Triticum vulgare Extract and Polyhexanide (Fitostimoline® Hydrogel/Fitostimoline® Plus Gauze) versus Saline Gauze Dressing in Patients with Diabetic Foot Ulcers: Results of a Randomized Controlled Trial.

BACKGROUND: The use of dressings is an essential component of the standard of care for diabetic foot ulcers (DFUs); however, despite the wide variety of dressings available, there is a lack of evidence from head-to-head randomized controlled trials. We evaluated the efficacy and safety of Triticum vulgare extract and polyhexanide (Fitostimoline® hydrogel/Fitostimoline® Plus gauze) versus saline gauze dressings in patients with DFUs. METHODS: This study involved a monocentric, two-arm, open-label, controlled trial in patients with DFUs (Grades I or II, Stage A or C, based on the Texas classification) randomized to 12 weeks of dressing with Fitostimoline® hydrogel/Fitostimoline® Plus gauze or saline gauze. The number of patients with complete healing, the reduction in DFU size, and the presence of local signs and symptoms of the wound and perilesional skin were evaluated every two weeks and at the end of treatment. RESULTS: A total of 40 adult patients were recruited (20 patients in each treatment group). The proportion of patients with complete healing was similar between the two groups (61% vs. 74%, p = 0.495, Fitostimoline® hydrogel/Fitostimoline® Plus gauze vs. saline gauze, respectively), without significant differences, as well as the reduction in DFU size. A significant improvement in local signs and symptoms of the wound and signs of perilesional skin in the Fitostimoline® hydrogel/Fitostimoline® Plus gauze compared with the saline gauze group was observed. CONCLUSIONS: In a clinical setting, the use of Fitostimoline® hydrogel/Fitostimoline® Plus gauze dressing in patients with DFUs significantly improves signs and symptoms of the wound and signs of perilesional skin compared with saline gauze dressing with a similar efficacy in terms of wound healing.

A Multi-professional Approach for Transition of Care at Discharge in Hyperglycemic Inpatients with COVID-19: A Single Center Study.

BACKGROUND: The discharge from the hospital of insulin-treated hyperglycemic patients is always challenging. This is even more so in patients requiring glucocorticoid treatment, such as those with COVID-19. PATIENTS AND METHODS: A retrospective monocentric study of 23 inpatients was conducted with newly diagnosed or already known diabetes mellitus (DM) who were naïve to insulin treatment, and who were hospitalized with COVID-19 in non-critical settings and then discharged. Patients were followed up for one month after discharge for the management of insulin treatment by a multi-professional team through phone consultations. RESULTS: Insulin prescriptions at discharge were 24.6 ± 14 U/day injected in 2 ± 1.5 daily shots. A mean of three phone consultations was required. One month later, the mean insulin reduction was 1.5 ± 1.3 shots and 6 ± 5 U/day. All patients reached their glycemic target without hypoglycemic events, drop-outs, or readmissions. CONCLUSION: This study demonstrates the feasibility, efficacy, and safety of a multi-professional approach through telemedicine for managing DM patients after discharge during COVID-19.

Serum Phosphate: A Neglected Test in the Clinical Management of Primary Hyperparathyroidism.

BACKGROUND: Although the inverse correlation between serum PTH and phosphate (P) levels in patients with primary hyperparathyroidism (PHPT) is well known, the relationship between P levels and the clinical picture of the disease has not been well investigated. This was thus the aim of this paper. PATIENTS: A total of 472 consecutive patients with PHPT attending our center were retrospectively evaluated at diagnosis. RESULTS: P levels lower than 2.5 mg/dL (HypoP) were found in 198/472 patients (41.9%). HypoP was mild (2-2.5 mg/dL), moderate (1-1.9 mg/dL), and severe (<1 mg/dL) in 168 (84.9%), 30 (15.1%), and 0 cases, respectively. P levels were lower in males than females. Patients with more severe bone density impairment at the radial (but not the vertebral or femoral) site had P levels significantly lower than other patients. PHPT severity was worse in HypoP patients, both clinically (higher prevalence of renal stones, but not of osteoporosis) and biochemically (higher serum calcium and PTH levels). All patients in the moderate HypoP group were either symptomatic or asymptomatic reaching surgical indication according to the latest guidelines. CONCLUSIONS: We observed a relationship between P levels and biochemical and clinical features of PHPT severity. In asymptomatic PHPT patients, even moderate HypoP is predictive of surgical indication, regardless of age and hypercalcemia severity.

