Long-Term Outcomes of Patients with Acromegaly - A Report from the Swedish Pituitary Register

Objective: To describe treatment and long-term outcomes of patients with acromegaly from all health-care regions in Sweden. Design and Methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991-2011. The latest clinical follow-up date was December, 2012, while mortality data were collected for 28.5 years until June, 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy and 39% medical treatment. At the 5- and 10-year follow-ups, IGF-I levels were within the reference range in 69% and 78% of patients, respectively. In linear regression the proportion of patients with biochemical control including adjuvant therapy at 10 year follow-up increased over time with 1.23 % per year. The SMR (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed 1991-2000, SMR 1.06 (0.85-1.33) or 2001-2011, SMR 0.87 (0.61-1.24). In contrast, non- controlled patients at the latest follow up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AME) AND INTERNATIONAL CHAPTER OF CLINICAL ENDOCRINOLOGY (ICCE). POSITION STATEMENT FOR CLINICAL PRACTICE: PROLACTIN-SECRETING TUMORS

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century prolactinomas represented the paradigm of pituitary tumors for whom the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Recovery of Male Reproductive Function After Ceasing Prolonged Testosterone Undecanoate Injections

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later. Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since last injection. Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

High Prevalence of Subnormal Testosterone in Obese Adolescent Males: Reversal with Bariatric Surgery

Objective: Obesity in adolescent males is associated with lowering of total and free testosterone concentrations. Weight loss may increase testosterone concentrations. Design and Methods: We evaluated changes in sex hormones following bariatric surgery in 34 males (age range 14.6 – 19.8 years) with obesity. These participants were part of prospective multicenter study, Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS). Participants were followed for five years after surgery. Total testosterone, total estradiol, LH, FSH, SHBG, CRP, insulin and glucose were measured at baseline, six months and annually thereafter. Free testosterone, free estradiol and HOMA2-IR were calculated. Results: Study participants lost one-third of their body weight after bariatric surgery, with maximum weight loss achieved at 24 months for most participants. Free testosterone increased from 0.17 nmol/L(95% CI: 0.13, 0.20) at baseline to 0.34 (95% CI: 0.30, 0.38) at two years and 0.27(95% CI: 0.23, 0.32) nmol/L at five years (p<0.001 for both) respectively. Total testosterone increased from 6.7 nmol/L (95% CI: 4.7, 8.8) at baseline to 17.6(95% CI: 15.3, 19.9) and 13.8(95% CI: 11.0, 16.5) nmol/L at two and five years(p<0.001). Prior to surgery 73% of the participants had subnormal free testosterone(<0.23 nmol/L). After two years and five years, only 20% and 33%, respectively, had subnormal free testosterone concentrations. Weight regain was related to a fall in free testosterone concentrations. Conclusions: Bariatric surgery led to a robust increase in testosterone concentrations in adolescent males with severe obesity. Participants who regained weight had a decline in their testosterone concentrations.

Serum diiodotyrosine—a biomarker to differentiate destructive thyroiditis from Graves’ disease

Objective: Conventional diagnostic methods are limited in their ability to differentiate destructive thyroiditis from Graves’ disease. We hypothesised that serum diiodotyrosine (DIT) and monoiodotyrosine (MIT) levels could be biomarkers for differentiating destructive thyroiditis from Graves’ disease. Design: Patients with destructive thyroiditis (n = 13) and Graves’ disease (n = 22) were enrolled in this cross-sectional study. Methods: We assayed the serum DIT and MIT levels using liquid chromatography-tandem mass spectrometry. A receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity and specificity of the serum DIT and MIT levels as biomarkers for differentiating destructive thyroiditis from Graves’ disease. Results: The serum DIT and MIT levels were significantly higher in patients with destructive thyroiditis than in those with Graves’ disease. The ROC curve analysis showed that the serum DIT levels (≥ 359.9 pg/mL) differentiated destructive thyroiditis from Graves’ disease, significantly, with 100.0% sensitivity and 95.5% specificity (P < .001). The diagnostic accuracy of the serum MIT levels (≥119.4 pg/mL) was not as high as that of the serum DIT levels (sensitivity, 84.6%; specificity, 77.3%; P = .001). Conclusions: The serum DIT levels may serve as a novel diagnostic biomarker for differentiating destructive thyroiditis from Graves’ disease.

