Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12-month data from the OpT2mise randomized trial.

AIMS: To compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues. METHODS: After a 2-month dose-optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6-month continuation phase (CP). The primary endpoint was the between-group difference in change in mean HbA1c from baseline to the end of the RP. RESULTS: The mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (-1.1 ± 1.2% vs -0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI-pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia. CONCLUSIONS: Pump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes.

One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes.

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance.

PURPOSE: Preoperative localization of an insulinoma is recommended to improve the cure rate, but non-invasive procedures can fail to detect the tumour. The objective of the study was to assess the performance of a selective arterial calcium stimulation test in the preoperative localization of insulinomas that were not detected by conventional imaging procedures. METHODS: We conducted a monocenter retrospective case review of 13 patients who had endogenous hyperinsulinism and were treated between 1994 and 2013. Patients were selected on the basis of negative or doubtful non-invasive preoperative imaging. A selective arterial calcium stimulation test was performed by pancreatic and hepatic arteriography with selective intra-arterial calcium stimulation and hepatic venous sampling in order to obtain the plasma insulin measurement. We evaluated the efficacy of the test by comparing the results with an endoscopic ultrasound. RESULTS: Twelve of the 13 patients underwent surgery, and the presence of an insulinoma was proven in 11 patients by pathological analysis of the tumour. An endoscopic ultrasound was consistent with surgery in 71.4 % of cases, while selective arterial calcium stimulation was consistent with surgery in 90.9 % and allowed detection of an insulinoma in two additional patients with a negative endoscopic ultrasound. One false-negative and one false-positive arterial calcium test were observed. No adverse events were recorded except transient skin flush following calcium injection in one patient. CONCLUSION: The selective arterial calcium stimulation test is a sensitive diagnostic procedure for localizing insulinomas and may be considered when non-invasive radiological imaging does not allow the detection of an occult insulinoma.

Abnormal Sensitivity to Glucagon and Related Peptides in Primary Adrenal Cushing's Syndrome.

Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.

Early continuous glucose monitoring for predicting remission of type 2 diabetes 1 year after bariatric surgery.

BACKGROUND: Bariatric surgery in obese subjects can result in remission of type 2 diabetes (T2D) at a distant time post-surgery. The aim of our observational prospective single-centre study was to examine glycaemic patterns in adult T2D candidates for bariatric surgery using a continuous glucose monitoring (CGM) sensor for 14 days after surgery to search for indicators predictive of T2D remission 1 year later. METHODS: Patients underwent CGM preoperatively and for 14 days postoperatively. Thereafter, body weight and glycated haemoglobin (HbA1c) levels were monitored at 3, 6 and 12 months after surgery. RESULTS: A total of 31 patients (mean age 47±2 years) were analyzed. After surgery, mean interstitial glucose levels fell rapidly from 157±31mg/dL preoperatively to 109±35mg/dL postoperatively (P<0.001), reaching nadir levels from day 3 after surgery. Successful bariatric surgery (loss of excess weight ≥50%) was observed in 28 (90%) patients, and diabetes remission (HbA1c≤6% with no antidiabetic treatment) 1 year after surgery was noted in 21 (68%) patients. CGM for 14 days post-surgery allowed prediction of diabetes remission 1 year after surgery: time spent above range <14% and standard deviation (SD) of glucose levels <33mg/dL were both strong predictors of T2D remission. Indeed, the association of these two criteria predicted diabetes remission with a 100% positive predictive value, 81% sensitivity and 100% specificity and, when combined with the advanced Diabetes Remission (Ad-DiaRem) score, further increased predictive accuracy. CONCLUSION: The use of 14-day postoperative CGM recordings together with presurgical clinical scores can help to predict diabetes remission 1 year after bariatric surgery.

Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

Use of GLP-1 receptor agonists for type 2 diabetes treatment intensification after basal insulin failure.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are part of the armamentarium for the treatment of type 2 diabetes (T2D), although recent guidelines have mainly recommended their use on top of oral treatments when a single or combination of two or three oral hypoglycaemic agents has failed to lower HbA1c levels below the individualized target range. In such situations, the decision to use GLP-1RAs is mostly driven by their high level of efficacy, their effect on body weight balance and their safety considerations, such as low hypoglycaemic risk. According to the current guidelines, GLP-1RAs may also be used in T2D patients in addition to basal insulin, following specialist-care advice, in patients who are more severely obese or who may not have the capacity to handle the complexities of a multiple daily injection (MDI) insulin regimen. The present review looks at the scientific evaluations performed in this context as well as the clinical trials assessing the use of GLP-1RAs in combination with intensive insulin therapy as further step-up therapy.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Cost-effectiveness of continuous subcutaneous insulin infusion in people with type 2 diabetes in the Netherlands.

