Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women's Endocrinology.

PURPOSE: To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. METHODS: A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. RESULTS: A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. CONCLUSION: This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.

Pharmacological Approaches to Controlling Cardiometabolic Risk in Women with PCOS.

Polycystic ovary syndrome (PCOS) is characterized by elevated androgen production and subclinical changes in cardiovascular and metabolic risk markers. Total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and fasting insulin appear to increase specifically in PCOS compared with fertile women. PCOS also confers an increased risk of cardiometabolic disease in later life. Novel biomarkers such as serum's cholesterol efflux capacity and blood-derived macrophage activation profile may assist in more accurately defining the cardiometabolic risk profile in these women. Aldosterone antagonists, androgen receptor antagonists, 5α-reductase inhibitors, and synthetic progestogens are used to reduce hyperandrogenism. Because increased insulin secretion enhances ovarian androgen production, short-term treatment with metformin and other hypoglycemic agents results in significant weight loss, favorable metabolic changes, and testosterone reduction. The naturally occurring inositols display insulin-sensitizing effects and may be also used in this context because of their safety profile. Combined oral contraceptives represent the drug of choice for correction of androgen-related symptoms. Overall, PCOS management remains focused on specific targets including assessment and treatment of cardiometabolic risk, according to disease phenotypes. While new options are adding to established therapeutic approaches, a sometimes difficult balance between efficacy and safety of available medications has to be found in individual women.

Pacemaker-associated thrombosis in ongoing therapy with edoxaban tosylate.

Thromboembolism is a known complication of pacemaker implantation. However, published literature describes only a few cases, in which the events occurred in absence of antithrombotic prophylaxis, not routinely employed for its prevention in current clinical practice. We report a case of pacemaker lead-associated thrombosis in a patient taking continuative oral anticoagulant therapy with edoxaban tosylate (edoxaban). No data in present literature supports the use of anticoagulant prophylaxis for pacemaker lead thrombosis. In our report ongoing treatment with edoxaban proved ineffective for thrombosis prevention. We also discuss the role of three-dimensional transthoracic echocardiography for diagnostic assessment of thrombosis in a fragile patient.

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis.

OBJECTIVE: Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes. STUDY SELECTION: Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis. DATA SYNTHESIS: ACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35-1.30), p = 0.001, impaired FMD (ES = - 1.59, 95% C.I. - 2.33 to - 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37-1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02-0.84, p = 0.041) and FMD was impaired (ES = - 0.66, 95% C.I. - 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients. CONCLUSIONS: IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

Western diets are not responsible for chronic acid retention: a critical analysis of organic acid and phosphate contribution.

According to usual literature, the diet-dependent endogenous production of titratable acidity (TA) is contributed by sulphuric and phosphoric acids (NA) and by metabolizable acids (MAs), representing 'net-endogenous acid production' (NEAP). NEAP is mainly neutralised by diet-dependent [Formula: see text] salts of inorganic cations ([Formula: see text]), estimated in foods, faeces and urine from inorganic cation-anion difference (NB). It is claimed that urinary loss of organic acids' anions, '[Formula: see text]', induces metabolizable H+ ions' retention. Since '[Formula: see text]' is normally lost in urine as '[Formula: see text]' or '[Formula: see text]', no MA retention takes place. Therefore, in our approach, net acid production (NAP) reduces to endogenous sulphuric acidity only. Since in western diets (WDs) alkaline cations exceed inorganic anions (NB excess), acid excess from phosphorus is neutralized. Moreover, the renal reabsorption of ultra-filtered Pi takes place at [Formula: see text] ratios greater than '4/1', which means that the kidney operates as a dietary Pi-dependent NB generator ([Formula: see text] or [Formula: see text]). Since, in standard WDs, H2SO4 generation is less than '[Formula: see text]' production, the sulphuric acidity escaping the intestinal [Formula: see text] absorption is neutralized by [Formula: see text] and excreted as diet-dependent [Formula: see text], without interfering in normal A/B status. Only when extreme acidifying diets are ingested, sulphuric acidity may exceed '[Formula: see text]'. In this case, the excess of sulphuric acidity production is neutralised by the intervention of urinary [Formula: see text] excretion, whose employment is normally restricted to prevent loss of ultra-filtered NB. Finally, the whole body NA balance (NAb(W)) is calculated from the difference 'NAabs - NA(u)', where abs = intestinal absorption and u = urinary excretion. Being 'NAabs ≈ NA(u)', NAb(W) approximates zero, confirming WDs as non-acidifying foods.

