Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis

Abstract

Objective Hypogonadotropic hypogonadism is characterised by inadequate secretion of pituitary gonadotropins, leading to absent, partial or arrested puberty. In males, classical treatment with testosterone promotes virilisation but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for achievement of pubertal outcomes in males with hypogonadotropic hypogonadism. Design Systematic review and meta-analysis Methods A systematic review of Medline, EMBASE, Global Health, and PsychInfo databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I)/National Heart, Lung, and Blood Institute (NHLBI) tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713). Results After screening 3,925 abstracts, 103 studies were identified including 5,328 patients from 21 countries. Average age of participants was <25 years in 45.6% (n=47) of studies. Studies utilised human chorionic gonadotropin (hCG) (n=93, 90.3% of studies), human menopausal gonadotropin (hMG) (n=42, 40.8%), follicle-stimulating hormone (FSH) (n=37, 35.9%), and gonadotropin-releasing hormone (GnRH) (28.2% n=29). Median reported duration of treatment/follow-up was 18 months (interquartile range (IQR) 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% Confidence Interval (CI) 82-91%) as compared to hCG alone (40%, 95% CI 25-56%). However, study heterogeneity and treatment variability were high. Conclusions This systematic review provides convincing evidence of efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomised studies are needed.

Combined gonadotropin therapy to replace mini‐puberty in male infants with congenital hypogonadotropic hypogonadism

“…More recently, this has shown promise as a treatment option to induce puberty in adolescents and young adults. 22 The data suggest that gonadotropin therapy is both efficacious and safe in this cohort; however, study heterogeneity remains a limitation in the applicability of the data. 22 Currently, while the use of gonadotropins in puberty is becoming more widespread, testosterone therapy remains the most routinely used treatment for induction of puberty in male CHH.…”

“…22 The data suggest that gonadotropin therapy is both efficacious and safe in this cohort; however, study heterogeneity remains a limitation in the applicability of the data. 22 Currently, while the use of gonadotropins in puberty is becoming more widespread, testosterone therapy remains the most routinely used treatment for induction of puberty in male CHH. 1 With the belief that the optimum treatment modality in gonadotropin deficiency is replacement therapy mimicking physiology, mini-puberty has also gained attention as a potential diagnostic and therapeutic window for CHH, particularly in boys.…”

“…29 Over the past three or more decades, the literature has identified several variables that are likely to predict a poor response to gonadotropin therapy in adulthood. 22,25,30 It has been well documented that those men with a more severe phenotype, including a history of cryptorchidism, smaller testicular volumes, and lower inhibin B concentrations tend to respond less well to treatment to induce spermatogenesis. 25,30 Pitteloud and colleagues examined 76 men with idiopathic hypogonadotropic hypogonadism and found that a baseline inhibin B greater than 60 pg/mL was a favorable predictor for achieving an adult testicular volume and so improving spermatogenesis.…”

“…33 While the majority of studies in infants and young male children have not conducted testicular biopsies to enable evaluation of cellular response to gonadotropins, testicular volume appears to be a valid proxy measurement for testicular maturation and is a significant independent predictor for all spermatogenic thresholds. 22,24,26,[34][35][36] Raivio and colleagues demonstrated that priming treatment with rhFSH prior to pubertal induction-thus recapitulating the physiology of minipuberty by stimulating proliferation but not maturation of Sertoli cells in the absence of Leydig cell testosterone production-resulted in a significant increase in prepubertal testicular volume (n = 14, p<0.005) and inhibin B (p<0.01). 32 This is borne out by the literature to date on gonadotropin replacement in male infants with CHH, with stimulation of mini-puberty leading to an increase in testicular volume (Table 1).…”

“…38,43 In the adult population, longitudinal studies have demonstrated sustained improvements in pubertal progression and fertility outcomes from receiving gonadotropin treatment. 22,45 Since exogenous gonadotropin therapy during mini-puberty mimics the normal physiological surge, it is hypothesized that treatment during this early stage will re-establish normal HPG axis function during this vital development period. Considering this, combined gonadotropin therapy during mini-puberty should hypothetically offer better fertility outcomes compared to treatment in infancy with testosterone alone or no treatment.…”