Hypogonadism

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Osteoporosis, a disease classically attributed to postmenopausal women, is underappreciated, underdiagnosed, and undertreated in men. However, it is not uncommon for osteoporotic fractures to occur in men. About 40% of fractures occur in men with an incidence that has increased over the years. After a first fracture, the risk of a subsequent episode, as well as the risk of death, is higher in the male than in the female population. Despite these facts, only 10% of men with osteoporosis receive adequate treatment. Up to half of the cases of male osteoporosis have a secondary cause, the most common being hypogonadism, excessive alcohol consumption, and chronic use of glucocorticoids. The International Society for Clinical Densitometry (ISCD) recommends using the female database for the diagnosis of osteoporosis by DXA (T-score ≤ -2.5 in men over 50 years old). In addition, osteoporosis can also be diagnosed independently of the BMD if a fragility fracture is present, or if there is a high risk of fractures by FRAX. Treatment is similar to postmenopausal osteoporosis, because the data regarding changes in bone density track closely to those in women. Data concerning fracture risk reduction are not as certain because the clinical trials have included fewer subjects for shorter period of time. In men with symptomatic hypogonadism, testosterone replacement, if indicated, can improve BMD.

ImportanceThe effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown.ObjectiveTo compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism.Design, setting, and participantsThis placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023.InterventionParticipants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo.Main outcomes and measuresThe primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model.ResultsA total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men.Conclusions and relevanceIn a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT.Trial registrationClinicalTrials.gov Identifier: NCT03518034.

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κB (Rank) signaling. Whole-body and microglia Rank (mouse) depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK (human) in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.