Mathematical rationalization for the renal tubular transport: revised concepts.

The current emphasis on kinetics and in situ control of molecular exchanges, across the tubular membrane, has not been paralleled by corresponding improvements in our understanding of tubular behaviour at the macroscopic level of classical physiology. In this paper, we propose a mathematical rationalization of macroscopic tubular transport by means of a principal transport equation, originating from the law of mass action between substrate and carrier. The other equations, derived from the main one, demonstrate the possibility of distinguishing between transporters with low affinity and high capacity and transporters with high affinity and low capacity. Moreover, our model formalizes both tubular reabsorption and tubular secretion. Regarding the renal calcium handling, our model confirms the two-compartment system proposed by Mioni in 1971, with some important variants, which are in agreement with the fractional reabsorptions of this cation along the tubule, as verified by micro-puncture technique. To obtain the frequency distribution of saturated tubules, we have utilized the infinitesimal analysis method, starting from the equations proposed by Smith in 1943, concluding that all titration curves result from the combined effect of enzymatic approach and anatomical heterogeneity of the nephrons. The theoretical equations included in our manuscript reflect substantial and palpable physiological mechanisms able to suggest diagnosis and therapy of some electrolyte and hormonal disorders. At the end of this paper, we highlight advantages and disadvantages detectable by comparing our mathematical approach with Marshall's and Bijvoet's methods, proposed, respectively, in 1976 and 1984.

Old and new approaches to the interpretation of acid-base metabolism, starting from historical data applied to diabetic acidosis.

The approach to acid-base chemistry in medicine includes several methods. Currently, the two most popular procedures are derived from Stewart's studies and from the bicarbonate/BE-based classical formulation. Another method, unfortunately little known, follows the Kildeberg theory applied to acid-base titration. By using the data produced by Dana Atchley in 1933, regarding electrolytes and blood gas analysis applied to diabetes, we compared the three aforementioned methods, in order to highlight their strengths and their weaknesses. The results obtained, by reprocessing the data of Atchley, have shown that Kildeberg's approach, unlike the other two methods, is consistent, rational and complete for describing the organ-physiological behavior of the hydrogen ion turnover in human organism. In contrast, the data obtained using the Stewart approach and the bicarbonate-based classical formulation are misleading and fail to specify which organs or systems are involved in causing or maintaining the diabetic acidosis. Stewart's approach, despite being considered 'quantitative', does not propose in any way the concept of 'an amount of acid' and becomes even more confusing, because it is not clear how to distinguish between 'strong' and 'weak' ions. As for Stewart's approach, the classical method makes no distinction between hydrogen ions managed by the intermediate metabolism and hydroxyl ions handled by the kidney, but, at least, it is based on the concept of titration (base-excess) and indirectly defines the concept of 'an amount of acid'. In conclusion, only Kildeberg's approach offers a complete understanding of the causes and remedies against any type of acid-base disturbance.

A mathematical model of pH, based on the total stoichiometric concentration of acids, bases and ampholytes dissolved in water.

