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BACKGROUND: Double pituitary adenomas (DA) are two morphologically and immunohystochemically different tumours in the same gland. They are rare, generally small adenomas and divided in: separated, when clearly recognizable before or during surgery, and contiguous, when diagnosed only in the following histopathological examination. Acromegaly and Cushing's disease are the main prevalent clinical presentation. OBJECTIVE: We described two cases of DA in a surgical series over 16 years in a single center. METHODS: In September 2018, we diagnosed a DA in a man with acromegaly (case 1). In order to assess the presence of other cases of DA, we performed a retrospective analysis of the endonasal endoscopically operated sellar adenomas from January 2004 to December 2019. RESULTS: 468 pituitary adenomas were found. A DA with a Pit-1 positive macroadenoma (GH-TSH- PRL positive) and an ACTH microadenoma clinically silent in an acromegalic woman was retrospectively found (case 2). CONCLUSION: Our analysis confirms that DA are rare (0.4% of the pituitary adenomas) and often associated with acromegaly. Their pre-operatively diagnosis is difficult but clinician's awareness of DA can improve the diagnosis. The use of pituitary transcription factors could be useful in detecting DA.

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PURPOSE: The diagnosis of primary hyperparathyroidism (PHPT) and chronic hypoparathyroidism (HypoPT) is still challenging, especially in patients asymptomatic or with non-classical phenotypes and for physicians not skilled in calcium-phosphorous (Ca-P) disorders. The serum calcium/phosphorous (Ca/P) ratio has been proposed as accurate index to identify PHPT, while it has never been tested in HypoPT. The aim of this study is to investigate the diagnostic power of the serum Ca/P ratio in the diagnosis of primary parathyroid dysfunctions (both PHPT and HypoPT) in a large series of data. METHODS: A multicentric, retrospective, cross-sectional study (ClinicalTrials.gov: NCT03747029) was carried out including 432 PHPT patients and 217 HypoPT patients compared with 389 controls. Serum Ca, P, creatinine, parathyroid hormone and 25OH-vitamin D were collected. Serum Ca and P were expressed in mmol/L. Ca/P diagnostic performance was evaluated by receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy. RESULTS: The Ca/P ratio was significantly higher in PHPT and lower in HypoPT patients than controls (p < 0.0001). At ROC curve analysis, the Ca/P ratio above 2.55 was defined to identify PHPT patients (sensitivity 85.7%, specificity 85.3%) and below 1.78 to identify HypoPT patients (sensitivity 88.2%, specificity 87.9%). CONCLUSIONS: The Ca/P ratio is a highly accurate index to identify PHPT when Ca/P is above 2.55 and HypoPT when it is below 1.78. These results demonstrate the reliability of this index to rule in/out primary parathyroid dysfunctions and remark the importance of measuring serum P in clinical practice.

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A 75-year-old man was hospitalized because of severe hypokalaemia due to ACTH dependent Cushing's syndrome. Total body computed tomography (TBCT) and 68 Gallium DOTATATE PET/CT localized a voluminous prostate tumour. A subsequent transurethral prostate biopsy documented a small cell carcinoma positive for ACTH and calcitonin and negative for prostatic specific antigen (PSA) at immunocytochemical study; serum prostatic specific antigen (PSA) was normal. Despite medical treatments, Cushing's syndrome was not controlled and the patient's clinical condition progressively worsened. Surgical resection was excluded; the patient underwent a cycle of chemotherapy followed by febrile neutropenia and fatal intestinal perforation. This case report describes a rare case of Cushing's syndrome and hypercalcitoninaemia due to a small cell carcinoma of the prostate, a rare tumour with very few therapeutic options and negative prognosis.

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INTRODUCTION: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 ± 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.

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CONTEXT: Cushing's syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushing's syndrome in patients with type 2 diabetes. OBJECTIVE: Our aim was to evaluate the prevalence of unsuspected Cushing's syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING: This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS: Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS: Forty patients failed to suppress serum cortisol less than 5.0 µg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 µg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushing's syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS: The present data do not support widespread screening of patients with type 2 diabetes for Cushing's syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

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Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva, blood plasma and fat biopsies. The metabolome is now considered by some to be the most predictive phenotype: consequently, the comprehensive and quantitative study of metabolites is a desirable tool for diagnosing disease, identifying new therapeutic targets and enabling appropriate treatments. A wealth of information about metabolites has been accumulated with global profiling tools and several candidate technologies for metabolomic studies are now available. Many high-throughput metabolomics methodologies are currently under development and have yet to be applied in clinical practice on a routine basis. In the cardiovascular field, few recent metabolomic studies have been reported so far. This minireview provides an updated overview of alternative technical approaches for metabolomics studies and reviews initial applications of metabolomics that relate to both cardiovascular disease and lipid metabolism research.