Long-term body composition improvement in post-menopausal women following bariatric surgery: a cross-sectional and case-control study

Objective: Bariatric surgery (BS) induces loss of body fat mass (FM) with an inexorable loss of lean mass (LM). Menopause leads to deleterious changes in body composition (BC) related to estrogen deficiency including LM loss and increase in total and visceral adipose tissue (VAT). This study aims to describe long-term weight evolution of post-menopausal women after RYGB (Roux-en-Y gastric bypass) and to compare BC between BS patients versus post-menopausal non-operated women. Design: Cross-sectional study of 60 post-menopausal women who underwent RYGB ≥ two years prior to the study with nested case-control design. Methods: Post-menopausal BS women were matched for age and BMI with controls. Both groups had DXA scan, lipids and glucose metabolism markers assessment. Results: Median follow-up was 7.5(2–18) years. Percentage of total weight loss (TWL%) was 28.5±10%. After RYGB, LM percentage of body weight (LM%) was positively associated with TWL% and negatively associated with nadir weight. Forty-one post-BS women were matched with age- and BMI-controls. Post-BS patients showed higher LM% (57.7%[±8%] versus 52.5%[±5%], p=0.001), reduced FM% (39.4%[±8.4%] versus 45.9%[±5.4%] p<0.01) and lower VAT (750.6g[±496] versus 1295.3g[±688], p<0.01) with no difference in absolute LM compared to controls. While post-BS women showed a better lipid profile compared to controls, no difference was found in glucose markers. Conclusions: Post-menopausal women after RYGB have a lower FM and VAT, preserved LM and a better lipid profile compared to controls. Weight loss after RYGB seems to have a persistent positive impact on metabolic health.

The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes

Objective: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate consequences of hyperglucagonemia in type 2 diabetes. Design: A double-blinded, randomized, placebo-controlled crossover study was conducted. Methods: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity towards related incretin receptors was determined in vitro. Results: Compared to placebo, LY2409021 lowered fasting plasma glucose from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P<0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data. Conclusions: LY2409021 lowered fasting plasma glucose concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

Efficacy and tolerance of Osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas

no abstract needed

Metabolically healthy obesity was significantly associated with increased risk of gallstones

Objective The risk of gallstones among metabolically healthy obesity (MHO) individuals is largely unexplored. Therefore, the present study investigated the association between MHO and gallstones in a health check-up cohort of Chinese adults. Design A prospective cohort study. Methods Participants included 58,862 individuals from the MJ health check-up cohort aged ≥ 18 years without history of gallstones at baseline. Gallstones were diagnosed using abdominal B-type ultrasound. Metabolically healthy was defined as not having any one of the components of metabolic syndrome. Obesity was identified by body mass index (BMI) and waist circumference (WC). Participants were cross-classified at baseline by metabolic health and obesity. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of gallstones across BMI categories were estimated with Cox proportional hazard regression models. Results During a median follow-up of 3.0 (interquartile range, 1.6-6.1) years, 1,269 participants developed gallstones. Individuals with MHO (HR: 1.95, 95% CI: 1.23, 3.09 for BMI criteria; HR: 1.74, 95% CI: 1.37, 2.21 for WC criteria) had significantly higher risk of gallstones than those with metabolically healthy normal weight. In metabolically healthy individuals, BMI and WC both displayed linear dose-response relationships with gallstones (P for non-linearity > 0.05). The association between MHO and gallstones remained unchanged when using different criteria for metabolic health and obesity. Conclusions MHO was significantly associated with gallstones, suggesting that obesity can independently contribute to gallstones development, even among metabolically healthy individuals. These findings emphasize that metabolically healthy individuals may still benefit from maintaining normal body weight to prevent gallstones.