Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with a novel mutation in the DAX-1 gene.
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 i.v. injection of 100 microg GnRH. The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. During i.v. pulsatile GnRH administration (10 microg/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 microg/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 i.m. 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.
Caron
P
P
Service d'Endocrinologie et Maladies Métaboliques, CHU Rangueil, Toulouse, France. caron.p@chu-toulouse.fr
Imbeaud
S
S
Bennet
A
A
Plantavid
M
M
Camerino
G
G
Rochiccioli
P
P
D001483:Base Sequence / Q000235:genetics; D002675:Child, Preschool; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004359:Drug Therapy, Combination; D005837:Genitalia, Male / Q000503:physiopathology*; D015292:Glycoprotein Hormones, alpha Subunit / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008596:Menotropins / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D010375:Pedigree; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*
D006063:Chorionic Gonadotropin; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D015292:Glycoprotein Hormones, alpha Subunit; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D008596:Menotropins; D007986:Luteinizing Hormone