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Combined Hypothalamic-Pituitary-Gonadal Defect in a Hypogonadic Man with a Novel Mutation in the DAX-1 Gene¹

Service d’Endocrinologie et Maladies Métaboliques, CHU Rangueil (P.C., A.B.), 31054 Toulouse, France; Biologia Generale e Genetica Medica, Università di Pavia (S.I., G.C.), 27100 Pavia, Italy; Laboratoire de Biochimie, CHU La Grave (M.P.), and Service de Pédiatrie et Génétique Médicale, CHU Purpan (P.R.), Toulouse, France

Address all correspondence and requests for reprints to: Philippe Caron, M.D., Service d’Endocrinologie, CHU Rangueil, 1 avenue J. Poulhes, 31054 Toulouse Cedex, France. E-mail: caron.p{at}chu-toulouse.fr

We have studied a 20-yr-old male patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism (HH) due to a C to A transversion at nucleotide 825 in the DAX-1 gene, resulting in a stop codon at position 197. The same mutation was detected in his affected first cousin (adrenal hypoplasia congenita and HH) and in a heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2 yr and 6 months, bilateral cryptorchidism corrected surgically at the age of 12 yr, and failure of spontaneous puberty. Plasma testostereone (T) was undetectable (<0.30 nmol/L), gonadotropin levels were low (LH, <0.4 IU/L; FSH, 1.5 IU/L) and not stimulated after iv injection of 100 µg GnRH. The endogenous LH secretory pattern was apulsatile, whereas free -subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. During iv pulsatile GnRH administration (10 µg/pulse every 90 min for 40 h), each GnRH pulse induced a LH response of low amplitude (0.54 ± 0.05 UI/L), whereas mean LH (0.45 ± 0.01 IU/L) and FAS (63 ± 8 mU/L) levels remained low. Amplitude of LH peaks (0.83 ± 0.09 IU/L), mean LH (0.53 ± 0.02 IU/L), and FAS (161 ± 18 mU/L) levels increased (P < 0.01), whereas the T concentration remained low (0.75 nmol/L) when the pulsatile GnRH regimen was raised to 20 µg/pulse for a 40-h period, suggesting a partial pituitary resistance to GnRH. Thereafter, plasma T levels remained in prepubertal value after three daily im injections of 5000 IU hCG (3.6 nmol/L) and after 1-yr treatment with weekly im injections of 1500 IU hCG (1.2 nmol/L), implying Leydig cell resistance to hCG. The patient had a growth spurt, bone maturation, progression of genital and pubic hair stages, and normalization of plasma T level (15.8 nmol/L) after a 12-month treatment with twice weekly injections of hCG and human menopausal gonadotropin (75 IU International Reference Preparation 2) preparations, suggesting that, in presence of FSH, a Sertoli cell-secreted factor stimulated Leydig cell production of T. In conclusion, we report a novel mutation in the DAX-1 gene in patients with AHC and HH. Our results suggest that the hypogonadism is due to a combined hypothalamic-pituitary-gonadal defect and imply that the DAX-1 gene may play a critical role in human testicular function.

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