1/63. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred.Detailed endocrinological studies were performed in the three affected kindred of a family carrying mutations of the GnRH receptor gene. All three were compound heterozygotes carrying on one allele the Arg262Gln mutation and on the other allele two mutations (Gln106Arg and Ser217Arg). When expressed in heterologous cells, both Gln106Arg and Ser217Arg mutations altered hormone binding, whereas the Arg262Gln mutation altered activation of phospholipase C. The propositus, a 30-yr-old man, displayed complete idiopathic hypogonadotropic hypogonadism with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and alpha-subunit, absence of response to GnRH and GnRH agonist (triptorelin), and absence of effect of pulsatile administration of GnRH. The two sisters, 24 and 18 yr old, of the propositus displayed, on the contrary, only partial idiopathic hypogonadotropic hypogonadism. They both had primary amenorrhea, and the younger sister displayed retarded bone maturation and uterus development, but both sisters had normal breast development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GnRH. In the two sisters, there were no spontaneous pulses of LH, but pulsatile administration of GnRH provoked a pulsatile secretion of LH in the younger sister. The same mutations of the GnRH receptor gene may thus determine different degrees of alteration of gonadotropin function in affected kindred of the same family.- - - - - - - - - - ranking = 1keywords = administration (Clic here for more details about this article) |
2/63. A female case of Kallmann's syndrome.A case of 20-year-old woman with hypogonadotropic hypogonadism and anosmia is reported, since very few female cases of Kallmann's syndrome have been reported so far in japan. Three uncles on the father's side had no children. Height was 168 cm, and arm span 165 cm. The olfactory test revealed complete anosmia. Bone age was 13 year. Chromosome was 46 XX and normal karyotype. Basal levels of serum FSH, LH and estrogens (E1, E2 and E3) were low. serum FSH and LH levels rose slightly only after LH-RH administration, and did not increase in clomiphene test. plasma estrogens did not increase after daily injection of 150 IU of HMG for 3 successive days. The response of serum GH to arginine infusion was normal, while that to insulin-induced hypoglycemia was poor.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
3/63. 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.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
4/63. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor.In this study, we describe a patient with a phenotype of complete hypogonadotropic hypogonadism who presented primary failure of pulsatile GnRH therapy, but responded to exogenous gonadotropin administration. This patient bore a novel point mutation (T for A) at codon 168 of the gene encoding the GnRH receptor (GnRH-R), resulting in a serine to arginine change in the fourth transmembrane domain of the receptor. This novel mutation was present in the homozygous state in the patient, whereas it was in the heterozygous state in both phenotypically normal parents. When introduced into the complementary dna coding for the GnRH-R, this mutation resulted in the complete loss of the receptor-mediated signaling response to GnRH. In conclusion, we report the first mutation of the GnRH-R gene that can induce a total loss of function of this receptor and is associated with a phenotype of complete hypogonadotropic hypogonadism.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
5/63. melatonin hypersecretion in male patients with adult-onset idiopathic hypogonadotropic hypogonadism.Increased melatonin secretion observed in male patients with congenital isolated hypogonadotropic hypogonadism and its normalization during testosterone treatment had suggested that melatonin and the reproductive hormones are inter-related. Since these patients have a congenital form of hypogonadism, it is likely that hypermelatoninemia is the consequence of hypogonadism. To further study the relations between the pineal and the reproductive axis in humans, we evaluated melatonin secretion in two men (aged 35 and 50 yrs.) with acquired adult-onset hypogonadotropic hypogonadism. The diagnosis was based on the findings of normal testicular volume, azoospermia, low serum testosterone, normal LH and FSH levels, but apulsatile LH secretion, and intact anterior pituitary hormones secretion, normal findings on skull radiographic imaging, prior sexual maturation and paternity. melatonin secretion was assessed as urinary 24 h 6-sulphatoxymelatonin excretion (aMT6s) prior to and during the administration of 250 mg testosterone enanthate per month for 4 months. Pretreatment melatonin production was markedly increased in both patients: 427-915 ng/kg/24 h vs. 204 /-81 [mean /-SD] in 16 age-matched male controls. During testosterone treatment, aMT6s levels were normalized in one patient (range: 81-287 ng/kg/24 h) and remained elevated in the other patient (range: 830-1280 ng/kg/24 h). These data indicate that male patients with acquired GnRH deficiency have increased melatonin secretion. melatonin hypersecretion in these patients may reflect a functional association.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
