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

Abstract

SUMMARYA 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.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…[194][195][196][197][198] These therapies induce both testicular testosterone production by Leydig cells and spermatogenesis in the seminiferous tubules. [199][200][201][202] The majority of patients with CHH develop sperm in their ejaculate with longterm therapy. 149,193,196,197 Although these treatments seem to have similar fertility outcomes, [199][200][201][202] comparing their efficacy is difficult owing to the small numbers of patients studied, heterogeneity in terms of degrees of GnRH deficiency (testicular volume before treatment), prior treatment and a lack of randomized studies performed to date.…”

“…A 2014 meta-analysis identified a mean sperm count of 5.9 × 10 6 /ml (range: 4.7-7.1 × 10 6 /ml) for gonadotropin therapy and 4.3 × 10 6 /ml (range: 1.8-6.7 × 10 6 /ml) for GnRH therapy. 200 However, an important feature of patients with CHH is that low sperm concentrations do not preclude fertility. 205 In clinical practice, when testicular volume is <4 ml, the classic treatment is either pulsatile GnRH (25 ng/kg every 2 h, titrated for trough serum testosterone level) or combined gonadotropin therapy (hCG: 1,000-1,500 IU + FSH: 75-150 IU 2-3 times weekly, based on available formulations).…”

“…Anovulation and ovarian reserve can be assessed via a combination of history of menstrual cycle abnormalities, laboratory examination and pelvic ultrasonography. Couples should be counselled appropriately on the basis of the identified predictors of CHH fertility-inducing treatment, [193][194][195][196][197][198]200 as well as the partner's reproductive status and age in order to develop realistic expectations regarding treatment outcome.…”

Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders [Review]

“…Most of the results of FSH therapy have been achieved with men who have oligoasthenozoospermia (OAT) not NOA. Nonetheless, the efficacy of FSH therapy for treatment of OAT remains controversial [55][56][57]. Several studies have evaluated the efficacy of FSH administration for men with OAT with resultant improvements in sperm parameters, whereas other studies have not shown any significant effect.…”

A short evolutionary history of FSH-stimulated spermatogenesis

“…[68][69][70] The results are variable, although there are some promising new leads indicating that specific genetic polymorphisms in FSHb and FSHR may cause functional FSH deficiency, in which case FSH therapy may improve spermatogenesis. [71][72][73] To be effective, FSH therapy will therefore require stratification of men according to genotype into FSH-responsive and non-responsive individuals.…”