AIMS: Up to 30% of insulin-treated type 2 diabetes patients are unable to achieve HbA1c targets despite optimization of insulin multiple daily injections (MDI). For these patients the use of continuous subcutaneous insulin infusion (CSII) represents a useful but under-utilized alternative. The aim of the present analysis was to examine the cost-effectiveness of initiating CSII in type 2 diabetes patients failing to achieve good glycemic control on MDI in the Netherlands. METHODS: Long-term projections were made using the IMS CORE Diabetes Model. Clinical input data were sourced from the OpT2mise trial. The analysis was performed over a lifetime time horizon. The discount rates applied to future costs and clinical outcomes were 4% and 1.5% per annum, respectively. RESULTS: CSII was associated with improved quality-adjusted life expectancy compared with MDI (9.38 quality-adjusted life years [QALYs] vs 8.95 QALYs, respectively). The breakdown of costs indicated that ∼50% of costs were attributable to diabetes-related complications. Higher acquisition costs of CSII vs MDI were partially offset by the reduction in complications. The ICER was estimated at EUR 62,895 per QALY gained and EUR 60,474 per QALY gained when indirect costs were included. CONCLUSIONS: In the Netherlands, CSII represents a cost-effective option in patients with type 2 diabetes who continue to have poorly-controlled HbA1c despite optimization of MDI. Since the ICER falls below the willingness-to-pay threshold of EUR 80,000 per QALY gained, CSII is likely to represent good-value for money in the treatment of poorly-controlled T2D patients compared with MDI.

Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency.

CONTEXT: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic. OBJECTIVE: This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI. DESIGN AND SETTING: This was a case report and cohort study replicate conducted in academic medical centers. PATIENTS AND METHODS: A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients. RESULTS: We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans. CONCLUSION: Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

Liver transplant combined with heart transplant in severe heterozygous hypercholesterolemia: report of the first case and review of the literature.

Familial hypercholesterolemia (FH) is a dominant inherited disease of low-density lipoprotein (LDL) metabolism caused by mutations of LDL receptors mainly located in the liver. This metabolic disorder is responsible for severe cardiovascular disease, from coronary lesions to chronic heart failure (CHF). Liver transplantation in homozygous FH provides the missing functional LDL receptors and thus partially restores LDL receptor activity to more than 50% of normal. Combined heart and liver transplantation was successfully performed in a homozygous FH patient with end-stage heart failure. Herein we report our experience with a heterozygous male patient with terminal CHF, and review data from the literature on short- and long-term results of such procedures.

[Evaluation of diabetic retinopathy screening using non-mydriatic fundus camera performed by physicians' assistants in the endocrinology service]. / Évaluation du dépistage de la rétinopathie diabétique par rétinographe non mydriatique effectué par des aides-soignant(e)s d'un service d'endocrinologie.

INTRODUCTION: Since 2010, the High Authority for health (HAS) recommends the use of non-mydriatic fundus camera for diabetic retinopathy screening. The purpose of this study is to evaluate the results of screening for diabetic retinopathy using the non-mydriatic retinal camera by a physician's assistant in the endocrinology service. MATERIALS AND METHODS: This is a retrospective study of all diabetic patients hospitalized in the endocrinology department between May 2013 and November 2013. For each endocrinology patient requiring screening, a previously trained physician's assistant performed fundus photos. The ophthalmologist then provided a written interpretation of the photos on a consultant's sheet. RESULTS: Of the 120 patients screened, 40 (33.3%) patients had uninterpretable photos. Among the 80 interpretable photos, 64 (53.4%) patients had no diabetic retinopathy, and 16 (13.3%) had diabetic retinopathy. No patient had diabetic maculopathy. DISCUSSION: Specific quality criteria were established by the HAS for screening for diabetic retinopathy using the non-mydriatic retinal camera in order to ensure sufficient sensitivity and specificity. In our study, the two quality criteria were not achieved: the rates of uninterpretable photos and the total number of photos analyzed in a given period. CONCLUSION: In our center, we discontinued this method of diabetic retinopathy screening due to the high rate of uninterpretable photos. Due to the logistic impossibility of the ophthalmologists taking all the fundus photos, we proposed that the ophthalmic nurses take the photos. They are better trained in the use of the equipment, and can confer directly with an ophthalmologist in questionable cases and to obtain pupil dilation as necessary.

Rising plasma levels of 19-nortestosterone throughout pregnancy: determination by radioimmunoassay and validation by gas chromatography-mass spectrometry.