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INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are known to induce delayed orgasm and delayed ejaculation, while their effect on other aspects of sexual function, such as sexual motivation, arousal, and erectile function are unclear. AIM: In order to evaluate the effect of chronic administration of two SSRIs, citalopram and fluoxetine, on normal sexual function, we studied the parameters of male sexual behavior, erectile function, and ejaculation on 48 healthy male volunteers, aged 29.5 +/- 4.9, in a randomized, placebo-controlled, double-blind, double-dummy study. Methods. The subjects were randomized to receive placebo (16 subjects), or fluoxetine (20 mg/day) (16 subjects) or citalopram (20 mg/day) for the first week, and 40 mg/day in the following 3 weeks (16 subjects). MAIN OUTCOME MEASURES: Sexual function was investigated at the screening and at the end of the study by means of test of penile erection (TPE) and masturbation ejaculation latency time (MELT) performed during visual erotic stimulation, and at each visit by self-filled questionnaires (International Index Erectile Function [IIEF-15] and Golombock Rust Inventory of Sexual Satisfaction [GRISS]). RESULTS: All the erectile parameters, evaluated by means of RigiScan Plus during TPE, were not significantly different when both fluoxetine and citalopram were compared with placebo. A delay in the ejaculation time was observed both during citalopram and during fluoxetine treatment when compared with placebo, reaching a statistical significance only with citalopram. During the treatment with citalopram and fluoxetine, the IIEF-15 score of all items decreased except for those items related to sexual desire; however, the scores were significantly lower only for the citalopram treatment. CONCLUSIONS: The treatment with citalopram or with fluoxetine was confirmed to delay ejaculation, but was significant only for citalopram. Citalopram and fluoxetine did not affect sexual desire. Citalopram and fluoxetine did not directly affect penile erection as objectively assessed by RigiScan, although an impairment in the subjective assessment of erectile function was observed, but was significant only for citalopram, and it was thought to be a possible consequence of the delayed ejaculation perceived as a trouble.

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We know that the Yin Yang 1 protein (YY1) overexpression is positively and strongly correlated with the degree of malignancy of bone tumors. Therefore, we questioned whether we could influence cell invasiveness by deleting YY1 in human osteosarcoma cells (SaOs-2), as tested in Matrigel-coated filters and metastasis implantation of such osteosarcoma cells in vivo, by serial analysis with nuclear magnetic resonance. Moreover, we focused our work on the chemokine receptor CXCR4 and its inhibition by T22 antibody, as well as on systemic (direct in vivo assay) and computer-assisted imaging of angiogenesis-related metastasis. Results showed that cell invasiveness and metastasis implantation by wild-type SaOs-2 cells, as evaluated by histology and immunohistochemistry, are associated with up-regulation of CXCR4 expression, which in turn was significantly reduced by T22. In addition, deletion of YY1 (siRNAYY1-SaOs-2) induced a significant decrease of cell invasion and metastasis growth. This phenomenon was associated with decreased vascular endothelial growth factor (VEGF)/angiogenesis and a complex rearrangement of the gene expression profile as evaluated by microarray analysis. In conclusion, YY1 and VEGF/CXCR4 seem to intervene in the pathogenesis of the malignant phenotype of osteosarcoma by acting on cell invasiveness and metastasis growth.

