ORMAL pubertal development and fertility depend on the intricate interplay of hypothalamic, pituitary, and gonadal factors. Crucial in this respect are normal secretory patterns of follicle-stimulating hormone and luteinizing hormone. These hormones stimulate the production of estrogen and ovulation in women and the production of testosterone and spermatogenesis in men. Secreted from common gonadotroph cells, the hormones are heterodimers composed of a common a -subunit and a specific b -subunit, each encoded by a separate gene. Specificity of action depends on the recognition of these hormones by specific receptors on the surface of gonadal cells.Various genetic defects of the hypothalamic-pituitary-gonadal axis that cause hypogonadism have been identified. 1 At the level of the hypothalamus, secretion of gonadotropin-releasing hormone is disturbed by mutations in the KAL gene, 2 leading to Kallmann's syndrome, and in the DAX-1 gene, 3 causing X-linked adrenal hypoplasia and hypogonadotropic hypogonadism. At the pituitary level, mutations in the gene for the b -subunit of luteinizing hormone 4 cause hypogonadotropic hypogonadism, and at the gonadal level, loss-of-function mutations in the genes that encode the receptors for folliclestimulating hormone and luteinizing hormone cause hypergonadotropic hypogonadism. 5,6 Specifically, mutations in the gene for luteinizing hormone receptors result in Leydig-cell hypoplasia and undermasculinization in genetic males, 5,7,8 whereas mutations in the gene for follicle-stimulating hormone receptors cause primary gonadal failure and hypergonadotropic hypogonadism in genetic females. 6 Two female patients with follicle-stimulating hor-N mone deficiency caused by mutations in the gene for the b -subunit of follicle-stimulating hormone have been described. One presented with primary amenorrhea and infertility, 9 and the other with delayed puberty. 10 In this report, we describe a man with impaired secretion of follicle-stimulating hormone caused by a homozygous mutation in the gene for the b -subunit of follicle-stimulating hormone, as well as two asymptomatic heterozygous male members of his family.
METHODS
SubjectsThe proband was referred to our center at the age of 18 years for evaluation of delayed puberty. He reported normal erections and ejaculatory orgasms. He had a prepubertal physique and underdeveloped muscles. He was 178 cm tall (69th percentile) and weighed 59 kg. He had pubic hair (Tanner stage 4), scant axillary hair, and no facial hair. No breast tissue was palpated. The scrotum was thin, and two small, soft testicles (testicular volume, 1 to 2 ml) were palpated. There was no family history of consanguinity, infertility, or delayed puberty.Laboratory studies revealed low serum testosterone and follicle-stimulating hormone concentrations and high serum luteinizing hormone concentrations (Table 1). Serum thyrotropin, prolactin, and cortisol concentrations were normal. Chromosomal analysis revealed a 46,XY karyotype. After intravenous administration of 100 µg of gon...