Calcium/phosphate ratio: an additional tool for the clinical management of asymptomatic primary hyperparathyroidism?

PURPOSE: Serum calcium/phosphate ratio (Ca/P) has been recently proposed as an additional tool to identify primary hyperparathyroidism (PHPT), especially in patients with subclinical presentation, with a proposed cut-off of 3.3 when both values are expressed in mg/dL. No data are available on the relationship between Ca/P and the clinical presentation of PHPT. We thus evaluated this relationship in a large, single-center, unselected series. METHODS: 515 consecutive PHPT patients (mean age 65 ± 13.15 years, 77.1% females) were retrospectively evaluated at diagnosis. RESULTS: Mean Ca/P was 4.54 ± 1.5 (range 2.36-13.9), being higher than 3.3 in 88.5% of patients. Ca/P was significantly higher in (1) males, (2) symptomatic PHPT, (3) patients with 25-hydroxy vitamin D levels lower than 20 µg/L, (4) patients with osteitis fibrosa cystica, (5) patients with T score < - 2.5 at the radial site. In a multivariate regression analysis, Ca/P resulted significantly associated with PTH levels. After the exclusion of 57 patients with asymptomatic PHPT (aPHPT) patients and serum Ca higher than 1 mg/dL above the upper limit of normal range, no differences were found in Ca/P between aPHPT meeting or not surgical criteria. CONCLUSIONS: In PHPT Ca/P ratio is associated with increased biochemical and clinical severity of disease and represents a direct indicator of clinical bone damage. However, it does not seem an additional tool to identify aPHPT patients reaching surgical indication.

Functional hypothalamic and drug-induced amenorrhea: an overview.

BACKGROUND: Functional hypothalamic amenorrhea (FHA) is a form of chronic anovulation not due to identifiable organic causes and with adverse health consequences. The identification of women with this disorder or the precocious identification of women at risk is based on the knowledge of lifestyle risk factors or behaviors such as stress, weight loss, and excessive physical exercise that are known to negatively impact gonadal axis activity. METHODS: In this overview, we described the most common forms of FHA, in particular stress-induced amenorrhea and overtraining-induced amenorrhea. In addition, although its mechanisms can differ from those involved in FHA, we reviewed the available literature on drug-induced amenorrhea, highlighting the clear connection between this condition and psychoactive drugs such as antipsychotics, antidepressants and anti-epilectics thus raising concern about the role that the abuse of substances such as opioids or alcohol can possibly have on the growing unexplained infertility of the female population.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology's Consensus Statement: prevalence and clinical features.

BACKGROUND: Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients. DESIGN AND PATIENTS: We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria. RESULTS: Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar. CONCLUSIONS: Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.

Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis.

Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

Prevalence and characteristics of metabolic syndrome in primary hyperparathyroidism.

AIMS: Primary hyperparathyroidism (pHPT) is characterized by an increased frequency of glucose tolerance abnormalities associated with insulin resistance. Few studies evaluated the prevalence of metabolic syndrome (MetS) in pHPT and whether there are differences between asymptomatic pHPT patients and symptomatic ones. Thus, we sought to investigate the prevalence of MetS in pHPT patients in comparison to the prevalence of MetS in Italian population. SUBJECTS AND METHODS: We conducted a retrospective chart review of 294 pHPT patients, of these 154 [age (mean ± SD) 58.7 ± 13.3 yr, body mass index 25.6 ± 4.8 kg/m(2); serum calcium (11.3 ± 1.2 mg/dl) 2.8 ± 0.3 mmol/l; PTH 234.8 ± 224.3 ng/l] met the inclusion criteria. A modified National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) definition of the MetS was used. Prevalence of MetS was compared with that reported for the Italian population (Progetto Cuore Study). RESULTS: The prevalence of the MetS (34/154, 22.1%) was similar to that reported in the general Italian population. Asymptomatic pHPT patients were older (62.1 ± 12.7 vs 56.4 ± 13.2 yr, p<0.008) and showed higher prevalence of MetS than symptomatic ones (30.2% vs 16.5%, p<0.045). Moreover the prevalence of nephrolitiasis or overt bone disease was not different between patients MetS+pHPT compared to MetS-pHPT, whereas femoral bone mineral density (BMD) was higher in MetS+pHPT (p<0.003). In the logistic regression model age and femoral BMD were independent predictors of MetS. CONCLUSIONS: The prevalence of MetS in pHPT is not increased in comparison to the general population, thus, its diagnosis is not an appropriate tool to identify the additional cardiovascular risk related to pHPT. Difference in age affects the increased prevalence of MetS in asymptomatic pHPT patients.

