Second-line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis.

PURPOSE: The clinical and hormonal overlap between neoplastic (CS) and non-neoplastic (NNH/pCS) hypercortisolism is a challenge. Various dynamic tests have been proposed to allow an early discrimination between these conditions, but to date there is no agreement on which of them should be used. AIM: To provide an overview of the available tests and to obtain a quantitative synthesis of their diagnostic performance in discriminating NNH/pCS from CS. METHODS: The included articles, published between 1990 and 2022, applied one or more second line tests to differentiate NNH/pCS from CS patients. For the NNH/pCS group, we admitted the inclusion of patients presenting clinical features and/or biochemical findings suggestive of hypercortisolism despite apparent lack of a pCS-related condition. RESULTS: The electronic search identified 339 articles. After references analysis and study selection, we identified 9 studies on combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test, 4 on Desmopressin test and 3 on CRH test; no study on Dex-Desmopressin met the inclusion criteria. Dex-CRH test provided the highest sensitivity (97%, 95 CI% [88%; 99%]). CRH tests showed excellent specificity (99%, 95% CI [0%; 100%]), with low sensitivity. Although metaregression analysis based on diagnostic odds ratio failed to provide a gold standard, CRH test (64.77, 95% CI [0.15; 27,174.73]) seemed to lack in performance compared to the others (Dex-CRH 138.83, 95% CI [49.38; 390.32] and Desmopressin 110.44, 95% CI [32.13; 379.63]). DISCUSSION: Both Dex-CRH and Desmopressin tests can be valid tools in helping discrimination between NNH/pCS and CS. Further studies are needed on this topic, possibly focusing on mild Cushing's Disease and well-characterized NNH/pCS patients. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359774 , identifier CRD42022359774.

Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Frequently asked questions and answers (if any) in patients with adrenal incidentaloma.

PURPOSE: Adrenal incidentalomas (AIs) are incidentally discovered adrenal masses, during an imaging study undertaken for other reasons than the suspicion of adrenal disease. Their management is not a minor concern for patients and health-care related costs, since their increasing prevalence in the aging population. The exclusion of malignancy is the first question to attempt, then a careful evaluation of adrenal hormones is suggested. Surgery should be considered in case of overt secretion (primary aldosteronism, adrenal Cushing's Syndrome or pheochromocytoma), however the management of subclinical secretion is still a matter of debate. METHODS: The aim of the present narrative review is to offer a practical guidance regarding the management of AI, by providing evidence-based answers to frequently asked questions. CONCLUSION: The clinical experience is of utmost importance: a personalized diagnostic-therapeutic approach, based upon multidisciplinary discussion, is suggested.

Towards the tailoring of glucocorticoid replacement in adrenal insufficiency: the Italian Society of Endocrinology Expert Opinion.

CONTEXT: Glucocorticoid (GC) replacement therapy in patients with adrenal insufficiency (AI) is life saving. After over 50 years of conventional GC treatment, novel formulations are now entering routine clinical practice. METHODS: Given the spectrum of medications currently available and new insights into the understanding of AI, the authors reviewed relevant medical literature with emphasis on original studies, prospective observational data and randomized controlled trials performed in the past 35 years. The Expert Opinion of a panel of selected endocrinologists was sought to answer specific clinical questions. The objective was to provide an evidence-supported guide, for the use of GC in various settings from university hospitals to outpatient clinics, that offers specific advice tailored to the individual patient. RESULTS: The Panel reviewed available GC replacement therapies, comprising short-acting, intermediate and long-acting oral formulations, subcutaneous formulations and the novel modified-release hydrocortisone. Advantages and disadvantages of these formulations were reviewed. CONCLUSIONS: In the Panel's opinion, achieving the optimal GC timing and dosing is needed to improve the outcome of AI. No-single formulation offers the best option for every patients. Recent data suggest that more emphasis should be given to the timing of intake. Tailoring of GS should be attempted in all patients-by experts-on a case-by-case basis. The Panel identified specific subgroups of AI patients that could be help by this process. Long-term studies are needed to confirm the short-term benefits associated with the modified-release GCs. The impact of GC tailoring has yet to be proven in terms of hospitalization rate, morbidity and mortality.

Pasireotide treatment reduces cardiometabolic risk in Cushing's disease patients: an Italian, multicenter study.

PURPOSE: Patients with Cushing's disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients. METHODS: This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200-1800 mcg/daily). RESULTS: Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values. CONCLUSIONS: Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

First-line screening tests for Cushing's syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS.