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Chemokines, originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury, have a function beyond their role in leukocyte chemotaxis. Indeed, they participate in organ development, angiogenesis, tumourigenesis and, more importantly, in the immune response. The chemokine family characterized by four highly conserved cysteine amino acid residues, with two cysteine residues (C) and a non-cysteine amino acid (X) between them (CXC), is known for its ability to promote trafficking of various leukocytes and to regulate angiogenesis and vascular remodelling. Intriguingly, the presence or absence of a structural-functional domain constituted by glutamic acid-leucine-arginine motif that precedes the first cysteine amino acid residue accounts for their unique property to induce or inhibit angiogenesis (angiogenic or angiostatic activity). The ability of CXC chemokine receptor 3 to promote Th1-dependent immunity and, at the same time, inhibit angiogenesis (immunoangiostasis) is of critical importance for inducing tumour regression. Agents that are able to inhibit angiogenic activities or promote angiostatic activities of CXC chemokines are future targets for research on cancer treatment. Here, we review insights on CXC chemokines in the context of immunoangiostasis and vascular damage.

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Circulating endothelial progenitor cells (EPCs) play a significant role in neovascularization of ischaemic tissues and in re-endothelization of injured blood vessels. Identification of compounds able to enhance EPC levels and improve their functional activity, noticeably compromised by risk factors for coronary heart disease, is of clinical interest. This study evaluates the effects of red wine on EPCs. After being isolated from total peripheral blood mononuclear cells, EPC phenotype was confirmed by the presence of double positive cells for DiLDL uptake and lectin binding and by expression of CD34, CD133 and VE-cadherin cell surface markers. Long-term culture in the presence of red wine (1 microl/ml), containing resveratrol (Resv) at physiological concentration (nM), determined a time-dependent amelioration of cell number (P < 0.05). The presence of red wine prevented the TNF-alpha-induced reduction of EPC number (P < 0.05) and this effect was accompanied by reduced p38-phosphorylation expression levels (P < 0.05) and increased NOx levels (P < 0.05) Indeed, pure Resv alone significantly improved the TNF-alpha reduced EPC number (P < 0.05). This evidence indicates novel beneficial effects of red wine and Resv in the positive modulation of EPCs levels.

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Strong evidence indicates that bone marrow cells (BMCs) can contribute to the healing process of injured vascular system via CXCR4/Thymosin beta4/Integrin alpha4beta1/SDF-1 molecular pathways. We discuss the therapeutic approaches of BMCs and circulating endothelial progenitor cells (EPCs) to restore vascularization. Today some clinical trials employing BMCs in the treatment of peripheral vascular diseases have been completed with encouraging results. When large clinical controlled studies will be completed, the scientific community will evaluate this novel and promising therapeutic approach. Although some basic studies suggest the potential use of adult/somatic stem cell for vascular repair, other stringent data suggest that this potential is dependent also on growth factor synthesis rather than the formation of new arterial vessels. Considering the limitations of adult stem cells especially in elderly subjects, our point of view is that BMCs or exogenous BMC/EPC are candidate for adjunct cell-therapy applications in vascular repair.

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BACKGROUND: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown. OBJECTIVE: In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired. DESIGN: FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 microg transdermal estradiol twice weekly. METHODS: Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 microg GnRH i.v. bolus in phases 1 and 2. RESULTS: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses. Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects. Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects. CONCLUSIONS: The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.

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To study the effects of sildenafil on human sleep-related erections according to the state of androgenization, we evaluated the effects of sildenafil on sleep-related erections in hypogonadal men before and during testosterone replacement treatment and in control subjects. We enrolled 24 hypogonadal men and 24 healthy men as a control group. All hypogonadal subjects had very low testosterone levels (<200 ng/dL [6.9 nmol/L]) [corrected] All subjects underwent nocturnal penile tumescence and rigidity monitoring (NPTRM) for 3 consecutive nights and were randomly assigned to consume either 50 mg of sildenafil or placebo 1 hour before bedtime on the second or third night of nocturnal penile monitoring. The hypogonadal subjects were tested twice, first without replacement treatment (H-T) and then after at least 6 months of testosterone replacement therapy (H+T). The subjects of the control group (C) were tested once. The following parameters of sleep-related erections were analyzed: total number of valid erections, total duration of both rigidity greater than or equal 70% and increase in penile circumference greater than or equal 30 mm, maximum rigidity, and maximum increase in penile circumference. NPTRM parameters were reduced in hypogonadal men before testosterone treatment (H-T+P) when compared with control subjects taking placebo (C+P). NPTRM parameters after testosterone (H+T+P) and sildenafil (H-T+S) administration were similar to that of control subjects taking placebo (C+P). When the statistical analysis was restricted to the hypogonadal men before testosterone treatment, sildenafil alone significantly increased NPTRM parameters when compared with placebo (H-T+S vs H-T+P). Testosterone restored normal erections when administered to hypogonadal subjects (H+T+P vs H-T+P); in hypogonadal men, however, the combined treatment (sildenafil plus testosterone) resulted in the maximum positive effect on NPTRM parameters. When the increase from baseline was analyzed, the effects of testosterone plus sildenafil were greater than the sum of the effects of each drug used alone. In conclusion, sildenafil administered at bedtime improves sleep-related erections in hypogonadal men, suggesting that the nitric oxide pathway may be pharmacologically enrolled and enhanced despite low serum testosterone. Furthermore, these data strongly support the idea of a synergic effect on sleep-related erections of sildenafil and testosterone.