Interplay between serum osteocalcin and insulin sensitivity in primary hyperparathyroidism.

Osteocalcin (OC) has been proposed as a regulator of insulin sensitivity in both humans and other animals. Primary hyperparathyroidism (PHPT) is characterized by high OC levels and insulin resistance. The aim of this study was to evaluate whether in PHPT the link between OC levels and blood markers of insulin resistance was maintained. In a consecutive series of 219 adult PHPT patients, serum OC as well as fasting insulin and glucose levels were measured. Insulin sensitivity was estimated by homeostatic model assessment (HOMA2-S%). The same parameters were evaluated in a subgroup of 45 patients after parathyroidectomy (PTX). PHPT patients were characterized by markedly high OC levels. After subdividing them according to glucose tolerance, it was found that OC was similar in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), while diabetic subjects had lower serum OC than those with NGT (P < 0.02) or IGT (P < 0.04). OC was negatively associated with fasting glucose and positively associated with HOMA2-S%. OC independently predicted HOMA2-S% in a multivariate analysis. In the subgroup of surgically cured PHPT patients, OC levels significantly decreased after PTX, while HOMA2-S% did not change. Our findings indicate that in PHPT there is a positive relationship between OC and glucose metabolism, OC being one of the predictors of insulin sensitivity. However, data in surgically cured patients, showing OC normalization in spite of unchanged HOMA2-S%, suggest that OC does not likely play a major role in affecting insulin sensitivity in PHPT.

Insulin resistance is not coupled with defective insulin secretion in primary hyperparathyroidism.

AIMS: An increased frequency of both impaired glucose tolerance and Type 2 diabetes mellitus (DM) has been reported in primary hyperparathyroidism (pHPT), thus we sought to investigate insulin sensitivity and insulin secretion in a large series of pHPT patients. SUBJECTS AND METHODS: One hundred and twenty-two consecutive pHPT patients without known DM were investigated [age (mean +/- sd) 59.3 +/- 13.6 years, body mass index (BMI) 25.7 +/- 4.2 kg/m(2); serum calcium 2.8 +/- 0.25 mmol/l; PTH 203.2 +/- 145.4 ng/l]. Sixty-one control subjects were matched, according to the degree of glucose tolerance, in a 2 : 1 patient:control ratio. Fasting- and oral glucose tolerance test-derived estimates of insulin sensitivity and secretion were determined by means of the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) composite. RESULTS: Both the QUICKI and ISI composite were lower in pHPT patients than control subjects (P < 0.03 and P < 0.05, respectively) after adjusting for age, systolic blood pressure and BMI. Conversely, all insulin secretion estimates were significantly increased in pHPT patients than in control subjects (P < 0.04 and P < 0.03, respectively) and after adjusting for age, systolic blood pressure and BMI. Log serum calcium levels were negatively associated with the QUICKI and log ISI composite (R = -0.30, P = 0.001; R = -0.23, P = 0.020, respectively) in pHPT patients. Serum calcium levels significantly and independently contributed to impaired insulin sensitivity in multivariate analysis (QUICKI as dependent variable: beta = -0.31, P = 0.004, R(2) = 0.15; log ISI composite as dependent variable: beta = -0.29, P = 0.005, R(2) = 0.16). CONCLUSIONS: Our study confirms a reduction in both basal and stimulated insulin sensitivity in primary hyperparathyroidism, in spite of increased insulin secretion. Moreover, our data show for the first time a significant relationship between hypercalcaemia and insulin sensitivity in this condition.