In chemistry and in acid-base physiology, the Henderson-Hasselbalch equation plays a pivotal role in studying the behaviour of the buffer solutions. However, it seems that the general function to calculate the valence of acids, bases and ampholytes, N = f(pH), at any pH, has only been provided by Kildeberg. This equation can be applied to strong acids and bases, pluriprotic weak acids, bases and ampholytes, with an arbitrary number of acid strength constants, pKA, including water. By differentiating this function with respect to pH, we obtain the general equation for the buffer value. In addition, by integrating the titration curve, TA, proposed by Kildeberg, and calculating its Legendre transform, we obtain the Gibbs free energy of pH (or pOH)-dependent titratable acid. Starting from the law of electroneutrality and applying suitable simplifications, it is possible to calculate the pH of the buffer solutions by numerical methods, available in software packages such as Excel. The concept of buffer capacity has also been clarified by Urbansky, but, at variance with our approach, not in an organic manner. In fact, for each set of monobasic, dibasic, tribasic acids, etc., various equations are presented which independently fit each individual acid-base category. Consequently, with the increase in acid groups (pKA), the equations become more and more difficult, both in practice and in theory. Some examples are proposed to highlight the boundary that exists between acid-base physiology and the thermodynamic concepts of energy, chemical potential, amount of substance and acid resistance.

Titratable acidity: a Pitts concept revisited.

Titratable Acidity (TA) in urine can be measured directly or calculated from actual and reference pH, by using the pKa2 6,8 for phosphate. In urine, H2PO4(-) represents the excretion of filtered H2PO4(-), filtrated HPO4(2-) being completely reabsorbed by the proximal tubule (the Van Slyke approach). Since excretion of H2PO4(-) frequently exceeds its glomerular filtration, this approach is considered inadequate by Pitts. He claimed that it is the tubular H(+) secretion which converts filtered HPO4(2-) to H2PO4(-), thereafter excreted in urine. This is only true under conditions of inorganic acid or neutral phosphate loading, when the maximum tubular phosphate reabsorption (TmPi) is overcharged. In controls, H2PO4(-) excretion is lower than its glomerular filtration, provided that acid-base status is normal and tubular phosphate reabsorption is below the TmPi. The TmPi is lower than its glomerular filtration, provided that acid-base status is normal and tubular phosphate reabsorption is below the TmPi. When the TmPi is exceeded, a portion of HPO4(2-) escapes proximal reabsorption, reaching the distal tubule where its absorption is precluded, while tubular H(+) secretion converts HPO4(2-) to H2PO4(-). In man and dog, the attainment of TmPi is evidenced by a FE% of 20%, and only beyond this limit H2PO4(-) excretion exceeds glomerular filtration. When FE% is lower than 20%, H2PO4(-) filtration exceeds excretion, HPO4(2-) being completely reabsorbed at the proximal tubule by NaPi-2a and 2c cotransporters. While Van Slyke's approach is always valid, Pitts' approach is only valid under loading conditions, when the two processes of H2PO4(-) excretion overlap each other. NH (+4) increases inversely to TA excretion in conditions of acidosis and tP restriction, but is independent of TA in Pi-replete dogs, independently of acidosis.

Insulin and body weight but not hyperandrogenism seem involved in seasonal serum 25-OH-vitamin D3 levels in subjects affected by PCOS.

PCOS patients were frequently characterized by lower plasma vitamin D levels. The mechanisms involved in this dysfunction remains still debated, therefore we evaluated the role of androgen, insulin and body weight on the serum VitD levels in women with or without PCOS. Eighty one patients 18-42 yrs old were studied into "SUMMER" and "WINTER" seasonal period: thirty seven PCOS, seventeen no-ovarian hyperandrogenic (noPCOS), twelve functional hypothalamic amenorrhea (FHA) and finally fifteen healthy (Con). Patients were further divided into: lean (L), obese (O), normo- (nINS) and hyperinsulinemic (hINS). All hormonal and metabolic parameters were measured at 1-7 days of the menstrual cycle. Our results show that VitD levels were lower in PCOS and in noPCOS than in FHA and Con, in particular in (O) and (hINS) PCOSs. Both in summer and in winter, PCOSs had basal VitD levels significantly lower than FHA and Con, whereas they were similar to noPCOS. Yet, LhINS and OPCOS had VitD levels lower than Con and noPCOS. VitD levels were comparable in LnINS PCOS and Con. In conclusion, PCOSs had levels of VitD lower than controls. Weight and hyperinsulinemia had a significant influence on these values. Finally, over 70% of our healthy patients had VitD deficiency.