A Multicenter Epidemiological Study on Second Malignancy in Non-Syndromic Pheochromocytoma/Paraganglioma Patients in Italy.

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46-15.71) in males and 13.21 (95% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

Aldosterone Secretion in Patients With Primary Hyperparathyroidism Without Arterial Hypertension.

OBJECTIVE: There is a direct bidirectional link between parathyroid hormone (PTH) and the renin-angiotensin-aldosterone system (RAAS), but few studies evaluated the RAAS in patients with primary hyperparathyroidism (PHPT), mainly biased from concomitant antihypertensive treatment. METHODS: We retrospectively evaluated a consecutive series of 130 normotensive patients with PHPT comparing aldosterone (ALD) levels and plasma renin activity (PRA) with the demographic, biochemical, or clinical features of PHPT. RESULTS: No correlation was found between ALD and PRA, and the demographic, biochemical, and bone densitometry parameters in patients with PHPT without hypertension, with the exception of a negative correlation between age and serum PRA. Moreover, there was no significant correlation between PTH and ALD levels even in patients whose PTH level was >100 ng/L (P = .088). CONCLUSION: In our normotensive patients with PHPT, the ALD, PRA, and aldosterone/renin ratio were not correlated to PTH and calcium levels. In addition, they were neither related to PHPT clinical presentation nor renal function, vitamin D status, bone mass loss, or the presence of comorbidities such as diabetes and obesity. Further studies are needed to clarify the complex interplay between PTH and the RAAS in the modern PHPT presentation.

Reversibility of Acute Adrenal Insufficiency After Hip Replacement: A Case Series.

BACKGROUND: Acute adrenal insufficiency is a rare but potentially lethal condition, that is important to identify promptly and treat with replacement therapy. It can be consequent to adrenal hemorrhage that can occur after major orthopedic surgery. Few data are available about potential recovery of adrenal function, as well as both timing and modality of cortisone acetate withdrawal, probably due to the assumption that adrenal failure should be definitive. The extension of adrenal damage can be different, so justifying a partial, or potentially complete, recovery of adrenal function. The aim of our article is to highlight the opportunity of a periodical revaluation of adrenal reserve in order to identify those patients which are able to interrupt replacement therapy. CASE PRESENTATION: We had recently described one case of acute adrenal insufficiency, which developed short time after hip replacement; the patient was able to discontinue cortisone acetate treatment 46 months after the diagnosis and remained untreated up to five years later. We collected other two cases of acute adrenal insufficiency, developed about one week after major orthopedic surgery. We followed such patients for about three years, repeatedly reassessing adrenal imaging and cortisol response to 250 µg ACTH test, in order to ascertain the real need of lifetime substitutive treatment with cortisone acetate. Acute adrenal insufficiency partially reverted during the follow up for both patients. We observed a reduction in adrenal glands' volume and a progressive improvement of cortisol basal levels, without response (or with a poor one) to ACTH stimulation, as well as with ACTH basal levels persistently above the normal range after 36 and 28 months respectively spent from the acute event. CONCLUSION: The present finding suggests the opportunity that patients developing acute adrenal insufficiency after major orthopedic surgery undergo long-term surveillance, in order to establish if steroid replacement has to be continued, or it can be safely withdrawn.

Adrenal Incidentalomas are Tied to Increased Risk of Diabetes: Findings from a Prospective Study.