B-type natriuretic peptide levels and insulin resistance in patients with severe ischemic myocardial dysfunction.

B-type natriuretic peptide (BNP) is an important clinical parameter of severity in congestive heart failure (CHF). Recent findings suggest a close relation between lipid and glucose metabolism and the natriuretic peptide axis, even if conflicting data exist on the relationship between natriuretic peptide levels and insulin resistance (IR). Thus, we sought to investigate potential relations between BNP level and IR in 134 patients with severe ischemic myocardial dysfunction [mean+/-SD: age =64.8+/-9.6 yr, male/female =104/30; body mass index (BMI) =25.5+/-4.05 kg/m2, 26.1% diabetics; ejection fraction (EF) = 30.2+/-7.7%]. In univariate analysis, an inverse relationship between BNP levels and EF% was observed (R=-0.43, p=0.0006). Moreover, we found an inverse association between BNP levels and BMI (R=-0.27, p=0.036), and also between BNP and homeostasis model assessment of insulin resistance (HOMA-IR) (R=-0.27, p=0.039). In multivariate analysis, EF% and HOMA-IR were significantly and independently associated with logarithmically transformed BNP levels (beta=-0.40, p=0.019 and beta=-0.26, p=0.042, respectively; R2=0.36). In conclusion, in patients with severe ischemic myocardial dysfunction EF and IR are independently associated with BNP levels explaining about 1/3 of the variability of this parameter. Multiple potential mechanisms may underlie this association, but it seems now clinically important to take into account also metabolic features when interpreting plasma natriuretic peptide concentrations obtained for diagnostic or prognostic purposes.

Surgical management of hepatocellular carcinoma within and beyond BCLC indications in a middle volume center.

AIM OF THE STUDY: Current criteria for hepatic resection in patients with hepatocellular carcinoma (HCC) according to Barcellona Clinic Liver Cancer (BCLC) classification is debated. Actually, patients with multinodular or large HCC>5cm are excluded from surgical treatment following the algorithm, but several studies from referral centers showed that such patients may benefit from surgical resection in the clinical practice. The aim of this study was to compare short- and long-term outcomes after liver resection for HCC in stage 0/A or B in a middle volume center. PATIENTS AND METHODS: Patients were grouped according to BCLC classification. Postoperative mortality, morbidity, overall and disease-free survival, univariate analysis of prognostic factors on survival was analyzed. RESULTS: Among 66 surgical procedures in 64 patients included in the study, 41 were BCLC stage 0/A (62.1%) and 25 BCLC stage B (37.9%). The overall 30- and the 90-days mortality rates were 1.5% and 3%. Patients in BCLC stage B had higher transfusion rate (P=0.04) but similar morbidity and mortality compared to patients in BCLC stage 0/A. After a median follow-up of 35 months (range: 14-147), the overall survival at 1, 3 and 5 years resulted 95%, 61.1%, 46.2% for stage 0-A and 83.3%, 50%, 41.2% for stage B (P=0.73). Univariate analysis identified poorly differentiated tumors (P=0.02) and positive margin (P=0.02) as negative prognostic factors on survival. CONCLUSIONS: Surgical treatment of HCC in BCLC stage B offers similar results than the ones in BCLC stage 0/A and consequently should not be considered contraindicated for such patients.

Ghrelin and other gastrointestinal peptides involved in the control of food intake.

The increasing prevalence of obesity has triggered intense research on its pharmacotherapy. Besides central neuroendocrine pathways, many peripheral endocrino-metabolic signals have been investigated, but only few are probably of some utility in weight loss. This review reports about ghrelin and other gastrointestinal peptides involved in hunger and satiety.

Systematic review and meta-analysis of frailty as a predictor of morbidity and mortality after major abdominal surgery.

