1/86. 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 = bone (Clic here for more details about this article) |
2/86. Effect of venesection on bone mineral density in an eugonadal woman with haemochromatosis.BACKGROUND: A 41-year-old premenopausal woman with newly diagnosed haemochromatosis was found to have osteopenia on screening bone mineral densitometry. methods AND RESULTS: liver biopsy showed grade 3 haemochromatosis with an hepatic iron index of 4. Investigation for secondary factors for osteopenia revealed no cause. The patient was clinically and biochemically eugonadal. Following venesection of 8 L blood (4 g iron) over 17 months and calcium supplementation, her bone density rose significantly. neck of femur bone density increased by 6.0% over 13 months and lumbar vertebral bone density increased by 7.2%. There are no previous reports of response of bone density to venesection in eugonadal patients or in women with haemochromatosis.- - - - - - - - - - ranking = 9keywords = bone (Clic here for more details about this article) |
3/86. Pituitary deficiency and lack of gonads in an XY pseudohermaphrodite with beta 39/lepore haemoglobinopathy.We describe the occurrence of hypothyroidism and hypogonadotropic hypogonadism in an XY pseudohermaphrodite subject affected by beta-thalassemia. The patient, reared as female, diagnosed at 14 months of age as having a beta 39/Lepore hemoglobinopathy, treated with multiple transfusion therapy, was referred at age of 15 years because of delayed puberty. Complete endocrine evaluation showed low levels, both basal and after combined LHRH-TRH and hCG stimuli, of FSH, LH, TSH, estradiol (E2), testosterone (T), progesterone (P), androstenedione (A), and FT4 levels, and normal PRL, cortisol, 17OHP and ACTH levels. Imaging studies (ultrasound, magnetic resonance, radioisotope scanning and gonadal vessels phlebography) did not show internal genitalia and gonads. karyotype resulted 46,XY. PCR amplification of the SRY gene confirmed the presence of the y chromosome. female genitalia without uterus in a subject with y chromosome SRY gene, and no detectable testes indicate a condition of male pseudohermaphroditism associated with testicular regression. Low gonadotropin and sex steroid levels are suggestive of combined acquired hypothalamic-pituitary and gonadal impairment, due to iron deposition in both organs. We cannot exclude congenital failure of testosterone synthesis and action in this case, because lack of gonads is an unusual finding in thalassemic hypogonadic subjects.- - - - - - - - - - ranking = 194.63200262867keywords = endocrine (Clic here for more details about this article) |
4/86. A microdeletion within DAX-1 in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a developmental disorder characterized by primary adrenal gland failure, which produces extreme and potentially fatal endocrine deficiencies. Hypogonadotrophic hypogonadism (HHG) also may be associated with AHC. AHC has been shown to result from a variety of mutations in the DAX-1 gene, which encodes a member of the nuclear hormone receptor superfamily. methods: The proband, one of the world's oldest living patients with AHC and HHG, was diagnosed in 1955. He was on corticosteroid replacement therapy since that time and androgen replacement therapy since puberty. We sequenced his DAX-1 gene. RESULTS: We found a 4 bp ACTC deletion between nucleotides 1464 and 1467 in the second exon of the normal DAX-1 sequence. This mutation caused a shift in the reading frame and predicted a premature stop codon at amino acid position 416. The mutation abolished a recognition site for DdeI, allowing for confirmation by restriction analysis. CONCLUSIONS: The position of the mutation confirms the functional importance of the COOH-terminal 10% of the DAX-1 sequence. The clinical history also reinforces the importance of early diagnosis in AHC, which can be associated with longevity and no obvious morbidity after more than 40 years of hormone replacement therapy.- - - - - - - - - - ranking = 194.63200262867keywords = endocrine (Clic here for more details about this article) |
5/86. Mobius sequence, hypogenitalism, cerebral, and skeletal malformations in two brothers.Two brothers born to a healthy, consanguineous Spanish couple have a syndrome of Mobius sequence with involvement of cranial nerves V, VI, VII, IX, and XII, central nervous system malformations; characteristic face with creased earlobes, short philthrum, and a short, arched upper lip, skeletal anomalies with short sternum and delayed bone maturation, hypogenitalism, and profound mental retardation. We suggest that this is a new multiple congenital anomalies condition and mental retardation (MCA/MR) syndrome with autosomic recessive inheritance.- - - - - - - - - - ranking = 1keywords = bone (Clic here for more details about this article) |
6/86. 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 = 1keywords = bone (Clic here for more details about this article) |