Cyclic variations of bone resorption mediators and markers in the different phases of the menstrual cycle.

Female hormones are very important in regulating bone homeostasis; the drop of estrogen levels occurring at menopause is linked to a dramatic prevalence of bone resorption on formation. Only a small number of studies investigated the relationship between changes in circulating female sex hormones and the markers and mediators of bone homeostasis and they showed conflicting results. To explore such relationships we studied 20 young fertile healthy women, aged between 19 and 32 years. None had received hormone treatment for at least 6 months. We assayed luteinizing hormone, follicle-stimulating hormone, progesterone and 17ß-estradiol, as well as the levels of osteoprotegerin (OPG), C-terminal telopeptide of collagen type I (CTx) and RANKL (receptor activator of nuclear factor-B ligand) in samples drawn from every subject at four different times during the menstrual cycle when estrogens are lowest, at the start of the cycle: T 0 (2-4th day); when estrogens are highest, in the pre-ovulatory period: T 14 (12-14th day); when progesterone activity is highest, in the advanced luteal phase: T 26 (24-26th day); and again at the start of the next cycle: T 01 (2-4th day). We observed that CTx levels are highest at the start of the cycle, decreased significantly from T 0 to T 26 (pfwe = 0.0455) and then increased from T 26 to T 01 (pfwe = 0.0415); OPG, on the other hand, which was also highest at the start of the cycle, decreased significantly from T 0 to T 14 (pfwe = 0.02) and then increased, though not significantly, from T 14 to T 01; no variation was observed in RANKL values at any time. We observed inverse correlations between estradiol and OPG levels, which became highly significant at T 01 between estradiol nadir and OPG peak levels (pfw = 0.0095). Furthermore, the increase of estradiol from T 0 to T 14 was negatively correlated with the concomitant decrease of OPG (pfwe = 0.0277), as was the fall of estradiol from T 26 to T 01 with the OPG peak levels, both at T 01 (pfw = 0.0045) and at T 0 (pfwe = 0.0381). We also observed direct correlations between the OPG levels and the variations of progesterone in the preceding intervals, but they never attained statistical significance. We conclude that OPG and CTx fluctuation during the menstrual cycle are likely due to the physiological variations of sex steroids levels.

Sertoli-Leydig cell tumors: current status of surgical management: literature review and proposal of treatment.

To identify the appropriate management we review the current literature on the diagnostic and different surgical procedures to which the patients affected by Sertoli-Leyding cell tumors (SLCTs) were submitted. Through the description of a case report we also propose an interdisciplinary diagnostic approach and a laparoscopic surgical staging, with a long-term follow-up. The analysis shows that pelvic ultrasound is primary diagnostic procedure, and only 36% of publications clearly describe to have performed more specific investigation. The hormone assessment is performed in the presence of specific endocrine symptoms. Laparoscopic approach is chosen by a few surgeon. Laparotomic surgery is preferred based in not recent recommendations for ovarian cancer treatment, although it is demonstrated the efficacy and safety of laparoscopy in the treatment of ovarian epithelial tumors. Different steps that are usually used for oncological ovarian cancer staging are not always performed. Conservative and fertility sparing surgery is commonly accepted, and even preferred due to the young age of patients. In the surgical treatment of SLCTs is necessary to adopt common guidelines, and evenly define the steps that the patient should be submitted. If are observed epithelial cancer oncological principles, laparoscopic surgery should be the approach of choice for these patients.

