Effect of pubertal induction with combined gonadotropin therapy on testes development and spermatogenesis in males with gonadotropin deficiency: a cohort study.

study questionAre recombinant FSH (rFSH) and hCG effective therapies for promoting testicular growth and spermatogenesis in male adolescents and young adults with gonadotropin deficiency? SUMMARY ANSWER: Combined gonadotropin therapy is effective in inducing puberty and promoting spermatogenesis in male adolescents and young adults with gonadotropin deficiency and has the potential to improve adult outcomes relating to both fertility and quality of life. WHAT IS KNOWN ALREADY: Deficiency of pituitary gonadotropins (LH and FSH) due to hypogonadotropic hypogonadism (HH) can result in poor testicular development, low testicular volumes, micropenis and cryptorchidism. Inadequate hormonal replacement can lead to long-term issues, including subfertility or infertility, and reduced quality of life. Exogenous testosterone for pubertal induction can elevate serum testosterone concentrations and induce virilization, but it does not promote testicular development nor induce spermatogenesis. Fertility and testes growth remain primary concerns for patients seeking treatment. STUDY DESIGN SIZE DURATION: We conducted a retrospective observational review of male adolescents and young adults with gonadotropin deficiency and seeking puberty replacement therapy at two large tertiary centre hospitals in London, UK, from 2010 to 2024. PARTICIPANTS/MATERIALS SETTING

methodsA total of 35 males, with diagnosis of congenital hypogonadotropic hypogonadism (CHH: n = 23; further subdivided into those with partial [pHH: n = 8] and those with complete gonadotropin deficiency [cHH: n = 15]), acquired HH (AHH: n = 4) or Kallmann syndrome (KS: n = 8), received combined gonadotropin therapy. We assessed testicular growth and semen quality post-treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The majority of patients were referred for pubertal delay, alone or in combination with cryptorchidism, micropenis or microorchidism. Out of 35 patients, 22 (63%) had previously received testosterone, and the median age at gonadotropin treatment initiation was 15.8 years (range: 11.8-22.7). Semen analysis was obtained in 18 out of 19 patients who had received gonadotropin therapy for a median treatment duration of 21.1 months (range: 4.5-66.9) for rFSH and 19.5 months (range: 8.3-61.1) for hCG. The median sperm count on semen analysis was 8.9 × 10 LIMITATIONS REASONS FOR CAUTION: The relatively low representation of patients with acquired HH in our study emphasizes the need to extrapolate the findings with caution in this specific subgroup of adolescent males with HH. The study is also an observational one, therefore meaning that some outcomes (such as change in inhibin B concentration) were not collected routinely and not reported for all patients. The observational nature of the study design also accounts for the differences in doses and duration observed in gonadotropin therapy. WIDER IMPLICATIONS OF THE

findingsThe treatment of adult male infertility is particularly difficult in severe forms of gonadotropin deficiency, where there has been no testicular stimulation during mini-puberty or puberty. Appropriate hormonal replacement in puberty with combined gonadotropins can induce testicular maturation and spermatogenesis, but data are limited and at present, there is no international consensus on best practice regimens in adolescent and young adult males. Our treatment protocol induced testicular growth and caused increases in serum testosterone and Sertoli cell biomarkers, and spermatogenesis in 15/18 of patients who had completed semen analysis. This indicates the potential to substantially improve the reproductive, physical, and psychological health of patients who have a significant and unmet need for adequate hormonal replacement during puberty. The study described here included patients with diverse forms of HH (congenital, acquired, complete, and partial HH), thereby providing encouraging results across a variety of subjects with impaired puberty facing increased odds of fertility problems in adulthood. Additionally, we observed similar sperm counts between those who received exogenous testosterone treatment prior to gonadotropin therapy and those who began directly on gonadotropins for pubertal induction. This last finding is aligned with previous data and may help to reassure paediatric endocrinologists with limited access to rFSH or hCG that the use of exogenous testosterone to induce androgen-dependent changes in patients seeking treatment for pubertal delay is unlikely to compromise spermatogenic potential, should gonadotropins become available at a later stage. STUDY FUNDING/COMPETING INTERESTS: S.C. was funded by an ESPE Early Career Scientific Development Grant. S.R.H. was funded by the Wellcome Trust (222049/Z/20/Z) and Barts Charity [MGU0552]. K.N.Y. was employed under the NIHR Specialist Foundation Programme. F.d.A. was funded by the student traineeship, University of Rome 'Tor Vergata', an Erasmus Grant and an ESPE Early Career Scientific Development Grant. E.C.A. was funded by an NIHR Academic Clinical Fellowship (ACF-2021-19-002). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care. G.B. received an ESPE Mid-Career Research Fellowship to enable the development of the clinical treatment schedule. The authors have no conflicting interests. TRIAL REGISTRATION NUMBER: N/A.