Testicular Growth and Spermatogenesis: New Goals for Pubertal Hormone Replacement in Boys With Hypogonadotropic Hypogonadism?

A Multicentre Prospective Study of hCH/rFSH Treatment Outcomes During Adolescence

Julia Rohayem; Berthold P. Hauffa; Margaret Zacharin; Sabine Kliesch; Michael Zitzmann


Clin Endocrinol. 2017;86(1):75-87. 

In This Article

Abstract and Introduction


Context/objective Testosterone treatment for pubertal induction in boys with hypogonadotropic hypogonadism (HH) provides virilization, but does not induce testicular growth or fertility. Larger studies evaluating the outcomes of gonadotropin replacement during adolescence have not been reported to date; whether previous testosterone substitution affects testicular responses is unresolved.

We aimed to assess the effects of human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) in boys and adolescents with HH with respect to a) testicular growth, b) spermatogenesis, c) quality of life (QoL) and to identify factors influencing therapeutic success.

Design/setting A prospective case study was conducted in 26 paediatric endocrine centres

Patients/interventions HCG and rFSH were administered until cessation of testicular growth and plateauing of spermatogenesis to (1) prepubertal HH boys with absent or early arrested puberty (group A) and to (2) HH adolescents who had previously received full testosterone replacement (group B).

Outcome measures Bi-testicular volumes (BTVs), sperm concentrations and QoL.

Results Sixty (34 A/26 B) HH patients aged 14–22 years were enrolled. BTVs rose from 5 ± 5 to 34 ± 3 ml in group A vs 5 ± 3 to 32 ± 3 ml in group B, with normal final BTVs (≥24 ml) attained in 74%/70% after 25/23 months in A/B, respectively. Sperm in the ejaculate were found in 21/23(91%)/18/19(95%), with plateauing concentrations after 31/30 months of hCG and 25/25 months of combined treatment in A/B. Sperm concentrations were normal (≥15 mill/ml) in 61%/32%, with mean concentrations of 40 ± 73 vs 19 ± 38 mill/ml in A/B (n.s.). Outcomes were better in patients without bilateral cryptorchidism, with non-congenital HH causes, higher baseline BTVs, and higher baseline inhibin B and AMH levels. QoL increased in both groups.

Conclusions HCG/rFSH replacement during adolescence successfully induces testicular growth and spermatogenesis, irrespective of previous testosterone replacement, and enhances QoL.


In boys ≥14 years with hypogonadotropic hypogonadism (HH) and absent or arrested puberty, pubertal induction is performed by administering increasing doses of testosterone-enanthate i.m every 3–4 weeks. This regimen, established as a therapeutic standard in paediatric endocrinology, stimulates normal linear growth, pubertal virilization and psycho-sexual maturation, but neglects testicular growth and the acquisition of fertility as components of normal puberty; the testes remain in an immature prepubertal state (i.e. < 4 ml), and spermatogenesis is not initiated. Replacement of gonadotropins in adulthood has repeatedly been proven to be safe and effective in initiating testicular growth and spermatogenesis, sufficient for fertility.[1–5] Small adolescent case studies have demonstrated the 'proof of principle' that, along with pubertal virilization, pubertal testicular maturation with increase in testis sizes and initiation of spermatogenesis can be achieved by combined hCG/FSH replacement.[6–11] However, prospective studies in HH adolescents, large enough for evaluation of outcomes of hCG and FSH have not been reported to date. Although a recent paper[12] specifically addressed quality of life (QoL) in relation to gonadotropin treatment for adult HH, the impact of gonadotropin substitution on QoL during adolescence is largely unknown. Whether preceding testosterone replacement may adversely affect therapeutic responses of HH adolescents also remains unresolved to date.

In this prospective multicentre study, we aimed to assess the effects of human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) treatment in young patients with HH of various origins with respect to testicular growth and induction of spermatogenesis. We compared the outcomes of prepubertal HH boys with those of HH adolescents who had previously received full testosterone replacement for pubertal virilization. Furthermore, we evaluated pre- and post-treatment QoL in each patient using validated questionnaires. Finally, we assessed the dependence of therapeutic responses on variables at baseline.