From tablets to targeted therapy: the APHRODITE era in male infertility

Treatment of idiopathic male infertility has traditionally relied on the empirical use of oral agents such as clomiphene citrate and aromatase inhibitors, often prescribed without rigorous endocrine phenotyping. The newly proposed APHRODITE criteria (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) introduce a biologically rational framework for stratifying infertile men and tailoring hormonal therapy. This opinion article draws a conceptual parallel with the evolution of ovarian stimulation in IVF, in which exogenous gonadotropins supplanted oral agents due to their superior physiological control and better outcomes. Similarly, the APHRODITE system may catalyze a paradigm shift in male infertility treatment-from empirical, tablet-based regimens to biology-driven gonadotropin therapy. Here, we revisit the hormonal regulation of spermatogenesis, critically appraise the limited efficacy of selective estrogen receptor modulators and aromatase inhibitors, and summarize evidence supporting gonadotropin therapy. We further highlight the potential impact of FSH and LH/hCG genetic polymorphisms on treatment responsiveness. While clomiphene citrate and aromatase inhibitors retain a role in specific endocrine profiles, the new positioning of exogenous gonadotropins-LH/hCG and FSH-as targeted, earlier-line interventions holds promise to improve outcomes and efficacy in male fertility care. Future progress will depend on prospective trials that apply the APHRODITE criteria and on comparative analyses of oral agents versus injectable gonadotropin regimens in well-defined patient phenotypes.