BACKGROUND: Frailty is associated with poor prognosis, but the multitude of definitions and scales of assessment makes the impact on outcomes difficult to assess. The aim of this study was to quantify the effect of frailty on postoperative morbidity and mortality, and long-term mortality after major abdominal surgery, and to evaluate the performance of different frailty metrics. METHODS: An extended literature search was performed to retrieve all original articles investigating whether frailty could affect outcomes after elective major abdominal surgery in adult populations. All possible definitions of frailty were considered. A random-effects meta-analysis was carried out for all outcomes of interest. For postoperative morbidity and mortality, overall effect sizes were estimated as odds ratios (OR), whereas the hazard ratio (HR) was calculated for long-term mortality. The potential effect of the number of domains of the frailty indices was explored through meta-regression at moderator analysis. RESULTS: A total of 35 studies with 1 153 684 patients were analysed. Frailty was associated with a significantly increased risk of postoperative major morbidity (OR 2·56, 95 per cent c.i. 2·08 to 3·16), short-term mortality (OR 5·77, 4·41 to 7·55) and long-term mortality (HR 2·71, 1·63 to 4·49). All domains were significantly associated with the occurrence of postoperative major morbidity, with ORs ranging from 1·09 (1·00 to 1·18) for co-morbidity to 2·52 (1·32 to 4·80) for sarcopenia. No moderator effect was observed according to the number of frailty components. CONCLUSION: Regardless of the definition and combination of domains, frailty was significantly associated with an increased risk of postoperative morbidity and mortality after major abdominal surgery.

The prognostic impact of para-aortic lymph node metastasis in pancreatic cancer: A systematic review and meta-analysis.

PURPOSE: To evaluate by a meta-analytic approach the long-term prognostic impact of para-aortic lymph node (PALN) involvement in resected ductal adenocarcinoma of the pancreas. METHODS: MEDLINE, Embase, PubMed and the Cochrane Library were searched from January 1990 to June 2015. Trials reporting Kaplan-Meier curves and comparing overall long-term survival of negative and metastatic PALN in patients who underwent resection for pancreatic cancer were included. Lymph nodes were classified according to the Japan Pancreatic Society rules and identified using hematoxylin and eosin staining. Hazard ratios (HRs) and 95%CI were estimated for each trial and pooled in a meta-analysis. RESULTS: Thirteen eligible studies including 2141 patients (364 positive PALN; 1777 negative PALN) were identified. Most of the studies were retrospective. Heterogeneity among trials was high (I(2) = 98.7%; p < .001). PALN metastasis was associated with increased mortality when compared with patients with negative PALN regardless regional nodal status [HR 1.85, 95%CI 1.48-2.31; p < .001]. Median survival was significantly decreased in patients with positive PALN (WMD = -4.92 months 95%CI -6.40; -3.43; p < .001). Moreover, metastatic PALN affected mortality also when regional lymph nodes were positive [HR 1.67, 95%CI 1.34-2.08; p < .001]. No publication bias was detected. CONCLUSIONS: PALN metastasis appears to correlate with poor prognosis in patients with pancreatic adenocarcinoma. The assessment of PALN status may be considered for a more accurate staging of the disease and appropriated subgroup survival reporting. However, the definitive avoidance of the resection in case of intraoperative metastatic PALN needs further investigation.

Hormonal and metabolic responses to acute ghrelin administration in patients with bulimia nervosa.