INTRODUCTION AND AIM: Patients with adrenal incidentaloma present a wide range of cortisol secretion, which is not always properly defined by first-line screening tests recommended to rule out Cushing's syndrome (CS), such as 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), or 24-h urinary free cortisol (UFC). Therefore, we examined the diagnostic performance of each screening test in patients with adrenal incidentaloma. MATERIALS AND METHODS: In a series of 164 consecutive patients with adrenal incidentaloma, we measured serum cortisol after 1-mg DST, LNSC, and UFC (with LC-MS/MS). Medical history was investigated for cardiovascular events (CVE) in a subgroup of 93 patients with at least 2 years of follow-up. RESULTS: Serum cortisol <50 nmol/L after 1-mg DST presented the highest sensitivity (100%) to rule out CS, despite a low specificity (62%). UFC > 170 nmol/24 h achieved the highest diagnostic accuracy (sensitivity 98%, specificity 91%, and negative/positive likelihood ratios of 0.02/10.83, respectively). The prevalence of CVE was higher in patients with non-suppressed cortisol after 1-mg DST and high UFC levels (p = 0.018). Traditional cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, BMI > 30 kg/m2, smoke or high gender-based waist circumference) were not associated with CVE. CONCLUSIONS: The 1-mg DST at its lowest threshold presented high sensitivity in identifying CS, but its low specificity encourages us to consider UFC levels, measured with LC-MS/MS, to reduce false-positive test results. High UFC levels could also be considered as markers to stratify cardiovascular risk in patients with adrenal incidentaloma.

A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

Medical Treatment for Acromegaly does not Increase the Risk of Central Adrenal Insufficiency: A Long-Term Follow-Up Study.

Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138 nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4-fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment.

Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI.

PURPOSE: Spironolactone (SP) is an effective treatment for polycystic ovary syndrome (PCOS), but it is often associated with menstrual abnormalities whose mechanism is still under investigation. In this study, we investigated the serum sex steroids and endometrial thickness in 30 PCOS patients, before and after one-month 100 mg SP treatment. METHODS: Serum FSH, LH, estradiol, progesterone and endometrial thickness were evaluated at the 14th and 16th day of the menstrual cycle, before and during short-term SP treatment. According to the presence (15 cases) or absence (15 cases) of menstrual bleeding at the 14th day during SP, the patients were divided into two groups, which were then compared using a two-tailed Student's t test. RESULTS: Serum estradiol and endometrial thickness were lower than pretreatment at both determinations in all patients, but patients with bleeding had significantly lower estradiol values than non-bleeding ones, both before and after therapy. Endometrial thickness was significantly lower in the bleeding group compared with non-bleeding group only at the 16th day of the cycle. These differences were significant, even though the values of estradiol and endometrial thickness remained in the normal range. CONCLUSIONS: SP therapy can reduce the values of estradiol and the endometrial thickness in patients with PCOS compared with pretreatment, but PCOS patients with bleeding had pretreatment estradiol values lower than the patients who did not complain of this side effect. Intermenstrual abnormalities may represent the low estrogen impregnation of endometrium due to SP, whose mechanism is complex, involving several factors, such as the effects of some metabolites of SP on estradiol and progesterone production, on their receptors, and the individual metabolism of SP in vivo.

A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome.

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor(®); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

25-Hydroxycholecalciferol response to single oral cholecalciferol loading in the normal weight, overweight, and obese.

UNLABELLED: After a single cholecalciferol load, peak serum 25-hydroxycholecalciferol (25OHD) is lower in individuals with a higher body mass index (BMI), probably due to it being distributed in a greater volume. Its subsequent disappearance from the serum is slower the higher the individual's BMI, probably due to the combination of a larger body volume and a slower release into the circulation of vitamin D stored in adipose tissue. INTRODUCTION: The aim of the study is to examine 25-hydroxycholecalciferol (25OHD) response to a single oral load of cholecalciferol in the normal weight, overweight, and obese. METHODS: We considered 55 healthy women aged from 25 to 67 years (mean ± SD, 50.8 ± 9.5) with a BMI ranging from 18.7 to 42 kg/m(2) (mean ± SD, 27.1 ± 6.0). The sample was divided into three groups by BMI: 20 were normal weight (BMI ≤ 25 kg/m(2)), 21 overweight (25.1 ≤ BMI ≤ 29.9 kg/ m(2)), and 14 obese (BMI ≥ 30 kg/m(2)). Each subject was given 300,000 IU of cholecalciferol orally during lunch. A fasting blood test was obtained before cholecalciferol loading and then 7, 30, and 90 days afterwards to measure serum 25OHD, 1,25 dihydroxyvitamin D [1,25 (OH)2D], parathyroid hormone (PTH), calcium (Ca), and phosphorus (P). Participants' absolute fat mass was measured using dual energy X-ray absorptiometry (DEXA). RESULTS: The fat mass of the normal weight subjects was significantly lower than that of the overweight, which in turn was lower than that of the obese participants. Serum 25OHD levels increased significantly in all groups, peaking 1 week after the cholecalciferol load. Peak serum 25OHD levels were lower the higher the individuals' BMI. After peaking, the 25OHD levels gradually decreased, following a significantly different trend in the three groups. The slope was similar for the overweight and obese, declining significantly more slowly than in the normal weight group. In the sample as a whole, there was a weakly significant negative correlation between fat mass and baseline 25OHD level, while this correlation became strongly significant at all time points after cholecalciferol loading. CONCLUSIONS: The lower peak 25OHD levels seen in the obese and overweight is probably due to the cholecalciferol load being distributed in a larger body volume. The longer persistence of 25OHD in their serum could be due to both their larger body volume and a slower release into the circulation of the vitamin D stored in their adipose tissue.

