Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

OBJECTIVE: Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1. DESIGN AND PATIENTS: This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012. RESULTS: Hypercalcaemia was diagnosed at a median age of 53 years [IQR: 38-61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63-2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1-7.1], and the median 24-hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9-4.0]. Osteoporosis (dual X-ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established. CONCLUSION: This large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.

Characterization of the EM66 Biomarker in the Pituitary and Plasma of Healthy Subjects With Different Gonadotroph Status and Patients With Gonadotroph Tumor.

Granins and their derived-peptides are useful markers of secretion from normal and tumoral neuroendocrine cells. The need to identify new diagnostic markers for neuroendocrine tumors, including pituitary tumors prompted us to determine plasma levels of the secretogranin II-derived peptide EM66 in healthy volunteers with different gonadotroph status and to evaluate its usefulness as a circulating marker for the diagnosis of gonadotroph tumor. Using a radioimmunoassay, we determined plasma EM66 concentrations in healthy men and women volunteers in different physiological conditions in relation with the gonadotroph function. Our results revealed that in men, in women with or without contraception, in pregnant or post-menopausal women, plasma EM66 concentrations are not significantly different, and did not show any correlation with gonadotropin levels. In addition, stimulation or inhibition tests of the gonadotroph axis had no effect on EM66 levels, whatever the group of healthy volunteers investigated while gonadotropin levels showed the expected variations. Immunohistochemical experiments and HPLC analysis showed the occurrence of EM66 in pituitary gonadotroph, lactotroph and corticotroph tumors but not in somatotroph tumor. In patients with gonadotroph or lactotroph tumor, plasma EM66 levels were 1.48 (0.82-4.38) ng/ml and 2.49 (1.19-3.54) ng/ml, respectively. While median value of EM66 was significantly lower in patients with gonadotroph tumor compared to healthy volunteers [2.59 (0.62-4.95) ng/ml], plasma EM66 concentrations were in the same range as normal values and did not show any correlation with gonadotropin levels. These results show that plasma EM66 levels are independent of the activity of the gonadotroph axis in healthy volunteers and, while EM66 levels are reduced in gonadotroph tumors, plasma EM66 does not provide a helpful marker for the diagnosis of these tumors.

Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences.

CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.

Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey.

CONTEXT: Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men. OBJECTIVE: The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility. METHODS: From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men. RESULTS: Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. CONCLUSION: We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

Comparison of the effectiveness of four bariatric surgery procedures in obese patients with type 2 diabetes: a retrospective study.

AIM: The aim of the present retrospective study was to evaluate the efficacy of four bariatric surgical procedures to induce diabetes remission and lower cardiovascular risk factors in diabetic obese patients. Moreover, the influence of surgery on weight evolution in the diabetic population was compared with that observed in a nondiabetic matched population. METHODS: Among 970 patients who were operated on in our center since 2001, 81 patients were identified as type 2 diabetes. Laparoscopic adjustable gastric banding (GB), intervention type Mason (MA), gastric bypass (RYGB), and sleeve gastrectomy (SG) were performed, respectively, in 25%, 17%, 28%, and 30% of this diabetic population. RESULTS: The resolution rate of diabetes one year after surgery was significantly higher after SG than GB (62.5% versus 20%, P < 0.01), but not significantly different between SG and RYGB. In terms of LDL-cholesterol reduction, RYGB was equivalent to SG and superior to CGMA or GB. Considering the other cardiovascular risk factors, there was no significant difference according to surgical procedures. The weight loss was not statistically different between diabetic and nondiabetic matched patients regardless of the surgical procedures used. CONCLUSION: Our data confirm that the efficacy of surgery to treat diabetes is variable among the diverse procedures and SG might be an interesting option in this context.

[Plasma testosterone, obesity, metabolic syndrome and diabetes]. / Testostérone plasmatique, obésité, syndrome métabolique et diabète.

The frequency of diabetes and/or metabolic syndrome rises concurrently with that of body mass index (BMI). In adult men, plasma testosterone level changes evolve inversely to that of BMI. Plasma total testosterone, sex hormone-binding globulin (SHBG) and free testosterone are significantly lower in adult men with a clinical and biological pattern of metabolic syndrome (MetS) than in those without such a pattern. After adjustment for confounding factors, diabetes type 2 (DT2) remains associated with a significant decrease of plasma testosterone level. The androgenic blockade, used as a treatment for disseminated prostate cancer, induces a metabolic pattern similar to MetS. In men older than 65 years, a decrease of plasma testosterone level is associated with an increased risk of stroke or of death linked to a cardiovascular event. After exclusion of contraindications, the substitution with androgens of a demonstrated hypogonadism in a obese patient, notably when obesity is associated with a pattern of MetS and/or a DT2, could have some metabolic and cardiovascular advantages.

