Leydig cell hypoplasia

Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis or luteinizing hormone (LH) resistance, is a rare disorder of sex development caused by impaired development or function of Leydig cells in the testes. Leydig cells are responsible for producing testosterone in response to luteinizing hormone (LH). The condition is caused by inactivating mutations in the LHCGR gene, which encodes the receptor for LH and human chorionic gonadotropin (hCG). Without functional Leydig cells or adequate LH signaling, testosterone production is severely reduced or absent, leading to undervirilization of 46,XY individuals. LCH is classified into two types based on severity. Type I (complete) presents with severe undervirilization, typically resulting in female or ambiguous external genitalia in 46,XY individuals at birth, absent or rudimentary Wolffian duct derivatives, and inguinal or intra-abdominal testes. Müllerian structures are absent because Sertoli cell function and anti-Müllerian hormone (AMH) production remain intact. Type II (partial or incomplete) presents with milder undervirilization, including micropenis, hypospadias, and reduced but not absent masculinization. Affected individuals typically present at birth with atypical genitalia or at puberty with absent or incomplete virilization, elevated LH levels, and low testosterone levels. Management of Leydig cell hypoplasia involves a multidisciplinary approach including endocrinologists, urologists, psychologists, and geneticists. Treatment considerations include sex hormone replacement therapy — testosterone supplementation for individuals raised as male to promote virilization at puberty and maintain secondary sexual characteristics, or estrogen therapy for those raised as female. Surgical interventions may be considered for genital reconstruction or gonadectomy depending on the clinical scenario and cancer risk. Genetic counseling is recommended for affected families. Fertility is generally impaired in affected individuals, as spermatogenesis requires adequate intratesticular testosterone levels.

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