CONTEXT: The frequency of adrenal incidentalomas and their association with comorbid conditions have been assessed mostly in retrospective studies that may be prone to ascertainment bias. OBJECTIVE: The objective of this work is to evaluate the frequency of adrenal incidentalomas and their associated comorbid conditions. DESIGN: A prospective cohort study was conducted. SETTING: This study took place at a radiology department at a public hospital. PARTICIPANTS: Unselected outpatients who underwent an abdominal computed tomography (CT) from January 2017 to June 2018. Patients with known or suspected adrenal disease or malignancy were excluded. EXPOSURE: All abdominal CT scans were evaluated by an experienced radiologist. Hormonal workup including a 1-mg dexamethasone suppression test was performed in patients bearing adrenal incidentalomas. MAIN OUTCOME AND MEASURE: Frequency of adrenal incidentalomas in abdominal CT of unselected patients; frequency of comorbid conditions, and hormonal workup in patients bearing adrenal incidentalomas. RESULTS: We recruited 601 patients, and in 7.3% of them an adrenal tumor was found serendipitously. The patients bearing an adrenal incidentaloma had higher body mass index (P = .009) and waist circumference (P = .004) and were more frequently diabetic (P = .0038). At multivariable regression analysis, diabetes was significantly associated with the presence of adrenal incidentalomas (P = .003). Autonomous cortisol secretion was observed in 50% of patients who did not suppress cortisol less than 50 nmol/L after 1 mg dexamethasone. CONCLUSIONS: The frequency of adrenal incidentalomas is higher than previously reported. Moreover, adrenal incidentalomas are tied to increased risk of type 2 diabetes. This finding is free from ascertainment bias because patients with adrenal incidentalomas were drawn from a prospective cohort with the same risk of diabetes as the background population.

Acute Primary Adrenal Insufficiency after Hip Replacement in a Patient with Acute Intermittent Porphyria.

Adrenal insufficiency is a potentially life-threatening condition when it occurs acutely, as in adrenal hemorrhage. Generally it is not reversible and requires chronic replacement therapy. Acute intermittent porphyria (AIP) is a rare genetic disease characterized by alterations in heme biosynthesis that result in accumulation of precursors in tissues. A crisis can be triggered by many conditions such as surgery and infections. Symptoms are similar to those of acute hypoadrenalism. Moreover, both conditions are characterized by hyponatremia. We describe the case of a postmenopausal woman known to be affected by AIP who developed after surgery a primary adrenal insufficiency associated with adrenal enlargement; the latter completely reverted in six months.

Sex Difference in the Clinical Presentation of Primary Hyperparathyroidism: Influence of Menopausal Status.

Context: Female-to-male ratio in primary hyperparathyroidism (PHPT) is 3:1, but data on sex impact on the clinical presentation are limited. Design: We evaluated, retrospectively, sex difference in biochemistry and clinical presentation at diagnosis in a monocentric series of 417 patients with PHPT: 93 men (58.6 ± 14.5 years), and 324 women (61.7 ± 12.8 years), of whom 54 were premenopausal (pre-F) and 270 postmenopausal (post-F). Results: Men were significantly younger (P = 0.046) and more frequently symptomatic than women (62.3% vs 47%, P = 0.016). No sex difference was found in serum parathyroid hormone, calcium, creatinine, 25-hydroxy-vitamin D, and urinary calcium levels, whereas serum phosphate was higher in women. Nephrolithiasis (detected by imaging or history of passing stones) was more frequent in men (50.5% vs 33% in women, P = 0.003) and osteoporosis (T-score <-2.5 at any site) was more frequent in women (52.2% vs 35.5% in men, P = 0.0066). Symptomatic patients were 43.3%, 64.8%, and 62.3% in post-F women, pre-F women, and men, respectively. Kidney stones were less frequent and osteoporosis more frequent in post-F women than in pre-F women (28.1% vs 59.2% and 58.9% vs 18.5%, respectively). After combining symptomatic and asymptomatic patients meeting surgical criteria recommended by current guidelines, no sex difference was observed in the proportion of patients to be referred for surgery (84.6% in men vs 84.9% in women). Conclusion: Biochemical activity of PHPT seems to be independent of sex, but clinical presentation is different, mostly due to menopausal state. However, surgical referral was indicated equally in men and women.

KDIGO CATEGORIES OF GLOMERULAR FILTRATION RATE AND PARATHYROID HORMONE SECRETION IN PRIMARY HYPERPARATHYROIDISM.