7/86. Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin-releasing hormone.The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH action. Because of the anatomical inaccessibility of the hypophyseal portal circulation, direct measurement of GnRH levels in human subjects is not possible. Previous investigators have attempted to unravel this problem through the use of GnRH stimulation tests and the limitations of this approach may explain the differing results obtained. We used the more physiological approach of treating a male GHS patient for four weeks with GnRH, 7-10 microg/pulse, delivered subcutaneously at 90 minute frequency via a portable minipump. This therapy failed to induce any rise in plasma gonadotrophin and testosterone concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins maintained physiological plasma testosterone concentrations and induced testicular enlargement with induction of spermatogenesis. The data indicate that the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two clinical observations are consistent with progressive involution of gonadotrophic function, rather than a congenital gonadotrophin deficiency. First, the patient's development was arrested at early mid-puberty at the time of original presentation and, second, effective spermatogenesis was induced extremely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary dysfunction might thus have been in evolution since late childhood.- - - - - - - - - - ranking = 194.63200262867keywords = endocrine (Clic here for more details about this article) |
8/86. Efficacy of total androgen blockade in metastatic prostatic carcinoma with transient hypogonadotropic hypogonadism: a case report.A patient affected by metastatic prostatic carcinoma and hypogonadotropic hypogonadism (HH) was treated with flutamide 750 mg/day plus an LH-RH analog. After confirmation of basal castration during treatment, he continued with antiandrogens alone. Following the normalization of gonadic function and subjective mild bone flare-up, the patient resumed the initial treatment and obtained a partial response. When flutamide was interrupted because of liver toxicity, the patient showed progressive disease in the bone, which was unresponsive to both flutamide resumption and salvage hormone therapy (bicalutamide). The patient is currently receiving chemotherapy with VP16 and estramustine phosphate and is showing both serologic (PSA) and symptomatic response. The interest of this case lies in the incidental detection of HH during therapy and in the responsiveness to treatment.- - - - - - - - - - ranking = 2keywords = bone (Clic here for more details about this article) |
9/86. IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies.We report three boys with adrenal hypoplasia congenita (AHC) and additional findings that represent a new syndrome, IMAGe: Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after birth with growth retardation and severe adrenal insufficiency. Each of the three patients had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all three and epiphyseal dysplasia in two. The patients had documented or suspected hypercalciuria and/or hypercalcemia, resulting in nephrocalcinosis in one and in prenatal liver and spleen calcifications in another. AHC presents most often either as an isolated abnormality, caused by mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome, caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes. All three patients with the IMAGe association had normal creatine kinase levels and no evidence of glycerol kinase deficiency. sequence analysis of dna from these patients revealed no mutation in the DAX1- or steroidogenic factor-1-coding sequences, nor was a deletion of DAX1 detected. Identification of the molecular basis of the IMAGe association will give new insight into the pathogenesis of this syndromic relationship involving bone, adrenal cortical, and pituitary development.- - - - - - - - - - ranking = 1keywords = bone (Clic here for more details about this article) |
10/86. Hormonal side effects in women: typical versus atypical antipsychotic treatment.Neuroleptic-induced hyperprolactinemia can cause menstrual disorders, impaired fertility, galactorrhea, and sexual dysfunction, as well as hypoestrogenism secondary to disruption of the hypothalamic-pituitary-ovarian axis. The development of the prolactin-sparing atypical antipsychotic drugs offers prevention and resolution of these adverse reactions. Thus far, this property of the new medications has received insufficient clinical attention. The authors use case vignettes to discuss assessment and management of clinical situations that arise as a result of antipsychotic-induced endocrine changes.- - - - - - - - - - ranking = 194.63200262867keywords = endocrine (Clic here for more details about this article) |
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