Ghrelin is generally influenced by energy balance status and is inversely associated with body mass index (BMI), being reduced in simple obesity, notable exception being Prader Willi syndrome, and elevated in several conditions of undernutrition, including anorexia nervosa (AN). Interestingly, ghrelin levels have also been found elevated in patients with bulimia nervosa (BN) in spite of normal BMI. In humans, intravenous (iv) ghrelin administration induces endocrine (increase in GH, PRL, ACTH and cortisol) and metabolic (increase in glucose and decrease in insulin) effects as well as an increase in appetite and food intake. In AN, ghrelin administration surprisingly leads to a decreased GH response and absence of glycemic variations but normal PRL, ACTH and insulin response. This pattern would reflect a decrease in sensitivity to ghrelin or, alternatively, the metabolic status of AN. To further clarify the function of ghrelin in eating disorders, the endocrine and metabolic response to acute iv ghrelin (1.0 microg/kg) was studied in seven young women with purging BN (BW, BMI, mean+/-SEM: 20.3+/-0.5 kg/m2). Circulating total ghrelin levels were also measured. The results in BW were compared to those recorded in a group of nine healthy women (HW; BMI 22.3+/-2.5 kg/m2). The GH response to ghrelin in BW overlapped with that in HW. Ghrelin administration also led to a similar increase in PRL, ACTH, cortisol and glucose levels in the two groups. Insulin levels were not significantly modified by ghrelin administration in either group. The overlapping endocrine and metabolic response to ghrelin in the two groups occurred with regard to circulating total ghrelin levels which were higher in BW than in HW. In conclusion, BN, a condition of ghrelin hypersecretion, is connoted by a normal endocrine and metabolic response to exogenous ghrelin administration.

Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man.

We evaluated the GH-releasing activity of hexarelin, a new synthetic hexapeptide, after i.v. (1 and 2 micrograms/kg), sc (1.5 and 3 micrograms/kg), intranasal (20 micrograms/kg), and oral (po; 20 and 40 mg) administration to 12 healthy young volunteers. Reference treatments were i.v. saline and GH-releasing hormone (GHRH; 1 microgram/kg). GH release (mean +/- SEM) after the i.v. dose of 1 microgram/kg hexarelin [area under the curve (AUC), 3175 +/- 506 micrograms/min.L] was about 2 times higher than that induced by 1 microgram/kg GHRH (AUC, 1544 +/- 161 micrograms/min.L; P < 0.001). Hexarelin (2 micrograms/kg, i.v.) elicited a further increase in GH levels (AUC, 4422 +/- 626 micrograms/min.L) compared to the 1 microgram/kg dose. The GH response to 2 micrograms/kg hexarelin, i.v., was very reproducible (AUC, 4016 +/- 563 vs. 3959 +/- 803 micrograms/min.L). The sc administration of hexarelin produced a dose-dependent GH response (AUC, 3180 +/- 392 and 4459 +/- 566 micrograms.min.L with 1.5 and 3 micrograms/kg, respectively). Intranasal administration of 20 micrograms/kg hexarelin induced GH release (AUC, 2642 +/- 452 micrograms/min.L) similar to that caused by 1 microgram/kg, i.v. Twenty and 40 mg hexarelin, po, produced a dose-related increase in GH levels (AUC, 2278 +/- 442 and 4079 +/- 514 micrograms/min.L). Biological bioavailabilities were 77.0 +/- 10.5%, 4.8 +/- 0.9%, and 0.3 +/- 0.1% for the sc, intranasal, and po routes, respectively. This study shows that the GH response to hexarelin administered by the i.v. route has a limited variability and is superior to the response to GHRH. The GH-releasing activity appeared to be dose dependent. Thus, hexarelin could be clinically useful to stimulate GH secretion in humans.

Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing's syndrome.