OBJECTIVE: The recent Fourth Workshop on the Management of Asymptomatic primary hyperparathyroidism (PHPT) maintained the threshold of 60 mL/min for decreased renal function, below which surgery is recommended. This study investigated the relationship between different stages of renal insufficiency and parathyroid hormone (PTH) levels in an updated case series of PHPT patients. METHODS: This was a retrospective, cross-sectional study involving 379 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 (25[OH]D3) levels in the fasting state. Glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Mean CKD-EPI estimated GFR was 81.9 ± 20.3 mL/min/1.73 m(2), and median GFR was 84.0 mL/min/1.73 m(2) (interquartile range, 26.8 mL/min/1.73 m(2)). The patients were divided into 5 groups according to the Kidney Disease: Improving Global Outcomes 2012 guidelines: group 1 with normal or increased GFR (>90 mL/min/1.73 m(2)); group 2 with mild GFR decrease (60 to 89 mL/min/1.73 m(2)); group 3a with mild to moderate GFR decrease (45 to 59 mL/min/1.73 m(2)); group 3b with moderate to severe GFR decrease (30 to 44 mL/min/1.73 m(2)); and group 4 with severe GFR decrease (<30 mL/min/1.73 m(2)). Among the 5 groups of patients, serum calcium levels were different (P = .025), whereas 25(OH)D3 levels were not (P = .36). PTH levels were comparable across groups 1 through 3a, but they were significantly higher in groups 3b and 4 (P<.0001). CONCLUSION: In our series of PHPT patients, PTH levels did not rise as a result of renal impairment until GFR decreased below 45 mL/min/1.73 m(2).

Silent renal stones in primary hyperparathyroidism: prevalence and clinical features.

OBJECTIVE: (1) To evaluate the prevalence of silent nephrolithiasis in patients with primary hyperparathyroidism (PHPT) compared with controls, and (2) To characterize clinically PHPT patients with silent renal stones. METHODS: We reviewed clinical data for 141 patients with PHPT and without symptoms or history of nephrolithiasis in whom renal ultrasonography was performed at diagnosis. A total of 141 sex- and age- matched subjects with abdomen ultrasonography obtained for reasons different from urinary symptoms served as controls. RESULTS: Silent nephrolithiasis was more prevalent in PHPT patients than in controls (11.35% vs. 2.13%; P = .003). Among patients with PHPT, those with silent renal stones showed higher serum calcium and parathyroid hormone levels and met surgical criteria, regardless of nephrolithiasis, more frequently than those without renal stones. CONCLUSION: The prevalence of silent nephrolithiasis is increased in patients with PHPT as compared with controls. Moreover, it seems likely that silent renal stone disease could identify a subset of PHPT patients with more severe disease. Accordingly, we suggest ultrasonographic screening of nephrolithiasis in all PHPT patients. Further studies are needed to better characterize this clinical entity.

Relationship between insulin sensitivity and bone mineral density in primary hyperparathyroidism.

INTRODUCTION: Evidence of crosstalk between bone and insulin metabolism has been identified. In primary hyperparathyroidism (PHPT), scant data exist on this relationship. AIM: To evaluate the relationship between insulin levels or sensitivity and bone mineral density (BMD) in PHPT. SUBJECT AND METHODS: Two hundred and sixty-seven patients with PHPT without known diabetes mellitus were studied. Fasting blood glucose and insulin levels as well as BMD at lumbar spine, femoral neck and forearm were measured. Insulin sensitivity was assessed using Quantitative Insulin Sensitivity Check Index (QUICKI). The same parameters were measured 2 years (interquartile range 2·8 years) after surgery (PTX) in a subgroup of patients (n = 51). RESULTS: In univariate analysis, a positive relationship between insulin levels and BMD (R = 0·17, P < 0·03) or T-score (R = 0·20, P < 0·005) was found at femoral neck level. Consequently, a negative relationship between QUICKI and femoral BMD (R = -0·20, P < 0·01) or T-score (R = -0·21, P < 0·004) was found. In multivariate analysis, when femoral BMD was the dependent variable, age (beta = -0·35, P < 0·000004), BMI (beta = 0·39, P < 0·00001), PTH (beta = -0·18, P < 0·05) and QUICKI (R = -0·15, P < 0·05) had an independent effect (R(2) = 0·29). Insulin levels and QUICKI did not change after PTX. No relationship was found between QUICKI or insulin levels at the time of diagnosis and change in BMD at any site at follow-up. CONCLUSIONS: Our data show a weak relationship between insulin levels and/or insulin sensitivity and BMD in PHPT. However, the insulin state does not influence change in bone density after PTX in PHPT.

