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Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in patients with hypopituitarism and hypothalamic damage (HHD), that might be associated with neuropsychological deficits and sexual dysfunction, leading to worse quality of life (QoL). Therefore, identifying a provocative test to diagnose an OXT-D will be important. Corticotropin-releasing hormone (CRH) is a candidate for such a test as it increases oxytocin secretion in animal models. This study aimed to examine the effects of CRH on oxytocin release in HHD compared to healthy controls (HC) and to describe the psychopathology, sexual function and QoL and their associations with oxytocin. This is a single-blind, randomized, placebo-controlled, proof-of-concept study (NCT 04902235) with crossover assignment (CRH vs. placebo). Nineteen HHD patients (10 females) and 20 HC (11 females) completed two visits, receiving CRH or placebo in random order and completed validated questionnaires to assess psychopathology, sexual function and QoL. Samples were collected over 120 min to assess oxytocin. Linear mixed-effects regression model evaluated the change in oxytocin after CRH/placebo in HHD vs. HC. CRH administration did not impact oxytocin concentrations across groups over time (p = 0.97). HHD had greater psychopathology (most ps < 0.05), sexual dysfunction (p < 0.03) and worse QoL (p < 0.001) compared to HC, nevertheless, baseline oxytocin concentrations and area under the curve of oxytocin were not significantly associated with psychopathology, sexual function or QoL, neither in HHD or HC. In conclusion, CRH administration does not appear to be a suitable provocative test for diagnosing OXT-D in HHD. Identifying a reliable diagnostic test for OXT-D remains crucial. Alternative provocative tests or biomarkers should be explored.

Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging. To evaluate relationships between TL, CVR and inflammation markers in CS. In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL. Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL. TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a \"low\" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.

PurposeThis review is aimed at examining whether the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is higher in Caucasian, adult, treatment-naïve patients with acromegaly (ACRO) than in the reference population independently of diabetes presence and to evaluate the impact of treatment [surgery and somatostatin analogues (SSAs)] on its assessment.MethodsWe systematically reviewed in PubMed and Web of Science from July 1985 to December 2019, registered with the code number CRD42020148737. The inclusion criteria comprised studies conducted in Caucasian adult treatment-naïve patients with active ACRO in whom HOMA-IR or basal insulin and glucose were reported. Three reviewers screened eligible publications, extracted the outcomes, and assessed the risk of biases.ResultsOf 118 originally selected studies, 15 met the inclusion criteria. HOMA-IR was higher in ACRO than the reference population, with mean difference and (95% confidence intervals) of 2.04 (0.65–3.44), even in ACRO patients without diabetes, 1.89 (1.06–2.73). HOMA-IR significantly decreased after treatment with either surgery or SSAs − 2.53 (− 3.24– − 1.81) and − 2.30 (− 3.05– − 1.56); respectively. However, the reduction of HOMA-IR due to SSAs did not improve basal glucose.ConclusionHOMA-IR in treatment-naïve ACRO patients is higher than in the reference population, even in patients without diabetes. This finding, confirms that insulin resistance is an early event in ACRO. Our results also suggest that HOMA-IR is not an adequate tool for assessing insulin resistance in those patients treated with SSAs.

Abstract Context Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established. Objectives We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology. Design Cross-sectional. Setting Clinical research center. Participants Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years. Interventions Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology. Main Outcomes Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life. Results The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009). Conclusions We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency. Plasma OT levels are low and psychopathy is increased in hypopituitary men with CDI, suggestive of a possible OT-deficient state.

Abstract Context Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear. Objective We explored the potential nexus between GCs or stress exposure and telomere length. Methods In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans. Results (1) Exposure to stress in rats was associated with a 54.5% (P = 0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P = 0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P = 5.75 × 10-5) and 58.8% reduction in telomere length in the dentate gyrus (P = 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P = 0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P = 0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2 = 0.22, P = 0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P = 0.019). Conclusion Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible.

Abstract Context Oxytocin regulates a range of physiological processes including eating behavior and oxytocin administration reduces caloric intake in males. There are few data on oxytocin and eating behavior in healthy females or on the response of endogenous oxytocin to food intake and its relationship to appetite in humans. Objectives To determine the postprandial pattern of oxytocin levels, the relationship between oxytocin and appetite, and the impact of menstrual cycle phase and age on oxytocin levels in females. Design Cross-sectional. Setting Clinical research center. Participants Fifty-five healthy females (age 10 to 45 years). Interventions A standardized mixed meal was administered. Main Outcome Measurements Blood sampling for oxytocin occurred at fasting and at 30, 60, and 120 minutes postmeal. Appetite was assessed using Visual Analogue Scales pre- and postmeal. Results Mean fasting oxytocin levels were 1011.2 ± 52.3 pg/mL (SEM) and decreased at 30 and 60 minutes postmeal (P = 0.001 and P = 0.003, respectively). Mean oxytocin levels decreased19.6% ± 3.0% from baseline to nadir. Oxytocin area under the curve was lower in the early to midfollicular menstrual cycle phase (P = 0.0003) and higher in younger females (P = 0.002). The percent change in oxytocin (baseline to nadir) was associated with postprandial hunger (rs = -0.291, P = 0.03) and fullness (rs = 0.345, P = 0.009). These relations remained significant after controlling for calories consumed, menstrual cycle status, and age (P = 0.023 and P = 0.0001, respectively). Conclusions Peripheral oxytocin levels in females decrease after a mixed meal and are associated with appetite independent of menstrual phase, age, and caloric intake, suggesting that endogenous oxytocin levels may play a role in perceived hunger and satiety. Peripheral oxytocin levels decrease after a meal and are associated with postprandial appetite independent of menstrual phase, age, and food intake in females.

