Efficacy and Safety of Recombinant Human Follicle-Stimulating Hormone in Men with Hypogonadotropic Hypogonadism: A Meta-Analysis of 4 Trials in Europe, Australia, USA and Japan

(1) To assess the efficacy and safety of recombinant human follicle-stimulating hormone (r-hFSH; follitropin alfa, freeze-dried formulation) in increasing sperm concentration in men with hypogonadotropic hypogonadism (HH). (2) To assess the impact of baseline data on outcome data. Meta-analysis of 4 clinical and endocrine studies using a similar open design. Four clinical studies were performed in university clinical sites in Europe (26 patients), Australia (8 patients), USA (29 patients) and Japan (18 patients), in a total of 81 patients.[100 started pretreatment with hCG but 19 did not reach the criteria to start r-hFSH]. Patients were azoospermic men with classical symptoms of HH. Inclusion criteria in the European study excluded patients with prior gonadotropin therapy. Patients received hCG (1000 IU 3x/week) for up to 6 months to normalise testosterone levels. When T levels were within normal range and patients confirmed azoospermic, they received r-hFSH (150 IU 3x/week) in combination with hCG for 18 months. Sperm count, motility, morphology and mean testicular volume (MTV) were assessed every 3 months. Main outcome measure was achievement of a sperm concentration of ≥1.5 x 106/mL. Spermatogenesis was achieved in 68 out of 81 patients, 56 achieving a sperm concentration ≥1.5 x 106/mL. Time to achieve spermatogenesis ranged between 3 and 18 months (median 6 months) and time to achieve ≥1.5 x 106/mL ranged between 3 and 18 months (median 9 months). In all studies, sperm concentration and MTV increased significantly during the treatment period. Ejaculate volume as well as the percentage of sperm with normal morphology and progressive motility increased over treatment. The baseline parameters found to impact on efficacy were MTV and BMI: large MTV and low BMI (<30 kg/m2) were predictors of sperm concentration of ≥1.5 x 106/mL (p=0.0290 and p=0.0691 respectively). In contrast, the origin of the disease (Idiopathic MHH, Acquired MHH or Kallmann’s syndrome) had no influence on treatment outcome. Safety data were in line with the current safety profile for this drug in this indication. The local tolerability of subcutaneous injections was excellent. Recombinant-hFSH administered in combination with hCG is effective in initiating spermatogenesis in patients with HH, and is well tolerated.