Vitamin D status in primary hyperparathyroidism: a Southern European perspective.

BACKGROUND: Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one-third of the patients. SUBJECTS AND METHODS: Vitamin D status was evaluated both in an observational study in a series of 206 consecutive patients with pHPT at diagnosis and in a case-control analysis with 113 age- and sex-matched healthy blood donors. Vitamin D status was assessed by measuring plasma 25-hydroxy-vitamin D (25OHD) levels and was defined as VDD or severe VDD if 25OHD was <20 ng/ml (<50 nm) and <10 ng/ml (<25 nm), respectively. RESULTS: No seasonal variability was observed in 25OHD levels. VDD was observed in 75 of 206 patients (36·4%). The VDD was severe in 24 of 75 patients (11·7%). There was no difference in prevalence of VDD between men and women nor between asymptomatic and 'bone and stone' symptomatic patients. 25OHD levels was negatively correlated with parathyroid hormone, ionized calcium, and bone turnover markers, and positively correlated with phosphate. 25OHD levels were also positively correlated with bone mineral density at all sites measured. In the case-control study, the overall prevalence of VDD and severe VDD was higher in patients with pHPT compared with controls (33·6% vs 10·6%, P < 0·0001, and 8·8% vs 1·8%, P = 0·0337, respectively). CONCLUSIONS: Our study shows that VDD occurs in about one-third of patients with pHPT resident in a Southern European area, a lower figure than previously reported. Moreover, VDD is related to a more severe bone disease, and its prevalence is higher in patients with pHPT than in healthy matched subjects.

Neuroblastoma in the Elderly and SIADH: Case Report and Review of the Literature.

Objective. To report the rare case of a thymic neuroblastoma, in an elderly woman with SIADH at presentation. Methods. Clinical and biochemical data of the patient are presented and the pertinent literature is reviewed. Results. a 79-year-old woman was admitted into our department with worsening asthenia, severe hyponatremia (114.8 mEq/L), low plasma osmolarity (253 mEq/L), and inappropriate urinary sodium concentration (151 mEq/L). CT scan showed an a large solid inhomogeneous mass in the anterior mediastinum. (18)F-FDG-PET/CT showed uptake in the mass. On continuous 3% hypertonic saline infusion, sodium gradually increased without achieving normal values. The patient underwent surgery, followed by full normalization of sodium levels. Tumor cells were positive for neuroendocrine markers. Thymic neuroblastoma with SIADH was diagnosed. Conclusions. Neuroblastoma is an extremely rare tumor in the elderly. Contrary to children and younger adults, neuroblastoma in older adults is typically localized in the anterior mediastinum and is often associated with SIADH. Moreover, it has mainly local aggressiveness in this age group, without metastatic spread; thus radical surgery achieves cure in most cases.

Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagogue-receptor modulation.

The hypothalamus-pituitary-adrenal (HPA) axis exerts a variety of effects at both the central and peripheral level. Its activity is mainly regulated by CRH, AVP, and the glucocorticoid-mediated feedback action. Moreover, many neurotransmitters and neuropeptides influence HPA axis activity by acting at the hypothalamic and/or suprahypothalamic level. Among them, GABA and Growth Hormone Secretagogues (GHS)/GHS-receptor systems have been shown to exert a clear inhibitory and stimulatory effect, respectively, on corticotroph secretion. Alprazolam (ALP), a GABA-A receptor agonist, shows the most marked inhibitory effect on both spontaneous and stimulated HPA axis activity, in agreement with its peculiar efficacy in panic disorders and depression where an HPA axis hyperactivation is generally present. Ghrelin and synthetic GHS possess a marked ACTH/cortisol-releasing effect in humans and the ghrelin/GHS-R system is probably involved in the modulation of the HPA response to stress and nutritional/metabolic variations. The glucocorticoid-mediated negative feedback action is mediated by both glucocorticoid (GR) and mineralocorticoid (MR) receptors activation at the central level, mainly in the hippocampus. In agreement with animal studies, MRs seem to play a crucial role in the maintenance of the circadian ACTH and cortisol rhythm, through the modulation of CRH and AVP release. GABA agonists (mainly ALP), ghrelin, as well as MR agonists/antagonists, may represent good tools to explore the activity of the HPA axis in both physiological conditions and pathological states characterized by an impaired control of the corticotroph function.

Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralocorticoid receptor blockade.

CONTEXT: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level. DESIGN: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 +/- 3.2 yr) and eight young (25.0 +/- 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg i.v. bolus followed by 200 mg infused over 4 h). RESULTS: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P < or = 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P < or = 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P < or = 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo. CONCLUSIONS: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.

Free fatty acids exert an inhibitory effect on adrenocorticotropin and cortisol secretion in humans.

Free fatty acid (FFA) administration stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rats, suggesting that the HPA axis and lipolysis may be linked by a positive-feedback loop. To clarify the influence of FFA on the HPA axis in humans, we studied the effect of lipid load on both basal and stimulated ACTH and cortisol secretion in normal subjects. In six young female volunteers [(mean +/- SEM) age, 24.4 +/- 2.1 yr; body mass index, 23.1 +/- 1.2 kg/m(2)), ACTH, cortisol, FFA, glucose, and insulin levels were measured every 30 min for 330 min during the following procedures: 1) i.v. saline infusion (from 0 to 330 min); 2) i.v. FFA infusion (Intralipid 10%, from 0 to 210 min) followed by saline infusion (from 210 to 330 min); 3) human CRH (hCRH) administration (2 microg/kg i.v. at 90 min) during saline infusion (from 0 to 330 min); and 4) hCRH administration during FFA infusion (Intralipid 10%, from 0 to 210 min, followed by saline infusion from 210 to 330 min). During saline infusion, ACTH and cortisol levels progressively declined. Lipid-heparin emulsion (LHE) infusion strikingly increased circulating FFA levels and, simultaneously, amplified the ACTH and cortisol decrease (P < 0.05). After LHE withdrawal, FFA decrease was associated with an increase (P < 0.05) in ACTH and cortisol levels (restored to baseline values within 60 min). The ACTH and cortisol responses to hCRH, however, were unaffected by LHE that, concomitantly, induced an increase (P < 0.05) in glucose but not in insulin levels. This study shows that an LHE-induced increase in FFA levels has an inhibitory effect on spontaneous ACTH and cortisol secretion in humans. Lipid load, however, does not affect the ACTH and cortisol responses to hCRH; this evidence would indicate that the negative influence of FFA on the HPA axis in humans takes place at the suprapituitary level.

Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans.

OBJECTIVE: Alprazolam (ALP), a benzodiazepine-activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH- and/or AVP-secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects. DESIGN: In eight normal subjects [four women and four men, 22-34 years old, body mass index (BMI) 20-25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin-induced hypoglycaemia [ITT, 0.1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0.02 mg/kg orally at -90 min) were studied in two sessions at least 10 days apart. MEASUREMENTS: Blood samples were taken basely at -90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions. RESULTS: All subjects experienced hypoglycaemia (plasma glucose levels below 2.2 mmol/l). After placebo ITT induced clear-cut increases in ACTH (peak vs. baseline, mean +/- SEM: 27.9 +/- 3.9 vs. 7.1 +/- 1.5 pmol/l), cortisol (438.1 +/- 32.0 vs. 237.7 +/- 19.3 nmol/l) and GH (38.1 +/- 9.7 vs. 5.7 +/- 2.0 micro g/l) levels (P < 0.05). Marked increase in A (6627.2 +/- 116.7 vs. 263.7 +/- 71.4 pmol/l) and NA (3.8 +/- 1.5 vs. 1.6 +/- 1.0 nmol/l) levels were also recorded (P < 0.05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17.8 +/- 5.0 pmol/l, P < 0.05), while the cortisol response showed a non significant reduction (342.1 +/- 38.7 nmol/l). ALP also significantly reduced the GH (21.7 +/- 4.7 micro g/l, P < 0.02) and A (3828.0 +/- 1400.7 pmol/l, P < 0.02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0.05) but did not significantly affect its response to ITT (2.2 +/- 1.2 nmol/l). Glucose changes induced by ITT were not modified by ALP. CONCLUSIONS: This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.