Clinical case seminar - Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse

Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: New evidence for imprinting of the Gsα gene

Heterozygous inactivating mutations in the Gs\u3b1 gene cause Albright's hereditary osteodystrophy. Consistent with the observation that only maternally inherited mutations lead to resistance to hormone action [pseudohypoparathyroidism type Ia (PHP Ia)], recent studies provided evidence for a predominant maternal origin of Gs\u3b1 transcripts in endocrine organs, such as thyroid, gonad, and pituitary. The aim of this study was to investigate the presence of pituitary resistance to hypothalamic hormones acting via Gs\u3b1-coupled receptors in patients with PHP Ia. Six of nine patients showed an impaired GH responsiveness to GHRH plus arginine, consistent with a complete GH deficiency (GH peak from 2.6-8.6 \u3bcg/liter, normal > 16.5), and partial (GH peak 13.9 and 13.6 \u3bcg/liter) and normal responses were found in two and one patient, respectively. Accordingly, IGF-I levels were below and in the low-normal range in seven and two patients. All patients had a normal cortisol response to 1 \u3bcg ACTH test, suggesting a normal corticotroph function that was confirmed by a normal ACTH and cortisol response to CRH test in three patients. In conclusion, we report that in addition to PTH and TSH resistance, patients with PHP Ia display variable degrees of GHRH resistance, consistent with Gs\u3b1 imprinting in human pituitary

Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly

OBJECTIVE: Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF-I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP-3 and acid-labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking. DESIGN: Retrospective study. PATIENTS AND MEASUREMENTS: Sixty-seven acromegalic patients (20 males and 47 females, aged 40 \ub1 6 years) who underwent postoperative RT (in fractionated doses for a total of 40-75 Gy) were followed-up for 11 \ub1 6 years (range: 1-26 years, median: 10 years). Serum GH and IGF-I levels off medical therapy were measured in all patients; ALS and IGFBP-3 were measured in 11 patients with normalization of IGF-I concentrations. Computed tomography or nuclear magnetic resonance imaging periodically assessed possible development of pituitary deficiency along with imaging of the hypothalamic-pituitary region. RESULTS: Forty-one out of 67 patients (58%) achieved GH levels < 2.5 \u3bcg/l by 1-15 years after RT (mean 8 \ub1 6) and 37/67 patients (55%) had normal or low IGF-I levels 1-26 years after RT (mean: 12 \ub1 6), a normalization of both parameters being seen in 37 patients. GH < 2.5 \u3bcg/l and normal IGF-I levels were achieved in 17/26 (65%) patients followed-up for at least 15 years. ALS and IGFBP-3 concentrations paralleled IGF-I levels in all patients studied. With respect to secondary pituitary insufficiency, acquired ACTH deficiency was found in 25 patients, TSH deficiency in 20, gonadotropin deficiency in 23 and GH deficiency in seven. In total, two cases of meningioma and one pineal tumour, possibly related to RT, were seen 9-22 years after RT. CONCLUSIONS: RT is an effective, although slow-acting, therapeutic tool for acromegaly, with 'safe' GH levels and normal IGF-I concentrations being achieved in 65% of patients after 15 years. IGF-I levels normalize more slowly than GH levels. Radiotherapy is able to normalize the concentration of all three components of the circulating 150 kDa complex. Checks for loss of pituitary function and appearance of second brain tumours must be carried out life-long

Impact of resistance to thyroid hormone on thecardiovascular system in adults.

Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 +/- 12 yr, range 21-45 yr) and 16 controls (nine males; aged 33 +/- 5 yr, range 24-42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded.Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patient

Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels

Ghrelin, the recently identified endogenous ligand of the GH secretagogue receptor, is a gut-brain peptide with endocrine, orexigenic, and gastrointestinal effects. In rodents it increases circulating gastrin and insulin levels, whereas in man it appears to decrease insulin secretion despite a rise in blood glucose levels. The aim of the present study was to evaluate the effects of ghrelin administration on total circulating somatostatin (SS), pancreatic polypeptide (PP), and gastrin levels compared with those elicited on insulin, glucose, and GH. Eight healthy volunteers of normal weight (four women and four men) were injected with 3.3 \u3bcg/kg ghrelin or saline after an overnight fast on 2 different days. Blood was taken every 15 min for 1 h and then every 30 min for 2 h. As expected, ghrelin injection elicited a prompt GH and glucose increase with a peak at 30 min and an insulin decrease with a nadir at 60 min. Gastrin concentrations were not modified, whereas significant rises were observed in both SS (in a biphasic pattern with peaks at 15 and 120 min) and PP (which increased promptly with a peak at 15 min). A significant negative correlation was found between SS (first peak) and insulin changes (r = -0.86; P < 0.01). In conclusion, this study clearly demonstrates that ghrelin stimulates SS and PP release in man. Although the underlying mechanisms and biological significance of these pharmacological effects remain to be elucidated, a causal relationship between the SS increase and the insulin changes may be hypothesized. Finally, these findings strongly support ghrelin's postulated role in linking the endocrine control of energy balance and growth with the regulation of gastrointestinal functions

Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia : first Italian series

Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder

The third intracellular loop of the human somatostatin receptor 5 is crucial for arrestin binding and receptor internalization after somatostatin stimulation

Somatostatin (SS) is a widely distributed polypeptide that exerts inhibitory effects on hormone secretion and cell proliferation by interacting with five different receptors (SST1-SST5), that display important differences in tissue distribution, coupling to second messengers, affinity for SS and intracellular trafficking. SS analogues currently used in the treatment of acromegaly inhibit hormone secretion and cell proliferation by binding to SST2 and 5. Beta-arrestins have been implicated in regulating SST internalization but the structural domains mediating this effect are largely unknown. The aim of this study was to characterize the intracellular mechanisms responsible for internalization of human SST5 in the rat pituitary cell line GH3. To this purpose we evaluated by fluorescence microscopy SS28-mediated trafficking of receptor fused to DsRed and beta-arrestin2 fused to GFP. To identify the SST5 structural domains involved in these processes, we evaluated progressive C-terminal truncated proteins, SST5 mutants in which serine or threonine residues within the third cytoplasmic domain were mutated (S242A, T247A) and a naturally occurring R240W mutant in the third loop previously found in one acromegalic patient resistant to somatostatin analogues. We tested the ability of these mutants to associate with beta-arrestin2 and to internalize under agonist stimulation. The truncated mutants are comparable to the wild-type receptor with respect to beta-arrestin recruitment and internalization, whereas third cytoplasmic loop mutants show a significantly reduced internalization and arrestin translocation upon SS28 stimulation. Surprisingly, SST5 with both C-terminal truncation and third loop mutation exhibits normal internalization and beta-arrestin recruitment. Our results indicate SST5 third intracellular loop as an important mediator of beta-arrestin/receptor interaction and receptor internalization, while the role of the C-terminal tail would be to sterically prevent beta-arrestin/receptor interaction in basal conditions. Further elucidation of the molecular signals underlying SST5 intracellular trafficking will provide a better understanding of its function during prolonged agonist treatment

Gamma-Knife Radiosurgery in Acromegaly: A 4-Year Follow-Up Study

Stereotactic radiosurgery by gamma-knife (GK) is an attractive therapeutic option after failure of microsurgical removal in patients with pituitary adenoma. In these tumors or remnants of them, it aims to obtain the arrest of cell proliferation and hormone hypersecretion using a single precise high dose of ionizing radiation, sparing surrounding structures. The long-term efficacy and toxicity of GK in acromegaly are only partially known. Thirty acromegalic patients (14 women and 16 men) entered a prospective study of GK treatment. Most were surgical failures, whereas in 3 GK was the primary treatment. Imaging of the adenoma and target coordinates identification were obtained by high resolution magnetic resonance imaging. All patients were treated with multiple isocenters (mean, 8; range, 3\u201311). The 50% isodose was used in 27 patients (90%). The mean margin dose was 20 Gy (range, 15\u201335), and the dose to the visual pathways was always less than 8 Gy. After a median follow-up of 46 months (range, 9\u201396), IGF-I fell from 805 \u3bcg/liter (median; interquartile range, 640\u2013994) to 460 \u3bcg/liter (interquartile range, 217\u2013654; P = 0.0002), and normal age-matched IGF-I levels were reached in 7 patients (23%). Mean GH levels decreased from 10 \u3bcg/liter (interquartile range, 6.4\u201315) to 2.9 \u3bcg/liter (interquartile range, 2\u20135.3; P < 0.0001), reaching levels below 2.5 \u3bcg/liter in 11 (37%). The rate of persistently pathological hormonal levels was still 70% at 5 yr by Kaplan-Meier analysis. The median volume was 1.43 ml (range, 0.20\u20133.7). Tumor shrinkage (at least 25% of basal volume) occurred after 24 months (range, 12\u201336) in 11 of 19 patients (58% of assessable patients). The rate of shrinkage was 79% at 4 yr. In no case was further growth observed. Only 1 patient complained of side-effects (severe headache and nausea immediately after the procedure, with full recovery in a few days with steroid therapy). Anterior pituitary failures were observed in 2 patients, who already had partial hypopituitarism, after 2 and 6 yr, respectively. No patient developed visual deficits. GK is a valid adjunctive tool in the management of acromegaly that controls GH/IGF-I hypersecretion and tumor growth, with shrinkage of adenoma and no recurrence of the disease in the considered observation period and with low acute and chronic toxicit