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.

Caveolar Dysfunction and Lipodystrophies

Congenital generalized lipodystrophy (CGL) is a rare, heterogeneous, autosomal recessive disorder characterized by near total absence of body fat with increased muscularity noticed at birth or in early infancy. Four distinct genetic subtypes of CGL have been reported to date. Types 1 and 2 are caused by biallelic variants in the 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) genes, respectively, and are the most common subtypes (1). Types 3 and 4 are extremely rare and are caused by biallelic variants in the caveolin 1 (CAV1) (2), and Caveolae Associated Protein-1 (CAVIN1; also known as polymerase I and transcript release factor (PTRF)]) genes (3), respectively. Patients with all CGL subtypes are predisposed to metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis; however, each subtype presents with some unique clinical features.