GH-releasing peptides (GHRPs) are synthetic, nonnatural molecules that strongly stimulate GH secretion, but also slightly increase PRL, ACTH, and cortisol levels in man. To investigate the mechanism underlying the ACTH- and cortisol-releasing activity of GHRPs in man, we compared the ACTH- and cortisol-releasing activity of Hexarelin (HEX; 2.0 micrograms/kg, iv), a hexapeptide belonging to the GHRP family, with that of human CRH (hCRH; 2.0 micrograms/kg, iv) in normal subjects (6 men and 6 women, 24-68 yr old) and patients with Cushing's syndrome (2 men and 15 women, 16-68 yr old). The GH response to HEX administration was also studied. In normal subjects, HEX administration significantly increased ACTH (peak us. baseline, mean +/- SD, 32.4 +/- 17.7 vs. 16.3 +/- 7.2 pg/mL; P < 0.005) and cortisol levels (135.9 +/- 51.0 vs. 110.0 +/- 31.6 micrograms/L; P < 0.01). The ACTH and cortisol responses to hCRH [35.7 +/- 13.2 vs. 17.1 +/- 7.7 pg/mL (P < 0.01) and 162.8 +/- 50.1 vs. 102.8 +/- 28.1 micrograms/L (P < 0.01), respectively] were similar to the responses to HEX. The stimulatory effect of HEX, but not that of hCRH, on both ACTH and cortisol secretion in Cushing's disease was clearly higher (P < 0.01) than that observed in normal subjects. In fact, in Cushing's disease both HEX and hCRH elicited a clear increase in ACTH levels [381.1 +/- 350.0 vs. 52.4 +/- 25.0 (P < 0.005) and 100.0 +/- 86.2 vs. 53.3 +/- 29.7 pg/mL (P < 0.01), respectively but the ACTH increase induced by HEX was about 7-fold greater (P < 0.02) than that induced by hCRH. Similarly, both HEX and hCRH elicited a significant increase in cortisol levels [366.9 +/- 189.5 vs. 189.7 +/- 86.3 micrograms/L (P < 0.005) and 209.9 +/- 125.4 vs. 167.2 +/- 96.3 micrograms/L (P < 0.02), respectively], but the cortisol increase induced by HEX was about 4-fold greater (P < 0.05) than that induced by hCRH. In patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either HEX or hCRH administration. The peak GH response to HEX in normal subjects was clearly higher (P < 0.03) than that in hypercortisolemic patients (45.8 +/- 20.5 vs. 22.4 +/- 21.1 micrograms/L). In conclusion, the ACTH- and cortisol-releasing activity of HEX is similar to that of hCRH in normal subjects, whereas it is dramatically enhanced in patients with Cushing's disease. This evidence indicates the importance of the ACTH-releasing activity of GHRPs and suggests that it could be at least partially independent of CRH-mediated mechanisms. As the stimulatory effect of HEX on ACTH and cortisol secretion is lost in patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in pathophysiological conditions and possibly to differentiate pituitary from ectopic ACTH-dependent Cushing's syndrome.

Arginine and growth hormone-releasing hormone restore the blunted growth hormone-releasing activity of hexarelin in elderly subjects.

Although both spontaneous and stimulated GH secretion undergo an age-related decline, the secretory capacity of somatotrope cells is preserved in human aging. In the present study we compared the GH responses to hexarelin, GHRH, and the combined administration of hexarelin and GHRH or arginine in young and elderly subjects. Thirteen young (24- to 30-yr-old) and 16 elderly (65- to 84-yr-old) normal males were divided into 2 groups. The first group (7 young and 8 elderly subjects) received the following as single iv injections during 3 different treatment sessions: hexarelin (2 micrograms/kg), GHRH (2 micrograms/kg), or hexarelin (2 micrograms/kg) plus GHRH (2 micrograms/kg). The second group (6 young and 8 elderly subjects) was administered single iv injections of hexarelin (2 micrograms/kg) or hexarelin (2 micrograms/kg) plus arginine (0.5 g/kg) during 2 different treatment sessions. In both groups basal IGF-I levels in the elderly were lower than those in young subjects (114.5 +/- 18.7 vs. 211.5 +/- 19.1 micrograms/L; P < 0.001). In the first group the GH response to hexarelin was greater in young compared to elderly subjects (area under the curve from 0-120 = 4849 +/- 601 vs. 2112 +/- 683 micrograms.min/L; P < 0.001). GHRH elicited a lower GH response than that induced by hexarelin in both young (1455 +/- 102 micrograms/h.L; P < 0.02) and elderly subjects (563 +/- 87 micrograms/min.L; P < 0.02). GHRH potentiated the somatotrope response to hexarelin in both young (7725 +/- 503 micrograms/min.L; P < 0.02) and elderly subjects (3895 +/- 612 micrograms/min.L; P < 0.02), but to a lesser extent in the latter (P < 0.001). In the second group, the GH response induced by hexarelin was also higher in young subjects than in elderly subjects (4819 +/- 668 vs. 1649 +/- 459 micrograms/min.L; P < 0.001). The GH response to hexarelin was potentiated by arginine in elderly (4139 +/- 1057 micrograms/min. L; P < 0.001), but not in young subjects (4743 +/- 774 micrograms/min.L). This study shows that the maximal effective dose of hexarelin releases more GH than the maximal effective dose of GHRH in both normal young and elderly subjects. The effect of hexarelin on GH secretion is age dependent, and the GH response to the combined administration of hexarelin and GHRH was significantly higher in young subjects compared to elderly subjects. Arginine does not potentiate the GH response to hexarelin in young subjects, whereas it significantly enhances it in elderly subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans.

