Improving hormonal treatment for men with infertility due to hypogonadotropic hypogonadism.

Research question The standard treatment for male hypogonadotropic hypogonadism (HH), testosterone replacement, does not improve fertility. When fertility is needed, men are switched to gonadotropin treatment consisting of human chorionic gonadotropin (hCG) with or without either human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH). This treatment is complex, expensive and takes up to 2 years. There is no consensus among experts on the best treatment protocol. Though studies have looked at sperm induction and pregnancy rates with gonadotrophin treatment, results vary widely. There is no data defining pregnancy rates with different gonadotrophin drug protocols or on factors associated with natural pregnancies or shorter time to pregnancy. Conducting prospective cohort or randomised-controlled clinical trials to answer these questions is not feasible due to the rarity and heterogeneity of the condition. Aims and Objectives For men with HH, we will: Investigate which gonadotrophin treatment protocol is associated with the best pregnancy rate and time to pregnancy. Identify other factors associated with the rate of, and time to pregnancy in partners. Identify factors associated with adverse outcomes, and assisted reproductive technology (ART) for partners. Methods This retrospective study of anonymised data from case notes will include adult men diagnosed with HH (congenital and acquired) based on the clinical features of hypogonadism, low testosterone, and low gonadotropins with a pre-treatment sperm concentration <5 million/mL treated with gonadotrophins between 1995 to 2023 and followed-up for at least 2 years or until pregnancy in the partner. We are collaborating with expert centres across the UK and internationally to share data. Collaborators from each centre will identify patients from local records and review them for eligibility. Data will be collected on reported pregnancy in the partner of the patient (primary outcome); use of ART; live birth; semen parameters; serum reproductive hormones and adverse events. Anonymised data will be transferred to the research team. Directed acyclic graphs (DAGs) will be conducted to assign candidate covariates identified in the literature review as confounders, mediators or intermediaries. Pregnancy rates with different protocols will be compared using a generalised linear model. We will use time-to-event analysis to define predictors of spontaneous pregnancy and semen outcomes. We anticipate that we will exceed the calculated sample size of 500 patients. Timelines for delivery Milestone 1 (ACHIEVED): Identify >500 patient records with information on fertility treatment by the start of the study. Out of 12 collaborating centres, 11 have already performed preliminary data collection identifying 900 men. Therefore, we have already achieved our first milestone. Milestone 2: Data sharing agreements with collaborators for >500 patients by Month 4 Milestone 3: Complete data collection by Month 6 Anticipated Impact and Dissemination This study will identify the best gonadotrophin protocol for these men, predictors of natural pregnancies, shorter time to pregnancies and time taken to achieve the outcomes of interest, immediately changing the clinical practice. With the help of our PPI lead, we will develop online resources which will be widely disseminated to patient groups in addition to traditional scientific publications and communications.