title: A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.
abstract: OBJECTIVE
  DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia.
  
  
  METHODS
  The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia.
  
  
  CONCLUSIONS
  Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.
authors: Service d'Endocrinologie, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, 92100 Boulogne, France.
authors: Marie-Laure
authors: ML
authors: Raffin-Sanson
authors: Bérénice
authors: B
authors: Oudet
authors: Sylvie
authors: S
authors: Salenave
authors: Sylvie
authors: S
authors: Brailly-Tabard
authors: Martine
authors: M
authors: Pehuet
authors: Sophie
authors: S
authors: Christin-Maitre
authors: Yves
authors: Y
authors: Morel
authors: Jacques
authors: J
authors: Young
mesh_terms: D000328:Adult; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics*; D005500:Follow-Up Studies; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009845:Oligospermia / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010913:Pituitary-Adrenal System / Q000502:physiology; D011627:Puberty / Q000235:genetics*; D013737:Testis / Q000473:pathology / Q000502:physiology*; D013997:Time Factors
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human