Puberty induction with Gonadotropin Treatment in Males with Hypogonadotropic Hypogonadism

The Pubertal Induction with Gonadotropins (PinG) study aims to resolve the question of what is the optimal replacement therapy to induce puberty in adolescent and young adult men (12-35 years) with gonadotropin deficiency (GD) and the mechanisms underlying the differential response to gonadotropin therapy. Individuals with central disorders of the hypothalamic-pituitary-gonadal axis leading to GD have lack of pubertal development in adolescence, but also suffer from under-stimulation of the gonads both in utero and postnatally. The postnatal period of 'mini-puberty', where healthy infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, especially in boys. The treatment of male infertility is particularly difficult in severe forms of GD, where there has been no testicular stimulation with follicle stimulating hormone (FSH) during mini-puberty. In this patient group, hormonal therapy to promote sperm production is unsuccessful in up to 50% in adulthood. This is largely due to lack of appropriate hormonal replacement in childhood. Previously published data suggest that FSH pre-treatment at puberty may simulate the physiological effects of mini-puberty. However, at present there is no consensus on best practice pubertal management in males with GD due to congenital hypogonadotropic hypogonadism or combined pituitary hormone deficiency. The PinG study, examining the clinical effectiveness and mechanisms of action of gonadotropins for pubertal induction in adolescent and young adult males with GD, aims to address this knowledge gap. The PinG study is an open-label randomised controlled study, stratified by disease severity, conducted across 16 UK research sites. We hypothesise that response to therapy will vary depending on disease severity and underlying molecular aetiology, and that FSH is required for successful completion of spermatogenesis. Firstly, we aim to assess the response to induction of puberty in males with partial GD, comparing the proportion of participants achieving spermatogenesis with monotherapy versus combined gonadotropin treatment. Secondly, in males with severe GD, we aim to compare the proportion of participants achieving spermatogenesis with or without pre-treatment with FSH, prior to combined gonadotropin treatment. Thirdly, we will assess mechanisms of response to gonadotropin therapy in patients with GD with differing molecular and genetic aetiologies, and the role of FSH in completing spermatogenesis. Fourthly, we will assess quality of life in patients with GD and their carers via age-appropriate questionnaires, and explore their experiences of pubertal induction with gonadotropins via qualitative interview methodology using purposive sampling. Participants will be recruited and receive treatment over the 58-month study, with a protocol mirroring standard NHS practice wherever possible. Findings of the project will be shared with patient groups and charities via our PPI partners, clinical teams looking after patients with GD and research teams globally at meetings and via freely accessible medical journals, with publication of study analyses and best practice guidelines. This study represents a unique opportunity to substantially improve the reproductive, physical and psychological health of patients who have a significant and unmet need for adequate hormonal replacement during puberty.