New insights into the comorbid conditions of Turner syndrome: results from a long-term monocentric cohort study.

PURPOSE: Many questions concerning Turner syndrome (TS) remain unresolved, such as the long-term complications and, therefore, the optimal care setting for adults. The primary aim of this long-term cohort study was to estimate the incidence of comorbid conditions along the life course. METHODS: A total of 160 Italian patients with TS diagnosed from 1967 to 2010 were regularly and structurally monitored from the diagnosis to December 2019 at the University Hospital of Bologna using a structured multidisciplinary monitoring protocol. RESULTS: The study cohort was followed up for a median of 27 years (IQR 12-42). Autoimmune diseases were the comorbid condition with the highest incidence (61.2%), followed by osteoporosis and hypertension (23.8%), type 2 diabetes (16.2%) and tumours (15.1%). Median age of onset ranged from 22 years for autoimmune diseases to 39 years for type 2 diabetes. Malignant tumours were the most prominent type of neoplasm, with a cumulative incidence of 11.9%. Papillary thyroid carcinoma was the most common form of cancer, followed by skin cancer and cancer of the central nervous system. Only one major cardiovascular event (acute aortic dissection) was observed during follow-up. No cases of ischaemic heart disease, heart failure, stroke or death were recorded. CONCLUSIONS: This cohort study confirms the need for continuous, structured and multidisciplinary lifelong monitoring of TS, thus ensuring the early diagnosis of important comorbid conditions, including cancer, and their appropriate and timely treatment. In addition, these data highlight the need for the increased surveillance of specific types of cancer in TS, including thyroid carcinoma.

Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature.

Immune Check-Point Inhibitors (CPIs) have improved long-term patients' outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs' side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.

Steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency in a population of PCOS with suspicious levels of 17OH-progesterone.

OBJECTIVE: We aimed at defining the most effective routine immunoassay- or liquid chromatography-tandem mass spectrometry (LC-MS/MS)-determined steroid biomarkers for identifying non-classic adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH) in a PCOS-like population before genotyping. METHODS: Seventy PCOS-like patients in reproductive age with immunoassay-determined follicular 17OH-progesterone (17OHP) ≥ 2.00 ng/mL underwent CYP21A2 gene analysis and 1-24ACTH test. Serum steroids were measured by immunoassays at baseline and 60 min after ACTH stimulation; basal steroid profile was measured by LC-MS/MS. RESULTS: Genotyping revealed 23 21-NCAH, 15 single allele heterozygous CYP21A2 mutations (21-HTZ) and 32 PCOS patients displaying similar clinical and metabolic features. Immunoassays revealed higher baseline 17OHP and testosterone, and after ACTH stimulation, higher 17OHP (17OHP60) and lower cortisol, whereas LC-MS/MS revealed higher 17OHP (17OHPLC-MS/MS), progesterone and 21-deoxycortisol and lower corticosterone in 21-NCAH compared with both 21-HTZ and PCOS patients. Steroid thresholds best discriminating 21-NCAH from 21-HTZ and PCOS were estimated, and their diagnostic accuracy in identifying 21-NCAH from PCOS was established by ROC analysis. The highest accuracy was observed for 21-deoxycortisol ≥ 0.087 ng/mL, showing 100% sensitivity, while the combination of 17OHPLC-MS/MS ≥ 1.79 ng/mL and corticosterone ≤ 8.76 ng/mL, as well as the combination of ACTH-stimulated 17OHP ≥ 6.77 ng/mL and cortisol ≤ 240 ng/mL by immunoassay, showed 100% specificity. CONCLUSIONS: LC-MS/MS measurement of basal follicular 21-deoxycortisol, 17OHP and corticosterone seems the most convenient method for diagnosing 21-NCAH in a population of PCOS with a positive first level screening, providing high accuracy and reducing the need for ACTH stimulation test.

Behavioral, socio-environmental, educational and demographic correlates of excess body weight in Italian adolescents and young adults.

BACKGROUND AND AIMS: Excess body weight (EBW) is the most prevalent nutritional disorder among adolescents worldwide. Identifying determinants of EBW may help find new intervention strategies. Behavioral, socio-economic, educational and demographic correlates of EBW were examined in a population of Italian adolescents, separately for males and females. METHODS AND RESULTS: As many as 1039 male and 2052 female students (aged 16-19 ys) attending the last three years of different types of high-school of the Emilia-Romagna region in Italy were offered participation, with 552 males and 841 females being finally evaluated. The prevalence of EBW was 21.0% in males and 14.1% in females. Step-wise multivariate logistic regression analyses were performed showing that EBW was negatively related to energy intake in males (odds ratio for 100 kcal/day (OR) = 0.94, 95% confidence interval (CI): 0.89 to 0.98; P = 0.008), and to father's educational attainment (OR = 0.70, 95% CI: 0.52 to 0.95; P = 0.020), but positively related to parental obesity (OR = 2.80, 95% CI: 1.65 to 4.76; P < 0.001). In females, EBW was positively related to parental obesity (OR = 1.94, 95% CI: 1.15 to 3.29; P = 0.013), but negatively to mother's educational attainment (OR = 0.66, 95% CI: 0.45 to 0.97; P = 0.034) and type of attended school (OR = 0.66, 95% CI: 0.49 to 0.89; P = 0.007). Mother's occupation was also an independent determinant of EBW status in females (OR = 0.39, 95% CI: 0.18 to 0.85; P = 0.018 for being unemployed vs blue-collar). CONCLUSION: Parental obesity is associated with EBW in male and female adolescents. Importantly, we found sex differences in socio-economic and educational factors impacting on EBW, supporting possible distinct area of investigation.

Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS. OBJECTIVE: To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men. DESIGN: A prospective, longitudinal, case-control, clinical trial. METHODS: Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG. RESULTS: Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001). CONCLUSION: This study demonstrates for the first time using LC-MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.

Short-term modification of sex hormones is associated with changes in ghrelin circulating levels in healthy normal-weight men.

The aim of this study was to evaluate the effect of selective and short-term sex hormone modifications on ghrelin levels in normal-weight eugonadal men undergoing hormonal contraceptive treatments. Seven men received an oral progestin [cyproterone acetate (CPA) or dienogest (DNG)] 10 mg/day for 3 weeks (CPA-DNG group), 7 CPA orally 5 mg/day in association with testosterone enanthate (TE) im 200 mg/week for 8 weeks (CPA-TE group), and 7 placebo (PLAC) for 8 weeks (PLAC group). Anthropometry and blood levels of LH, FSH, testosterone, estradiol, glucose, insulin and total ghrelin were evaluated. At baseline, no parameters differed among the three groups. After treatment, LH and FSH decreased in both CPA-DNG and CPA-TE groups, whereas they did not change in the PLAC group. Testosterone and estradiol decreased in the CPA-DNG group to the hypogonadal range, increased in the CPA-TE group to supraphysiological concentrations and, as expected, remained unchanged in the PLAC group. Total ghrelin levels increased in the CPA-DNG, decreased in the CPA-TE and did not change in the PLAC group. Ns modifications in the other parameters were observed in any group, demonstrating that the short-term changes of circulating sex hormones are able to modify ghrelin levels. These data, therefore, suggest that sex steroids are important regulators of ghrelin in normal-weight healthy men too.

Obesity and the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype. Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.