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

BACKGROUND: Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. METHODS: We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. RESULTS: The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. CONCLUSIONS: Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism.

CONTEXT: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant syndrome with incomplete penetrance that can associate in a single patient parathyroid adenoma or carcinoma, fibro-osseous jaw tumor, cystic kidney lesion, and uterine tumor. Germline mutations of the HRPT2 gene (CDC73) coding for parafibromin are identified in approximately 50%-75% of HPT-JT cases and in approximately 14% of familial isolated hyperparathyroidism. A whole deletion of this gene has recently been reported in 1 sporadic case and in a family presenting with HPT-JT. OBJECTIVE: The objective of the study was to report molecular abnormalities of the HRPT2 gene in patients with primary hyperparathyroidism in a French National cohort from the Groupe d'Étude des Tumeurs Endocrines. METHODS: Patients' genomic DNA was screened by PCR-based sequencing for point mutations affecting HRPT2 and real-time quantitative PCR analysis for gross deletions. RESULTS: We report 20 index patients with a germinal HRPT2 abnormality. Median age at diagnosis of primary hyperparathyroidism was 23 years (range 14-65 years). Median serum total calcium level at diagnosis was 3.19 mmol/L (range 2.8-4.3 mmol/L). Thirteen different mutations were identified by routine sequencing, including 7 mutations never reported. Seven patients (35%) carried a gross deletion of this gene (3 complete and 4 partial deletions). No genotype-phenotype correlation could be identified. A gross deletion of the HRPT2 gene was identified in 7% of patients for whom a routine screening by direct sequencing came up as negative. CONCLUSION: Gross deletion analysis of the HRPT2 gene is indicated for all patients negative for mutation, presenting with HPT-JT or familial isolated hyperparathyroidism, parathyroid carcinoma, or in patients with apparently sporadic parathyroid adenoma diagnosed at a young age, having a severe hypercalcemia.

Comparative validation of the growth hormone-releasing hormone and arginine test for the diagnosis of adult growth hormone deficiency using a growth hormone assay conforming to recent international recommendations.

CONTEXT: The GHRH plus arginine (GHRH+Arg) test is a promising alternative to the insulin tolerance test (ITT) for diagnosis of adult GH deficiency (AGHD). OBJECTIVES: The objectives of the study were to validate the GHRH+Arg test for diagnosis of AGHD, using the ITT as comparator and a GH assay calibrated according to recent international recommendations, and to study the repeatability and tolerance of both tests. DESIGN: This was a multicenter, randomized, open-label, phase III study. SETTING: The study was conducted at 10 French university hospitals. SUBJECTS: Sixty-nine subjects (38 and 15 with high and low probability of GH deficiency, respectively, and 16 healthy controls) were randomized: 35 to the GHRH+Arg-GHRH+Arg-ITT test sequence and 34 to the ITT-ITT-GHRH+Arg test sequence. INTERVENTIONS: Each subject underwent three tests of GH secretion separated by 24 h or more. MAIN OUTCOME MEASURES: The primary variable used for response assessments was serum peak GH response. Test results were compared with the final AGHD diagnosis. RESULTS: Peak GH responses in the two tests were strongly correlated. A cutoff value of 7.89 microg/liter for GHRH+Arg corresponding to 3 microg/liter for ITT was calculated. The cutoff value leading to 95% specificity with the GHRH+Arg test was measured at about 3.67 microg/liter (sensitivity 79.0%). Intermethod agreement and repeatability were high. Both tests were well tolerated. A preference for the GHRH+Arg test was expressed by 74% of subjects. CONCLUSIONS: The GHRH+Arg test demonstrated good accuracy and repeatability, was at least as sensitive as the ITT, and was associated with better subject acceptability. The GHRH+Arg test represents a good alternative to the ITT for the diagnosis of AGHD.

ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma.

CONTEXT: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome. OBJECTIVE: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma. DESIGN AND SETTING: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories. INTERVENTION: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies. MAIN OUTCOME MEASURE: Detection of 17alpha-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes. RESULTS: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17alpha-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway. CONCLUSION: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.

