Integrating hormonal analyses into the development of hormonal male contraception: geographic centre as a determinant of individual response

Abstract STUDY QUESTION Are the geographic recruitment centre and dynamic sex-steroid profiles, particularly for dihydrotestosterone, associated with inter-individual differences in libido and mood-related adverse events during hormonal male contraception? SUMMARY ANSWER In this multinational analysis of the WHO testosterone undecanoate/ norethisterone (TU/NETE) enanthate trial, geographic cluster was associated with distinct androgenic profiles and clinical responses; lower dihydrotestosterone exposure emerged as a consistent predictor of decreased libido and mood-related adverse events. WHAT IS KNOWN ALREADY Combined testosterone–progestin regimens can suppress spermatogenesis effectively, but the WHO TU/NETE trial was discontinued prematurely because of mood-related adverse events despite high contraceptive efficacy. The endocrine mechanisms underlying these adverse effects remain incompletely understood. STUDY DESIGN, SIZE, DURATION This secondary analysis used serial hormone and adverse-event data from the multinational WHO/CONRAD trial, which enrolled 320 men. However, 255 participants had serum samples available for centralised steroid analysis and constituted the present analytical cohort, as the samples from Jakarta, Indonesia (65 subjects) were not sent to the Central Laboratory. PARTICIPANTS/MATERIALS, SETTING, METHODS Healthy male participants were recruited across European/Australian, South American and Asian centres and grouped into geographic clusters. Serum testosterone, calculated free testosterone, dihydrotestosterone, estradiol and norethisterone were analysed centrally by gas chromatography–mass spectrometry (GC-MS). Longitudinal mixed-effects models and time-to-event analyses were used to evaluate associations between hormone trajectories, geographic cluster, age, libido changes and mood disorders. MAIN RESULTS AND THE ROLE OF CHANCE Marked cluster-dependent heterogeneity was observed. Participants from Chile showed higher total and free testosterone and persistently higher dihydrotestosterone concentrations over time, accompanied by a higher incidence of increased libido. Participants from India showed lower dihydrotestosterone exposure and higher norethisterone concentrations and no libido and mood changes. European/Australian participants showed comparatively lower dihydrotestosterone concentrations and the highest cumulative incidence of mood disorders. Declining dihydrotestosterone concentrations were associated with decreased libido and mood-related adverse events. LIMITATIONS, REASONS FOR CAUTION The analyses are exploratory and based on secondary evaluation of a completed clinical trial. Geographic clusters may reflect genetic, environmental, dietary, cultural, behavioural and reporting-related factors, and causality cannot be inferred. WIDER IMPLICATIONS OF THE FINDINGS Comprehensive androgen profiling, particularly assessment of dihydrotestosterone, may help identify men at increased risk of neuropsychological or sexual adverse effects during hormonal male contraception and may support more individualised contraceptive regimens. FUNDING The clinical study was cosponsored and funded by United Nations Development Programme; United Nations Population Fund; United Nations International Children’s Emergency Fund; World Health Organization; World Bank Special Programme of Research, Development, and Research Training in Human Reproduction (Human Reproduction Programme, World Health Organization, Geneva, Switzerland); and CONRAD (Eastern Virginia Medical School, Arlington, VA using funding from the Bill & Melinda Gates Foundation and U.S. Agency for International Development). DISCLOSURES R.I.M.is a Principal Research Fellow of the Australian National Health and Medical Research Council (1022327) and the Hudson Institute, which is supported by the Victorian Government’s Operational Infrastructure Scheme. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A