PurposeTo describe the clinical characteristics, management and pregnancy outcome of women with prepregnancy hypopituitarism (HYPO) that received care at our center.MethodsRetrospective study describing 12 pregnancies in women with prepregnancy HYPO (two or more pituitary hormonal deficiencies under replacement treatment) that received care during pregnancy at Hospital Santa Creu i Sant Pau. Clinical characteristics, management and pregnancy outcome were systematically collected.ResultsAverage patients’ age was 35 years and HYPO duration at the beginning of pregnancy was 19 years. The most frequent cause of HYPO was surgical treatment of a sellar mass (8 pregnancies). Eight pregnancies were in primigravid women and 10 required assisted reproductive techniques. The hormonal deficits before pregnancy were as follows: GH in 12 women, TSH in 10, gonadotropin in 9, ACTH in 5 and ADH in 2. All deficits were under hormonal substitution except for GH deficit in 4 pregnancies. During pregnancy, 4 new deficits were diagnosed. The dosage of replacement treatment for TSH, ACTH and ADH deficits was increased and GH was stopped. Average gestational age at birth was 40 weeks, gestational weight gain was excessive in 9 women, 8 patients required induction/elective delivery and cesarean section was performed in 6. Average birthweight was 3227 g. No major complications were observed. Five women were breastfeeding at discharge.ConclusionsIn this group of women with long-standing HYPO, with careful clinical management (including treatment of new-onset hormonal deficits) pregnancy outcome was satisfactory but with a high rate of excessive gestational weight gain and cesarean section.

Abstract Context In healthy females, oxytocin levels decrease postmeal, corresponding to increased satiety. The postprandial response of oxytocin in females with anorexia nervosa (AN)/atypical AN is unknown. Objectives To determine the pattern of postprandial serum oxytocin levels in females with AN/atypical AN, relationship with appetite, and effect of weight, eating behavior, and endogenous estrogen status. Design Cross-sectional. Setting Clinical research center. Participants 67 women (36 with AN [<85% expected body weight (EBW)]; 31 with atypical AN [≥ 85% EBW)]), age 22.4 ± 0.9 (mean ± SEM) years, categorized by weight, restricting vs binge/purge behavior, and estrogen status. Interventions Standardized mixed meal. Main Outcome Measurements Blood sampling for oxytocin occurred fasting and 30, 60, and 120 minutes postmeal. Subjective appetite was assessed using visual analog scales. Results In females with AN/atypical AN, oxytocin levels decreased from fasting to 60 (P = 0.002) and 120 (P = 0.005) minutes postmeal. The decrease in oxytocin from fasting to 120 minutes was greater in females with atypical AN than AN (P = 0.027) and did not differ by restricting vs binge/purge behavior or estrogen status. Controlling for caloric intake, the decrease in oxytocin was inversely related to the decrease in hunger postmeal in females with atypical AN (P = 0.04). Conclusions In females with AN/atypical AN, oxytocin levels decrease postmeal, as established in healthy females. Weight, but not restricting vs binge/purging nor endogenous estrogen status, affects postprandial oxytocin levels. The postprandial change in serum oxytocin levels is related to appetite in females with atypical AN only, suggesting a disconnect between oxytocin secretion and appetite in the undernourished state. Postprandial oxytocin (OT) decrease in anorexia nervosa (AN)/atypical AN. OT change is related to appetite in atypical AN only, suggesting a disconnect between OT and appetite in undernourished state.

Objective Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. Design Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR , AP2S1 and GNA11 genes. Methods Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. Results We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger ( p  = 0.029), reported more frequently a positive family history ( p  < 0.001), presented higher magnesium ( p  < 0.001) and lower parathormone levels ( p  < 0.001) and were less often treated for hypercalcemia ( p  = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709–0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826–0.991). Conclusions The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.

Introduction Cushing syndrome (CS) of any etiology (adrenal, pituitary or ectopic) impacts negatively on health-related quality of life (QoL), especially in active hypercortisolism but also after endocrine cure. Both generic questionnaires like the short-form 36 health survey -SF-36- and the derived SF-12, or the Hospital Anxiety and Depression Scale (HADS), and disease-specific measures like the CushingQoL and the Tuebingen CD-25 questionnaires have provided information on the impact of CS on patients perceived health. Materials and methods Studies published since January 2013 until November 2014 on QoL in patients with CS were identified, reviewed and summarized. Conclusions Treatment of CS improves patients perceived QoL, but it often takes many months and often never normalizes. In parallel to persistent QoL impairment in cured CS, brain and cerebellar volume are reduced. Depression, anxiety and cognitive dysfunction are common. Pediatric patients with CS also present worse QoL than normal children, as well as additional issues like delayed growth and pubertal development, next to abnormal body composition, psychological and cognitive maturation. Fluoxetine has been suggested as a neuroprotectant and antidepressant for patients with CS, although no prospective studies are yet available. The CushingQoL questionnaire has been mapped to well-validated instruments like SF-36 or EQ-5D, and therefore may be used in cost-utility and other health economy studies.