Long-term results of stereotactic radiosurgery in secretory pituitary adenomas.

CONTEXT: To date, no study reported long-term follow-up results of gamma knife stereotactic radiosurgery (SR). OBJECTIVE: The aim of the study was to determine long-term efficacy and adverse effects of SR in secreting pituitary adenomas. DESIGN: We conducted a retrospective study of patients treated by SR in the center of Marseille, France, with a follow-up of at least 60 months. PATIENTS: A total of 76 patients were treated by SR for acromegaly (n = 43), Cushing's disease (CD; n = 18), or prolactinoma (n = 15) as a primary (n = 27) or adjunctive postsurgical treatment (n = 49). MAIN OUTCOME MEASURES: After withdrawal of antisecretory drugs, patients were considered in remission if they had mean GH levels below 2 ng/ml and normal IGF-I (acromegaly), normal 24-h urinary free cortisol, and cortisol less than 50 nmol/liter after low-dose dexamethasone test (CD) or two consecutive normal samplings of prolactin levels (prolactinoma). RESULTS: After a mean follow-up of 96 months, 44.7% of the patients were in remission. Mean time to remission was 42.6 months. Twelve patients presented late remission at least 48 months after SR. Two patients with CD presented late recurrence 72 and 96 months after SR. Forty percent of patients treated primarily with SR were in remission. Target volume and initial hormone levels were significant predictive factors of remission in univariate analysis. Radiation-induced hypopituitarism was observed in 23% patients; in half of them, hypopituitarism was observed after a mean time of 48 to 96 months. Twenty-four patients were followed for more than 120 months; rates of remission and hypopituitarism were similar to the whole cohort. CONCLUSIONS: SR is an effective and safe primary or adjunctive treatment in selected patients with secreting pituitary adenomas.

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors.

UNLABELLED: The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT(4)) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT(4) receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine- and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT(4) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR. RESULTS: Metoclopramide and the 5-HT(4) receptor agonist cisapride were found to activate catecholamine- and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine- and granin-derived peptide productions were inhibited by the 5-HT(4) receptor antagonist GR 113808. 5-HT(4) receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT(4) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine- and granin-derived peptide secretion. All 5-HT(4) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.

Impact level of dihydrotestosterone on the hypothalamic-pituitary-leydig cell axis in men.

Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied. Group I included 10 gonadotropin-releasing hormone (GnRH)-deficient men who were evaluated before and during a pulsatile infusion of GnRH alone for 2 weeks and then in association with DHT given transdermally at doses used in the treatment of gynaecomastia for further two weeks. Luteinizing hormone (LH) pulsatility was assessed at the end of each step of the study. Plasma LH levels were measured every 15 min. Plasma testosterone (T), DHT, oestradiol (E2), free alpha-subunit (FAS) of glycoproteic hormones and LH bioactivity were measured on pooled plasma samples. Group II included 12 healthy men in whom plasma T, DHT and E2 were measured before and then 24, 48 and 72 h after the injection of 5000 IU hCG alone or in combination with either DHT or the pure anti-androgen nilutamide. Two weeks separated each of the 3 hCG testing. In group I, except for bioactive/immunoreactive (B/I) LH ratio which was unchanged, GnRH treatment induced significant rises (p < 0.01) in all plasma hormone levels, LH pulse amplitude and frequency. During treatment with GnRH+DHT, plasma DHT levels increased up to 16.8 +/- 2.5 nm, while plasma hormone levels, B/I LH ratio, LH pulse amplitude and frequency were similar to those obtained with GnRH alone. In group II, the peak of hCG-induced T rise was not modified by either DHT or nilutamide. In contrast, DHT reduced by 50% (p < 0.01) the E2 peak in response to hCG. These data show that DHT exerts no direct action on the pituitary to retroregulate LH secretion and to modify either B/I LH ratio or FAS secretion. Its reducing effect on LH secretion is likely mediated at the hypothalamic level. DHT does not appear to have a physiological influence on Leydig cells steroidogenesis. Administered at therapeutic doses, DHT directly reduces testicular aromatase activity that combined with its antigonadotropic effect leads to the gain in the symptomatic treatment of gynaecomastia.

Evaluation of endocrine testing of Leydig cell function using extractive and recombinant human chorionic gonadotropin and different doses of recombinant human LH in normal men.