Insulin receptor and glucose transporters mRNA expression throughout the menstrual cycle in human endometrium: a physiological and cyclical condition of tissue insulin resistance.

The expression of insulin receptor (IR), together with that of glucose transporters 1 and 4 (GLUT1-4) and of Insulin Growth Factor-I and -II (IGF-I,-II) in the endometrium of healthy and young women in both phases of menstrual cycle was assessed. Sixteen out of 20 healthy and normal menstruating volunteers were studied. Endometrial samplings were performed in every subject, twice in the same cycle, during the follicular and luteal phase respectively. The mRNA expression of IR, GLUT1-4, IGF-I and -II were evaluated by real-time quantitative RT-PCR and immunostaining reactions. Our results indicate that IR, GLUT1-4, IGF-I and -II mRNAs were expressed in both phases of the endometrial cycle: GLUT4 and IGF-I mRNA expression were significantly higher in the follicular phase and localized at the epithelial and stromal cell level, respectively, whereas IR, GLUT1 and IGF-II mRNA expression were mostly present in the secretory phase and mainly localized at the stromal level. An inverse tendency of IR and GLUT4 mRNA expression was respectively observed from follicular to luteal phase. In conclusion our data suggest that IR, glucose transporters and IGFs are significantly and differently expressed at the endometrial level throughout the menstrual cycle and that human endometrium cyclically undergoes through a transitory condition from normal to an insulin-resistance state.

Do Androgenic Pattern, Insulin State and Growth Hormone Affect Cardiorespiratory Fitness and Strength in Young Women with PCOS?

In this study, cardiorespiratory fitness (CRF) and strength level were assessed in women with and without polycystic ovary syndrome (PCOS), matched for age, body composition, androgenic pattern and insulinemic pattern. Patients with and without PCOS were evaluated at the Endocrinology Unit and Sport Medicine Division to assess endocrinological (insulinemic, androgenic pattern and growth hormone), anthropometric (with DEXA) and functional parameters (with cardiopulmonary exercise test and handgrip test), as well as physical activity level (with the Global Physical Activity Questionnaire). A total of 31 patients with PCOS and 13 controls were included. No statistically significant differences were found between groups in terms of age, body mass index, body composition, androgenic pattern, insulin state, growth hormone and physical activity level. The PCOS group demonstrated significantly better cardiorespiratory fitness (VO2max per kg (30.9 ± 7.6 vs. 24.8 ± 4.1 mL/kg/min; p = 0.010), VO2max per kg of fat-free mass (52.4 ± 8.9 vs. 45.3 ± 6.2 mL/kg/min; p = 0.018)), strength levels (handgrip per kg (0.36 ± 0.09 vs. 0.30 ± 0.08; p = 0.009), handgrip per kg of fat-free mass (13.03 ± 2.32 vs. 11.50 ± 1.91; p = 0.001)) and exercise capacity (METs at test (14.4 ± 2.72 vs. 12.5 ± 1.72 METs; p = 0.019)). In this study, women with PCOS showed a better cardiorespiratory fitness and strength than the control group. The only determinant that could explain the differences observed seems to be the presence of the syndrome itself. These results suggest that PCOS per se does not limit exercise capacity and does not exclude good functional capacity.

Elevated Intrarenal Resistive Index Predicted Faster Renal Function Decline and Long-Term Mortality in Non-Proteinuric Chronic Kidney Disease.