A highly sensitive and specific radioimmunoassay was developed to measure 19-nortestosterone (NT), which allowed us to demonstrate this steroid in the plasma of pregnant women. Plasma NT was detectable throughout gestation, reaching values of 12 to 60 pg/ml in the 3rd trimester. These results were validated by gas chromatography-mass spectrometry. No NT was detectable in the plasma of 12 normal men and 12 nonpregnant women in the mid follicular phase of their cycle (detection limit 4 pg/ml). Our results are compatible with current concepts concerning the possible involvement of 19-norsteroids in an accessory biosynthetic pathway for estrogen in the placenta.

Urinary nandrolone metabolites of endogenous origin in man: a confirmation by output regulation under human chorionic gonadotropin stimulation.

19-Nortestosterone (nandrolone) is an anabolic steroid compound widely used as a doping agent by athletes. The analysis of its urinary metabolites, 19-norandrosterone (NA) and 19-noretiocholanolone (NE) glucuronides, allows the detection of surreptitious administration of nandrolone in sport. A threshold concentration at 2 microgram/L urinary nandrolone metabolites is advocated by the International Olympic Committee for the detection of doping, but some controversy concerning the validity of this threshold arose from the demonstration of endogenous production of nandrolone in mammals, including humans. The regulation of human nandrolone production and its contribution in vivo to the process of aromatization remain unknown. In the present study 10 healthy men were successively submitted to insulinic stress and gonadal stimulation by hCG administration. Urinary NA and NE concentrations were quantified by gas chromatography-mass spectrometry. NA was detected in basal urine samples from all subjects, with a mean urinary excretion rate (UER) of 3.17 +/- 0.35 ng/h, whereas NE was detected in 4 of 10 (UER range, 0.8-4.7 ng/h). Insulinic hypoglycemia did not significantly modify mean NA UER despite random intraindividual variations between timed urine collections. After hCG administration, NA UER increased by 250% (P < 0.01) and estradiol (E(2)) UER by 260% (P < 0.001). The maximum NA concentration obtained after stimulation was 0.43 microgram/L. NA UER, plasma E(2), and E(2)/T ratio peaked on day 1 after hCG administration, whereas plasma T peaked later on day 3. NA UER correlated with plasma E(2) (r = 0.61; P < 0.001) and E(2)/T (r = 0.51; P < 0.001), but not with plasma T. In conclusion, insulinic stress did not significantly alter nandrolone metabolism, whereas the effect of hCG was a stimulation of NA excretion in all subjects, which constitutes strong support for the endogenous origin of low basal NA excretion. The comparative kinetics of NA UER, plasma E(2), and E(2)/T ratio suggest a contribution of the aromatase process to nandrolone biosynthesis in man.

Testicular steroidogenesis in adult men with human chorionic gonadotropin-producing tumors.

There are few critical studies on plasma testosterone (T) and 17 beta-estradiol (E2) levels in men with hCG-producing tumors, and the results are contradictory. Plasma E2 levels are most often elevated, whereas plasma T values are high or in the normal range. We studied the plasma levels of such steroids and of delta 4 and delta 5 T precursors in adult men with intact hCG-producing tumors to evaluate the relationship between hCG and steroid hormone levels or steroidogenic enzyme activities. Ten adult men with hCG-producing tumors and 25 normal adult men were investigated. Seven men with testicular tumors were studied before and after hemicastration. The 2 patients with extratesticular tumors were investigated before and during chemotherapy. The remaining patient was studied every 2 months for 1 yr during the spontaneous course of the disease. Plasma progesterone (P), 17 alpha-hydroxyprogesterone (17-OHP), androstenedione (A), 17-hydroxy-delta 5-pregnenolone (17-OH delta 5-P), dehydroepiandrosterone (DHEA), T, E2, and hCG were measured, and ratios of steroid levels were also calculated. In patients with increased hCG values (i.e. > 5 IU/L), the mean plasma P, 17-OHP, A, 17-OH delta 5-P, DHEA, T, and E2 levels were higher (P < 0.01 at least) than those in patients whose hCG values were normalized or in controls. The patterns of these steroids were very different according to plasma hCG levels. Indeed, for hCG levels between more than 5 and 3.5 x 10(3) IU/L, positive correlations (P < 0.05 at least) were found between hCG levels and delta 4 T precursor, delta 5 T precursor, T, or E2 values. Conversely, for hCG values greater than 3.5 x 10(3) IU/L, hCG levels were negatively correlated (P < 0.05 at least) to all steroid values. Furthermore, in patients with increased hCG levels, the mean plasma P to 17-OHP ratio, 17-OHP to A ratio, A to T ratio, 17-OHP to T ratio, and 17-OH delta 5-P to DHEA ratio were similar to those in patients with normalized hCG values or in controls. In contrast, in patients with increased hCG levels, the mean plasma T to E2 ratio value was lower (P < 0.001) than that in patients with normalized hCG levels or in controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Food-dependent Cushing's syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients.

In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.