BACKGROUND: The functional testing of endocrine testis uses extractive human chorionic gonadotropin (ehCG). Recombinant human hCG (rhCG), avoiding any contamination, should replace ehCG. Moreover, a functional evaluation with recombinant human LH (rhLH) would be closer to physiology than a pharmacological testing with hCG. METHODS: The study was conducted in normal men. We first evaluated the dose-effect of ehCG on plasma testosterone and estradiol levels, before and after injection of either hCG or vehicle. Secondly, the responses to the optimal dose of ehCG were compared with those of rhCG. Thirdly, we investigated the dose-effect of rhLH, on steroid hormone secretion. LH, testosterone, and estradiol plasma levels were measured after the injection of either rhLH or placebo. RESULTS: ehCG induced dose-dependent increases in plasma estradiol and testosterone levels. They respectively peaked at 24 and 72 h after the injection. The most potent dose of ehCG (5000 IU) induced results similar to those observed with 250 microg (6500 IU) rhCG. By comparison with placebo, rhLH induced a significant and dose-dependent increase in plasma testosterone levels 4 h after the injection. Peak response of testosterone to rhLH and rhCG was significantly correlated. rhLH did not induce significant change in plasma estradiol level. CONCLUSIONS: In normal men, a single i.v. injection of 150 IU rhLH induces a 25% rise in plasma testosterone levels by comparison with placebo. At the moment, the dynamic evaluation using hCG remains the gold standard test to explore the Leydig cell function. The use of 250 microg rhCG avoiding any contamination should be recommended.

No greater incidence or worsening of cardiac valve regurgitation with somatostatin analog treatment of acromegaly.

CONTEXT: Excess GH and IGF-I in acromegaly are associated with reduced life expectancy due to cardiovascular complications. OBJECTIVE: The objective of the study was to investigate the prevalence, incidence, and severity of cardiac valve regurgitation before and after somatostatin-analog treatment in acromegaly. DESIGN: This was a prospective, observer-blinded, multicenter, 12-month study. SETTING: The study was conducted at 33 specialist centers. PATIENTS: The study population consisted of 225 adult patients with acromegaly without significant cardiac valve abnormalities or prior valve-replacement surgery, matched for age, sex, and center/country/study. INTERVENTIONS: Interventions included initiation/continuation of lanreotide (n = 107) or octreotide treatment (n = 118), tailored for optimal disease control. MAIN OUTCOME MEASURES: Relative risk of new/worsening regurgitation in any valve at 12 months compared with baseline, was measured. RESULTS: At baseline, almost 80% of patients had some degree of cardiac valve regurgitation, although none was severe. The risk of developing new/worsening regurgitation in any valve at 12 months was nonsignificant and similar for the cohorts [adjusted odds ratio 0.86; 95% confidence interval (CI) 0.41-1.82; P = 0.694; relative risk 1.04; 95% CI 0.67-1.60; risk difference 0.01; 95% CI -0.13 to 0.16]. For 54% of patients, the severity of regurgitation stayed the same during the study. At baseline, significant valve regurgitation occurred in 18% of patients (lanreotide cohort) and 13% (octreotide cohort) and at 12 months in 18% of each cohort. CONCLUSIONS: The incidence of valve regurgitation did not change over 12 months of treatment with somatostatin analogs, and most cases were physiologic or mild in severity. There was no significant difference between somatostatin analogs in the risk of developing new/worsening valve regurgitation or significant regurgitation after 1 yr.

Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly.

BACKGROUND: An essential criterion for control of acromegaly is normalization of IGF-I levels. Somatostatin analogues act to suppress IGF-I and GH levels. OBJECTIVE: To assess the efficacy and safety of 48 weeks titrated dosing of lanreotide Autogel. DESIGN: Open-label, multicentre, phase III, 48-week trial. METHODS: Patients with active acromegaly (IGF-I levels > 1.3 times upper limit of age-adjusted normal range) were recruited. Twelve injections of lanreotide Autogel were given at 28-day intervals: during the 16-week fixed-dose phase, patients received 90 mg; in the 32-week dose-titration phase, patients received 60, 90 or 120 mg according to GH and IGF-I levels. Intention-to-treat analysis was performed to determine the proportion of patients with normalized age-adjusted IGF-I levels at study end. Secondary evaluations included GH levels, clinical acromegaly signs and safety. RESULTS: Fifty-seven of 63 patients completed the study. Lanreotide Autogel resulted in normalized age-adjusted IGF-I levels in 27 patients (43%, 95% CI 31-55). Mean GH levels decreased from 6.2 to 1.5 microg/l at study end, with 53 of 62 patients (85%) having GH levels < or = 2.5 microg/l (95% CI 76.7-94.3) and 28 of 62 patients (45%) with levels < 1 microg/l (95% CI 32.8-57.6). Twenty-four (38%) had both normal IGF-I levels and GH levels < or = 2.5 microg/l. Acromegaly symptoms reduced significantly in most patients throughout the study. The most common adverse events were gastrointestinal, as expected for somatostatin analogues. CONCLUSIONS: Using IGF-I as primary end-point, 48 weeks lanreotide Autogel treatment, titrated for optimal hormonal control, controlled IGF-I and GH levels effectively, reduced acromegaly symptoms and was well tolerated.