Background. Intrarenal resistive index (RI) ≥ 0.80 predicts renal outcomes in proteinuric chronic kidney disease (CKD). However, this evidence in non-proteinuric patients with CKD of unknown etiology is lacking. In this study, we assessed the effect of intrarenal RI on renal function and all-cause mortality in non-proteinuric patients with CKD of unknown etiology despite an extensive diagnostic work-up. Methods. Non-proteinuric CKD patients were evaluated in a retrospective longitudinal study. Progression of renal disease was investigated by checking serum creatinine levels at 1, 3, and 5 years and defined by a creatinine level increase of at least 0.5 mg/dL. The discrimination performance of intrarenal RI in predicting the 5-year progression of renal disease was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Results. One-hundred-thirty-one patients (76 ± 9 years, 56% males) were included. The median follow-up was 7.5 years (interquartile range 4.3−10.5) with a cumulative mortality of 53%, and 5-year renal disease progression occurred in 25%. Patients with intrarenal RI ≥ 0.80 had a faster increase of serum creatinine levels compared to those with RI < 0.80 (+0.06 mg/dL each year, 95% CI 0.02−0.10, p < 0.010). Each 0.1-unit increment of intrarenal RI was an independent determinant of 5-year renal disease progression (odds ratio 4.13, 95% CI 1.45−12.9, p = 0.010) and predictor of mortality (hazards ratio 1.80, 95% CI 1.05−3.09, p = 0.034). AUROCs of intrarenal RI for predicting 5-year renal disease progression and mortality were 0.66 (95% CI 0.57−0.76) and 0.67 (95% CI 0.58−0.74), respectively. Conclusions. In non-proteinuric patients with CKD of unknown etiology, increased intrarenal RI predicted both a faster decline in renal function and higher long-term mortality, but as a single marker, it showed poor discrimination performance.

Gene Polymorphism in Five Target Genes of Immunosuppressive Therapy and Risk of Development of Preeclampsia.

Pregnancy can be considered as an allogeneic transplant and preeclampsia can be seen as a failure of the acceptance mechanisms of this transplant as occurs in acute organ transplant rejection. Some genetic polymorphisms may be involved in its pathogenesis. Since the kidney is one of the organs mainly involved in preeclampsia, our study attempted to determine the frequencies of single nucleotide polymorphisms of DNA (SNP) in 3 genes (adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1)/multi drug reactivity 1 (MDR1) gene, interleukin 10 gene and tumor necrosis factor α gene) which are targets of immunosuppressive therapies and related to acute renal rejection. The study was an observational, monocentric, case-control study. We enrolled 20 women with severe preeclampsia and 10 women age-matched with regular pregnancy. Continuous variables were compared by the Student's t-test for independent variables or using the Mann-Whitney test depending on their distribution. We used Fisher test to compare categorical variables between cases and controls, while we used logistic regression model to evaluate which risk factor was associated with preeclampsia. Although there was no statistically significant difference between the two groups, we found different percentages of two of the polymorphisms considered (rs1045642 and rs2032582 in the gene ABCB1). Despite these results, our work may be helpful for future research to better understand the pathogenesis of preeclampsia.

Practical Considerations for the Management of Cushing's Disease and COVID-19: A Case Report.

Introduction: Italy, since the end of February 2020, is experiencing the corona virus disease 2019 (COVID-19) pandemic that may present as an acute respiratory infection. We report on COVID-19 pneumonia in the context of a complex case of Cushing's disease (CD). Case Report: A 67-year-old man with CD, who was admitted to our hospital, presented with signs and symptoms of adrenal insufficiency with persistent hypotension and glycemia toward the lower limits. We progressively withdrew almost all treatments for diabetes and CD (pasireotide and metyrapone), and i.v. hydrocortisone was necessary. A tendency to hyperkalemia was probably associated to enoxaparin. We summarized the many possible interactions between medications of Cushing's syndrome (CS) and COVID-19. Conclusion: Adrenal insufficiency might be a clinical challenge that needs a prompt treatment also in CS patients during COVID-19 infection. We should consider the possibility to titrate or temporary halt medical therapies of CS in the context of COVID-19 infection. Unexpected hyperkalemia in CS patients under treatment with heparin might be the signal of aldosterone suppression.

Activation profiles of monocyte-macrophages and HDL function in healthy women in relation to menstrual cycle and in polycystic ovary syndrome patients.