Alprazolam (ALP), a benzodiazepine that activates gamma-aminobutyric acid-ergic receptors, inhibits the activity of hypothalamo-pituitary-adrenal (HPA) axis, probably via inhibition of hypothalamic CRH and/or arginine vasopressin release. To further clarify the effects of ALP on the HPA axis in humans, in six normal young women (26-34 yr old) we studied the effects of 0.02 mg/kg ALP (administered orally at 0700 h) or placebo on ACTH, cortisol (F), and 11-deoxycortisol (S) levels assayed after placebo or metyrapone (MET; 0.04 g/kg administered orally at 2300 h the night before). After placebo administration, ACTH, F, and S levels showed a progressive decrease from 0700-1200 h (P < 0.03). At 0700 h, ACTH, F, and S levels before ALP overlapped with those after placebo. At 1200 h, ACTH, F, and S levels after ALP were lower than those after placebo (P < 0.03). MET pretreatment strongly increased ACTH (P < 0.03) and S (P < 0.02) while clearly inhibiting F (P < 0.03) levels at 0700 h. After MET, ACTH levels did not show any decrease up to 1200 h; similarly, S levels persisted similar up to 1200 h, whereas F levels at 1200 h were significantly increased (P < 0.03). At 0700 h, MET-induced ACTH and F levels before ALP overlapped with those after MET alone. The MET-induced ACTH levels at 1200 h were markedly inhibited by ALP (P < 0.05). At 1200 h after MET and ALP, a clear reduction of S levels (P < 0.02) and an insignificant F reduction were also found. In conclusion, our present data show that ALP inhibits basal and, much more, metyrapone-induced corticotroph secretion. These findings indicate that the inhibitory effect of central gamma-aminobutyric acid-ergic activation by ALP overrides the stimulatory effect of the MET-induced lack of negative F feedback on corticotroph secretion. These results also point toward potential contraindication of ALP administration in patients with suspected hypoadrenalism.

Effects of recombinant human insulin-like growth factor I administration on growth hormone (GH) secretion, both spontaneous and stimulated by GH-releasing hormone or hexarelin, a peptidyl GH secretagogue, in humans.

The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20 microg/kg s.c. at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 microg/kg i.v. at +180 min) or Hexarelin (HEX, 2.0 microg/kg i.v at +180 min), a GHS, in eight normal young women (age, mean +/- SEM, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 +/- 30.5 vs. 274.4 +/- 25.3 microg/L, P < 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)(0-300 min) 140.6 +/- 66.3 vs. 114.6 +/- 32.1 microg/L x h], whereas it inhibited the GH response to both GHRH (AUC(180-300 min) 447.7 +/- 159.4 vs. 715.9 +/- 104.3 microg/L x h, P < 0.05) and HEX (620.3 +/- 110.4 vs. 1705.9 +/- 328.9 microg/L x h, P < 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 +/- 12.8%) was lower than that on the response to HEX (57.7 +/- 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P < 0.05), whereas the GH responses to GHRH and HEXwere similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.