6/63. A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect.We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility. The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 microg/pulse, sc, every 90 min). However, GnRH triggered free alpha-subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced. This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.- - - - - - - - - - ranking = 3keywords = administration (Clic here for more details about this article) |
7/63. Estrogen therapy in a male patient with chronic hepatitis c and irradiation-induced testicular dysfunction.We report an 18-year-old male patient who developed chronic hepatitis c after blood transfusion and had testicular dysfunction after irradiation for a testicular relapse of childhood acute lymphocytic leukemia after cessation of maintenance therapy, and the initiation of testosterone replacement therapy at puberty. Concomitant administration of estradiol resulted in a reduction in serum alanine aminotransferase and ferritin levels and hepatic iron concentration and staining after 2 years of estrogen therapy, although interferon therapy was withdrawn because of adverse effects. This observation suggests that endogenous estradiol may play a beneficial role in male patients with chronic hepatitis c.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
8/63. diabetic ketoacidosis and hypogonadotropic hypogonadism in association with transfusional hemochromatosis in a man with beta-thalassemia major.We report a 23-year-old man with beta-thalassemia major and transfusional hemochromatosis, which manifested as diabetic ketoacidosis and hypogonadotropic hypogonadism. This unusual presentation of diabetic ketoacidosis in hemochromatosis has rarely been reported. magnetic resonance imaging of the abdomen showed decreased signal intensity in the liver, spleen, and pancreas. In addition, the pituitary gland also showed heterogeneous low signal intensity, compatible with hemochromatosis. He was treated with insulin supplements and pulsatile human chorionic gonadotropin administration. Clinical improvement was noted after hormone replacement. Intensive iron chelation therapy was given to prevent cardiac complications, and to restore his gonadal function. During follow-up, the patient experienced improvement in libido and sexual potency.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
9/63. Successful pregnancy following gonadotropin therapy in a patient with hypogonadotropic hypogonadism resulting from craniopharyngioma.The authors report a rare case of a patient with panhypopituitarism who became pregnant by gonadotropin therapy and gave birth to a healthy baby. A brain tumour and/or the surgical resection of a brain tumour occasionally results in pituitary dysfunction. An 18-year-old Japanese patient developed hypogonadotropic secondary amenorrhoea because of a craniopharyngioma, which was surgically removed. The patient came to us, and peripheral blood was collected every 15 minutes for four hours. The levels of luteinising hormone (LH) and follicle-stimulating hormone (FSH) were measured. Results showed that LH and FSH levels were very low and did not fluctuate. Several years later, the patient complained of infertility, and treatment with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) was started. The therapy was repeated for several cycles, but she did not conceive, so hMG-hCG therapy combined with conjugated oestrogen administration was started. The patient became pregnant at the seventh cycle of this combined therapy. She was not treated with supplementary growth hormone.- - - - - - - - - - ranking = 0.5keywords = administration (Clic here for more details about this article) |
10/63. Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR "knockout".Mutations in the GnRH receptor (GnRHR) have been shown to be responsible for a significant number of autosomic recessive and, less commonly, sporadic cases of idiopathic hypogonadotropic hypogonadism. We describe a woman with complete GnRH resistance secondary to a novel homozygous GnRHR gene mutation, transmitted as an autosomal recessive trait. The propositus presented with primary amenorrhea and absent thelarche and pubarche. Dynamic tests demonstrated absent spontaneous gonadotropin pulsatility, and no response to either exogenous pulsatile (10 microg/pulse at 90-min intervals over 6 h) or acute (100 microg) GnRH administration. However, she responded to exogenous gonadotropin administration, with a resulting normal pregnancy. Genomic dna extracted from peripheral blood was PCR amplified using amplimers spanning intron-exon boundaries for the three exons of GnRHR and revealed a homozygous splice junction mutation (G to A transversion) at the intron 1-exon 2 boundary. Her unaffected sister, with a totally normal phenotype, was heterozygous for this mutation. After lymphocyte Epstein-Barr virus transformation, rna was extracted and subjected to RT-PCR, using primers located in the first and third exons. Results showed a transcript lacking all of exon 2 (exon 2 skipping), with splicing of exon 1 to exon 3. This created a frame shift, generating a coding sequence for three new amino acids, followed by a stop codon. Although it is not clear whether the mutant receptor is actually expressed, the resultant mRNA sequence was presumed to produce a truncated receptor with no binding or signaling capacity.- - - - - - - - - - ranking = 1keywords = administration (Clic here for more details about this article) |
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