PURPOSE: Hormonal status and menopause affect human macrophage function and cardiometabolic risk. In polycystic ovary syndrome (PCOS) patients the cardiometabolic risk increases through mechanisms that are largely unknown. We tested the hypotheses that macrophage activation is influenced by menstrual cycle and that ovarian dysfunction in PCOS patients is associated with altered macrophage inflammatory responses and cholesterol efflux capacity of serum HDL. METHODS: Blood samples were obtained in the follicular and luteal phases from cycling women (n = 10) and on a single visit from PCOS patients with ovarian dysfunction (n = 11). Monocyte-derived macrophage activation and monocyte subsets were characterized ex vivo using flow cytometry. The capacity of HDL to promote cell cholesterol efflux through the main efflux pathways, namely aqueous diffusion, ATP-binding cassette A1 and G1, was also evaluated. RESULTS: Hormone and metabolic profiles differed as expected in relation to menstrual cycle and ovulatory dysfunction. Overall, macrophage responses to activating stimuli in PCOS patients were blunted compared with cycling women. Macrophages in the follicular phase were endowed with enhanced responsiveness to LPS/interferon-γ compared with the luteal phase and PCOS. These changes were not related to baseline differences in monocytes. HDL cholesterol efflux capacity through multiple pathways was significantly impaired in PCOS patients compared to healthy women, at least in part independent from lower HDL-cholesterol levels. CONCLUSIONS: Regular menstrual cycles entailed fluctuations in macrophage activation. Such dynamic pattern was attenuated in PCOS. Along with impaired HDL function, this may contribute to the increased cardiometabolic risk associated with PCOS.

Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy.

BACKGROUND AND AIMS: Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly. METHODS: We studied 40 acromegalic patients (23 male, age 52 ±â€¯11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity. RESULTS: CFR was lower in patients than in controls (2.9 ±â€¯0.8 vs. 3.7 ±â€¯0.6, p < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = -0.5, p < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381-898] µg/l versus 246 [186-484] µg/l, p < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8-13.7] µg/l versus 5 [2.8-8.9] µg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder. CONCLUSIONS: Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly.

Hyperinsulinemia and obese phenotype differently influence blood pressure in young normotensive patients with polycystic ovary syndrome.

To differentiate the impact of insulin levels/resistance per se from that of excess weight on blood pressure (BP) daily changes, we evaluated, using 24-h ambulatory blood pressure monitoring (ABPM), systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a cohort of young normotensive patients affected by polycystic ovary syndrome (PCOS). A cross-sectional study was performed. Fifty-four patients were studied according to (a) insulinemic state: 32 hyperinsulinemic and/or insulin-resistant (h-INS) and 22 normoinsulinemic (n-INS) patients; and (b) body mass index (BMI): 22 obese (BMI > 30) and 32 lean (18.0 < BMI < 24.9) patients. Each subject's SBP and DBP and heart rate (HR) were measured by ABPM. Supine and upright plasma renin activity (PRA), and aldosterone levels were also assayed. Patients in the h-INS group showed higher 24-h, daytime, and nighttime diastolic blood pressure (DBP), higher nighttime systolic blood pressure (SBP) levels, as well as an increased 24-h, daytime and nighttime HR, compared to both obese and lean patients in the n-INS group. In relation to BMI, only 24-h, daytime, and nighttime DBP were higher in obese than in lean patients. At variance, when both h-INS and obesity were considered, 24-h SBP and DBP were higher in h-INS obese subjects than in the other groups. In multivariate analysis, insulin (max peak), area under the curve of insulin and insulin sensitivity index was independently associated with SBP. (1) Within a normotensive range, hyperinsulinemia and/or insulin resistance influence daily BP variation more than obesity does, suggesting a pivotal role of insulin on BP control in PCOS; (2) altered insulinemic state and ABPM-derived higher nighttime BP and HR may represent early markers to identify PCOS subjects prone to high cardiovascular risk.