Evidence for a role of vasopressin in the control of aldosterone secretion in primary aldosteronism: in vitro and in vivo studies.

CONTEXT: Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor. OBJECTIVE: The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism. DESIGN: The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion. SETTING: The study was conducted at a university hospital and research laboratory. PATIENTS: The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism. MAIN OUTCOME MEASURES: Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured. INTERVENTION: SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout. RESULTS: We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH. CONCLUSIONS: The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.

Effectiveness and tolerability of 3-year lanreotide Autogel treatment in patients with acromegaly.

OBJECTIVE: During short-term treatment, monthly subcutaneous injections of lanreotide Autogel are effective in controlling GH/IGF-1 hypersecretion and are well tolerated in patients with acromegaly. This study reports the effectiveness and the tolerability of lanreotide Autogel for at least 3 years in acromegalic patients. PATIENTS: Fourteen patients (nine females, five males) were treated with titrated doses of lanreotide Autogel. DESIGN: This clinical study was an extension of a previous trial. After three fixed-dose lanreotide Autogel injections, treatment was adjusted according to mean GH and IGF-I levels. After 3 years of treatment, patients were receiving 120 (n=7), 90 (n=2) and 60 mg (n=4) monthly injections of lanreotide Autogel. MEASUREMENTS: Acromegalic symptoms, GH and IGF-1 concentrations were analysed at the end of lanreotide microparticle treatment, and after 4, 8, 12, 24, 30 and 36 months of lanreotide Autogel therapy. Tolerance and side-effects were monitored throughout the 3-year study. RESULTS Hormonal control (GH

Expression profile of serotonin4 (5-HT4) receptors in adrenocortical aldosterone-producing adenomas.

OBJECTIVE: We aimed to investigate the expression profile of serotonin4 (5-HT4) receptors in adrenocortical aldosterone-producing adenoma (APA) tissues in comparison with normal adrenal cortex. DESIGN AND METHODS: Total 5-HT4 receptor mRNAs were quantified by real-time quantitative polymerase chain reaction (PCR) assay, and the mRNAs encoding the 5-HT4 receptor isoforms were characterized by reverse transcription (RT)-PCR in seven normal adrenal cortices and 11 APA tissues. The distribution of 5-HT4 receptor mRNAs was investigated by in situ hybridization in both normal adrenal and APA tissues, and the presence of 5-HT in APA tissues was studied by immunohistochemistry. RESULTS: Real-time PCR analysis revealed that 5-HT4 receptor mRNA expression was 4.7-47 times higher in APA tissues than in normal glands. In situ hybridization studies showed that 5-HT4 receptor mRNAs were expressed in both zona glomerulosa and zona fasciculata/reticularis of the normal cortex and in groups of APA steroidogenic cells disseminated in the tumor tissues. Characterization of 5-HT4 receptor splice variants by RT-PCR revealed different profiles of expression in APAs versus normal adrenals. Isoforms (a) and (b) were not expressed in any APA but were present in the majority of normal adrenocortical tissues. Conversely, isoform (d) was expressed in 5/11 APAs but only in 1/7 adrenals. Immunohistochemical studies revealed the presence of 5-HT-immunoreactivity in both mast cells and clusters of steroidogenic cells in APA tissues. CONCLUSION: Our results show overexpression and different splicing of the 5-HT4 receptor in APA tissues in comparison with normal adrenocortical tissue. They also demonstrate the presence of 5-HT in both mast cells and tumor steroidogenic cells, providing evidence for a possible autocrine/paracrine activation of aldosterone secretion within adenoma tissues.