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This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.This Consensus Statement, which is endorsed by the Pituitary Society, offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas.

GH is banned by the World Anti-Doping Agency as a performance-enhancing anabolic agent. Doping with GH likely began in the early 1980s and became more prevalent with the advent of recombinant technology well before any scientific evidence of benefit. The expectation that GH improves physical function stems from its anabolic and lipolytic properties. Athletic performance depends on muscle strength and the energy required to power muscle function. In recreational athletes, GH selectively improves anaerobic sprint capacity but has not been proven to significantly enhance muscle strength, power, or maximum rate of oxygen consumption. GH is secreted as a family of isoform peptides in a pulsatile manner reflecting intermittent secretion and rapid clearance. Its anabolic actions are largely mediated by IGF-I, which stimulates whole-body protein synthesis, including skeletal muscle and collagen proteins. Two methods have been validated for detecting GH abuse in athletes. The first (the isoform method) is based on distinguishing pure recombinant 22-kDa GH from the heterogeneous isoforms secreted from the pituitary. The second (the marker method) is based on measuring blood levels of GH-responsive proteins, specifically IGF-I and the N-terminal propeptide of type III collagen (P-III-NP). Only a handful of athletes have been caught since the implementation of GH doping tests in 2004. The low rate likely reflects the limitation of in-competition testing using current methods. Improved detection rates may be achieved by more out-of-competition testing, introducing athletes’ biological passports, and the development of novel methods. Governance, operational, technical, and political factors influence the effectiveness of an anti-doping program.

ObjectiveHepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models.DesignWe established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells.ResultsProm1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation.ConclusionOur study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.

In the 2022 fifth edition of the WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, pituitary adenomas are reclassified as neuroendocrine tumours (NETs). This change confers an oncology label to neoplasms that are overwhelmingly benign. A comprehensive clinical classification schema is required to guide prognosis, therapy and outcomes for all patients with pituitary adenomas. Pituitary adenomas and NETs exhibit some morphological and ultrastructural similarities. However, unlike NETs, pituitary adenomas are highly prevalent, yet indolent and rarely become malignant. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the merit and clinical implications of the classification change of pituitary adenoma to NET. Many non-histological factors provide mechanistic insight and influence the prognosis and treatment of pituitary adenoma. We recommend the development of a comprehensive classification that integrates clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms.This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the implications of the WHO classification change of pituitary adenoma to neuroendocrine tumours. The authors propose that a comprehensive classification system be developed integrating clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms.

Acromegaly usually occurs owing to a growth-hormone-secreting adenoma in the pituitary gland, which leads to metabolic and anatomical changes in the patient. This Expert Consensus Document outlines the current recommendations for the treatment of acromegaly as determined by the Acromegaly Consensus Group in March 2013. In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.

Abstract Growth hormone (GH) regulates metabolic and physical health in the adult human. Because the GH system is regulated by estrogens, therapeutic estrogen compounds are likely to affect metabolic health. Estrogens are available for oral and parenteral use in natural, prodrug, and synthetic formulations including selective estrogen receptor modulators (SERMs). This review covers the pharmacology of estrogen and the effects on GH action to inform judicious use in the pituitary patient. The effects on the GH system are route dependent due to first-pass hepatic metabolism. Oral but not parenteral estrogen compounds inhibit GH action, reducing hepatic insulin-like growth factor-1 (IGF-1) production, protein anabolism, and fat utilization. In patients with GH deficiency, oral estrogen therapy exacerbates the degree of hyposomatotrophism and attenuates the beneficial effects of GH replacement therapy, effects that are greater with contraceptive than replacement doses. Surveys report that less than one-fifth of hypopituitary women are appropriately replaced by a transdermal route and up to half on oral therapy are inappropriately treated with contraceptive steroids. In acromegaly, however, estrogens, especially synthetic formulations of greater potency, reduce IGF-1, improving disease control, an effect also observed in men treated with SERMs. The route-dependent effects and potency of estrogen formulations are important considerations for optimizing the management of hypogonadal patients with pituitary disease, in particular GH deficiency and acromegaly. For hypopituitary women, estrogens should be replaced by a nonoral route. For acromegaly, oral estrogen formulations can be considered as simple adjuvant therapy for disease control.

Osteoarthritis is the main cause for total knee arthroplasty (TKA), followed by rheumatoid arthritis. Previous studies have reported conflicting results concerning the risk of surgical site infection after TKA for rheumatoid arthritis and osteoarthritis patients. Thus, this study aimed to examine whether rheumatoid arthritis patients had a higher risk of acute surgical site infection after TKA compared to osteoarthritis patients. We conducted a retrospective cohort study using Taiwan’s National Health Insurance Research Database of the whole population from 2012 to 2015, and collected the medical records of osteoarthritis patients or rheumatoid arthritis patients who underwent TKA. To evaluate the risk of acute surgical site infection in rheumatoid arthritis patients, propensity score matching was implemented for osteoarthritis patients. Acute surgical site infection was observed in 2.58% of TKA cases in rheumatoid arthritis patients and 2.66% of TKA cases in osteoarthritis patients. Rheumatoid arthritis and osteoarthritis patients had comparable risk for 90-day (odds ratio = 0.81, 95% confidence interval: 0.371–1.768) and 1-year (odds ratio = 0.463, 95% confidence interval: 0.121–1.766) surgical site infection. In conclusion, patients with rheumatoid arthritis were not at higher risk of acute surgical site infection after TKA compared to osteoarthritis patients. The current treatment strategy for patients with RA is safe and appropriate if they require TKA.

Abstract Context Estrogen receptor antagonism by tamoxifen inhibits GH secretion in both men and postmenopausal women, suggesting that estrogen, albeit at low concentration, stimulates GH secretion. However, systemic estrogen replacement in postmenopausal women does not enhance GH secretion. To clarify the role of estrogen in mediating GH secretion, we investigated the effect of estrogen deprivation by using aromatase inhibitors. Aim To determine whether estrogens mediate GH secretion in men and postmenopausal women. Design The effects of letrozole, an aromatase inhibitor, and tamoxifen were compared in an open-label crossover study. Eight men and 14 women received tamoxifen (20 mg/d) and letrozole (2.5 mg/d) for 2 weeks each. The primary endpoints were GH response to arginine stimulation and gonadal steroid levels. Results In men, letrozole significantly (P < 0.05) reduced the peak GH response to arginine (mean ± SEM; Δ −49.4% ± 18.1%). Tamoxifen also reduced the mean peak GH, but this did not reach statistical significance. In postmenopausal women, letrozole did not affect peak GH, whereas tamoxifen significantly (P < 0.05) reduced peak GH (Δ −47.3% ± 10%). In men, letrozole reduced circulating estradiol (from 43.1 ± 2.8 to 12.7 ± 1.3 pmol/L; P < 0.001), whereas in women estradiol was undetectable (<11 pmol/L) at baseline and throughout letrozole therapy. Conclusion Because estrogen deprivation reduced circulating GH, we conclude that estrogens regulate GH secretion in men. In postmenopausal women, the neutral effect of aromatase inhibition is likely explained by pre-existing estrogen deficiency. The inhibition of GH secretion by tamoxifen in menopause suggests a non–estrogen receptor-mediated mechanism of action. In contrast to men, estrogen is unlikely to mediate GH secretion in postmenopausal women. Aromatase inhibition significantly reduced GH secretion and circulating estradiol in men but not postmenopausal women, indicating that estrogen is unlikely to mediate GH secretion in menopause.