An analysis of different therapeutic options in patients with Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: a single-centre experience.

CONTEXT: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushing's syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients, but little is known about recurrence during follow-up. OBJECTIVE: To describe a series of patients with BMAH and CS treated by different approaches, with a particular focus on the benefit of UA. DESIGN AND PATIENTS: We retrospectively assessed 16 patients with BMAH and CS (11 females, five males), analysing the in vivo cortisol response to different provocative tests. Twelve of the 16 patients underwent UA and were monitored over the long term. RESULTS: Based on in vivo test results, octreotide LAR or propranolol was administered in one case of food-dependent CS and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response. UA was performed in 12 patients, producing long-term remission in three (106 ± 28 months; range: 80-135), recurrence in eight (after 54 ± 56 months; range 12-180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt CS, one received ketoconazole, and four other patients remain under observation for subclinical CS. CONCLUSIONS: Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas UA was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow-up is mandatory to identify it.

Systematic review of surgical treatment of subclinical Cushing's syndrome.

BACKGROUND: Subclinical Cushing's syndrome (SCS) is a condition of biochemical cortisol excess without the classical clinical features of overt hypercortisolism; it may be associated with some consequences of metabolic syndrome. The most appropriate treatment remains controversial. This study aimed to assess the outcomes of adrenalectomy for SCS. METHODS: A systematic review was performed. MEDLINE, Embase and Cochrane Databases (1980-2013) were searched for studies reporting the outcomes of unilateral adrenalectomy with respect to hypertension, diabetes, dyslipidaemia, obesity and osteoporosis in patients with SCS. Studies with a questionable diagnosis of SCS, bilateral adrenal involvement and insufficient data were excluded. RESULTS: Of the 105 papers screened, seven were selected; there were six retrospective studies and one randomized clinical trial, including 230 patients. Data analysis was limited by heterogeneity in definition of SCS and endpoints. Hypercortisolism was cured in all operated patients. Laparoscopy was the preferred approach, with a morbidity rate of 0·8 per cent. A beneficial effect of surgery on blood pressure, glucometabolic control and obesity was evident in all studies, with cure or improvement in 72, 46 and 39 per cent of patients respectively, compared with conservative management. The results for lipid metabolism were equivocal, because of a decrease in triglyceridaemia but discordant effects on cholesterol metabolism among the different studies. No beneficial effects on osteoporosis were found. CONCLUSION: Laparoscopic adrenalectomy seems to be beneficial in reversing several metabolic effects of hypercortisolism, with a low morbidity rate. However, the heterogeneity and low quality of the available studies preclude definitive recommendations.

Effect of a single injection of testosterone enanthate on 17ß estradiol and bone turnover markers in hypogonadal male patients.

PURPOSE: Several clinical studies testify the critical role played by estrogens in male bone metabolism. The aim of our study is to assess the effect of a single injection of testosterone enanthate in a group of hypogonadal men on 17ß estradiol serum levels and some bone metabolic parameters. METHOD: Twenty-one hypogonadal males were given one testosterone enanthate injection (250 mg). Blood samples were drawn before the injection and after 1, 2 and 3 weeks. The following variables were measured: Total testosterone (TT), 17ß estradiol (17ß E2), Sex hormone binding globulin, total alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen (CTx). RESULTS: After testosterone injection, both TT and 17ß E2 increased, peaking 1 week after the injection. Individual observation of the response of 17ß E2 to testosterone showed that a subgroup (n = 9) failed to respond with any increase in 17ß E2 at any of the weekly tests (group E2-), while the remainder (n = 12) showed a significant increase in 17ß E2, which reached a mean value three times higher than at baseline (group E2+). The E2- patients reached a TT peak lower than that observed in the E+ group. CTx serum levels declined progressively in the E2+ group, reaching the significance (p = 0.03) at the end of the study, while it did not change in E- group. CONCLUSION: This study suggests that a single injection of testosterone might have different effects on the production of endogenous estrogens, and a significant reduction of bone resorption parameters takes place only in the patients who show a significant increase of 17ß estradiol in response to testosterone administration.

