Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man

Abstract

Background and Methods: Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing. Results: The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral density of the lumbar spine was 0.745 g per square centimeter, 3.1 SD below the mean for age-matched normal women; there was biochemical evidence of increased bone turnover. The patient had no detectable response to estrogen administration, despite a 10-fold increase in the serum free estradiol concentration. Conformation analysis of his estrogen-receptor gene revealed a variant banding pattern in exon 2. Direct sequencing of exon 2 revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon. The patient's parents were heterozygous carriers of this mutation, and pedigree analysis revealed consanguinity. Conclusions: Disruption of the estrogen receptor in humans need not be lethal. Estrogen is important for bone maturation and mineralization in men as well as women., The actions of adrenal and gonadal steroids, thyroid hormone, and vitamin D are mediated by receptors encoded by a family of related genes. Mutations of glucocorticoid, androgen, thyroid hormone, and vitamin D receptors leading to syndromes of hormone resistance have been reported 1 – 4 . It has been thought that mutation of the estrogen-receptor gene would be lethal, affecting embryo implantation in particular 5 . Recent insertional disruption of the mouse estrogen-receptor gene 6 and two case reports, 7 , 8 however, raise questions about the validity of the lethality hypothesis and reveal intriguing phenotypes. In mice with disrupted estrogen-receptor genes, both sexes are viable… © 1994, Massachusetts Medical Society. All rights reserved.