 26 and 10 considered sperm concentration upon gonadotropin and GnRH, respectively. The combination of the study results showed an overall success rate of 75% (69-81) and 75% (60-85) in achieving spermatogenesis, with a mean sperm concentration obtained of 5.92 (4.72-7.13) and 4.27 (1.80-6.74) million/mL for gonadotropin and GnRH therapy, respectively. The results upon gonadotropin were significantly worse in studies involving only subjects with a pre-pubertal onset HHG, as compared with studies involving a mixed population of pre- and post-pubertal onset [68% (58-77) vs. 84% (76-89), p = 0.011 and 3.37 (2.25-4.49) vs. 12.94 (8.00-17.88) million/mL, p < 0.0001; for dichotomous and continuous data, respectively]. A similar effect was observed also upon GnRH. No difference in terms of successful achievement of spermatogenesis and sperm concentration was found for different FSH preparations. Previous use of testosterone replacement therapy (TRT) did not affect the results obtained with gonadotropins. Finally, a higher success rate was found for subjects with lower levels of gonadotropins at the baseline and for those using both human chorionic gonadotropin and FSH. Gonadotropin therapy, even with urinary derivatives, is a suitable option in inducing/restoring fertility in azoospermic HHG subjects. Gonadotropins appear to be more efficacious in subjects with a pure secondary nature (low gonadotropins) and a post-pubertal onset of the disorder, whereas previous TRT does not affect outcome.