Isolation and characterization of progenitor mesenchymal cells in human pituitary tumors.

The Cancer Stem Cells (CSCs) theory suggests that genetic alterations in stem cells are the direct cause for cancer. The evidence for a CSC population that results in pituitary tumors is poor. Some studies report the isolation of CSCs, but a deep characterization of the stemness of these cells is lacking. Here, we report the isolation and detailed characterization of progenitor mesenchymal cells (PMCs) from both growth hormone-secreting (GH(+)) and non-secreting (NS) pituitary adenomas, determining the immunophenotype, the expression of genes related to stemness or to pituitary hormone cell types, and the differentiative potential towards osteo-, chondro- and adipogenic lineages. Finally, the expression of CD133, known as a marker for CSCs in other tumors, was analyzed. Isolated cells, both from GH(+) and NS tumors, satisfy all the criteria for the identification of PMCs and express known stem cell markers (OCT4, SOX2, KLF4, NANOG), but do not express markers of pituitary hormone cell types (PITX2, PROP1, PIT1). Finally, PMCs express CD133. We demonstrated that pituitary tumors contain a stem cell population that can generate cell types characteristic of mesenchymal stem cells, and express CD133, which is associated with CSCs in other tumors.

The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study.

Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 µg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 µg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.

Vitamin D levels and bone mineral density: are LH levels involved in the pathogenesis of bone impairment in hypogonadal men?

BACKGROUND: Osteoporosis is a major public health problem also in men and it recognizes hypogonadism as a major cause. AIMS: To investigate the possible pathogenetic mechanisms on bone impairment in male hypogonadism and on its improvement in response to testosterone replacement treatment (TRT). METHODS: We retrospectively investigated the hormonal profile and bone mineral density (BMD), evaluated by DXA, in 17 middle-aged hypogonadal men treated for at least 5 years with TRT, compared with 21 recently diagnosed untreated hypogonadal males and 18 age- and BMI-matched healthy subjects. RESULTS: No significant differences in clinical, biochemical and densitometric parameters were found among the three groups, with the exception of 25-OH vitamin D levels that were significantly higher in healthy subjects compared with hypogonadal patients. Untreated patients affected by central hypogonadism, despite similar hormonal levels, displayed significantly lower BMD and decreased LH and 25-OH vitamin D levels, compared with patients with primary hypogonadism. Among the treated patients, BMD parameters were similar regardless of the formulation of TRT. CONCLUSIONS: A recent history of central hypogonadism, compared with primary hypogonadism, appears to adversely affect bone health independently of gonadal steroids levels. This could be due to lower LH levels and consequent reduction of vitamin D 25-hydroxylation in the testis.

Primary aldosteronism and essential hypertension: assessment of cardiovascular risk at diagnosis and after treatment.

BACKGROUND AND AIMS: Primary aldosteronism (PA), the most frequent form of secondary hypertension, is characterized by a higher rate of cardiovascular (CV) events than essential hypertension (EH). Aim of the study was to evaluate the cardiovascular risk according to the ESH/ESC 2007 guidelines, in patients with PA and with EH, at diagnosis and after treatment. METHODS AND RESULTS: We prospectively studied 102 PA patients (40 with aldosterone producing adenoma-APA and 62 with idiopathic hyperaldosteronism-IHA) and 132 essential hypertensives at basal and after surgical or medical treatment (mean follow-up period 44 months for PA and 42 months for EH). At baseline evaluation the stratification of CV risk was significantly different: the predominant risk category was the high CV risk (50% in total PA, 53% in PA matched for blood pressure values and 55% in EH), but the very high risk category was twice in PA than in EH patients (36% in total PA and 33% in matched PA vs. 17% in EH, p < 0.05). The worse risk profile of PA was due to a higher prevalence of glycemic alterations, metabolic syndrome and left ventricular hypertrophy (LVH) (p < 0.05). After adequate treatment, the CV risk was significantly reduced becoming comparable in PA and in EH patient due to a reduction of hypertension grading, prevalence of metabolic syndrome, hypertension persistence and LVH (p < 0.05). CONCLUSION: Patients with PA present a high CV risk, which is in part reversible after specific treatment, due both to the reduced blood pressure values and to the improvement of end-organ damage.