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The report focuses on the role of estrogens in human male, dealing with two human models of congenital estrogen deficiency: estrogen resistance and aromatase deficiency. Similarities and differences of clinical phenotypes of these models are described and progresses of estrogen treatment of aromatase-deficient men are reported. Finally, the putative use of estrogen in men and the use of aromatase inhibitors and antiestrogen for male disorders are discussed.

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We studied the effects of sildenafil on sleep-related erections in 44 adult healthy men not affected by erectile dysfunction (mean age +/- SD: 39.3 +/- 10.5 years). No subjects were administered any medication the first night, but all were randomly administered sildenafil 50 mg or placebo the second night and vice versa the third night. Sildenafil and placebo were administered 1 hour before bedtime. The following parameters of sleep-related erections, after taking sildenafil or placebo, were analyzed: total number of valid erections, total duration of rigidity more than or equal to 70% of a tightening force of 2.8 N applied by the recording device, total duration of increase in penile circumference more than or equal to 30 mm, maximum rigidity, mean of maximum rigidity, and maximum increase of tumescence. Apart from the maximum increase of tumescence, all the parameters analyzed were significantly higher after sildenafil than after placebo administration during the first 4 hours of monitoring in all subjects (n = 44) (study 1). All the parameters were significantly higher after sildenafil than after placebo administration during the whole 8 hours of monitoring in 25 of 44 subjects (study 2A) who slept at least 8 hours. Comparing both the first and the second 4 hours in the 25 of 44 subjects who slept at least 8 hours (study 2B), all the parameters were significantly higher after sildenafil than after placebo administration, apart from maximum rigidity and mean of maximum rigidity during the first 4 hours. Our data suggest that sildenafil, administered at bedtime, is efficacious in improving sleep-related erections in normal men, indirectly confirming that the nitric oxide pathway is crucial in the physiology of erections during sleep. The effect of sildenafil is prolonged up to 8-9 hours after its administration.

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To clarify the role of estrogen on male pituitary function, the effects of different doses of transdermal E2 on pituitary secretion were evaluated in a man with aromatase deficiency. The study protocol was divided into the following three phases: no E2 treatment (phase 1); 25 microg transdermal E2 twice weekly for 9 months (phase 2);12.5 microg transdermal E2 twice weekly for 9 months (phase 3). Pituitary function was studied in detail during each phase of the study protocol by measuring hormone levels in basal conditions and after dynamic testing (GnRH, insulin tolerance test, GHRH plus arginine, TRH, and corticotropin-releasing factor; tests). Basal and GnRH-stimulated gonadotropin levels resulted inversely related to E2 serum levels, according to the dosage of estrogen administered. Basal and stimulated GH, PRL, and TSH serum levels did not change during the protocol study. The secretory pituitary reserve of GH was clearly impaired. Basal and stimulated ACTH and cortisol serum levels were not modified by estrogen administration. This study demonstrated that in the human male E2 is required at pituitary level for normal functioning of gonadotropin feedback both in basal and stimulated conditions. In this patient GH deficiency seems to be an adult-onset event since he reached a tall stature. However, the finding of a severe impairment in GH response to potent provocative stimuli together with the insensitivity of GH/IGF-I axis to circulating estrogens strongly suggest a possible involvement of estrogens on both the development and maturation of the somatotrophic axis. Finally, the congenital lack of estrogen activity seems to be associated with a slightly impaired secretion of PRL and TSH, suggesting a possible role of estrogens on the pituitary secretion of these hormones in the human male.

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