Multiple endocrine neoplasia (MEN) syndromes constitute a heterogeneous group of hereditary disorders predisposing to endocrine tumours of varying malignant potential. Recent advances in molecular genetics and tumour biology have significantly reshaped our understanding of underlying pathophysiology, enabling earlier diagnosis, genotype-specific surveillance and the emergence of targeted therapies. This review provides a contemporary overview of key recent advances and consensus guidelines across MEN syndromes, including MEN1, MEN2, MEN4, and MEN5 syndromes, SDHx syndrome, Carney complex, McCune–Albright syndrome, DICER1 syndrome and von Hippel–Lindau syndrome. These insights reflect a rapidly evolving field with genetic diagnosis at the centre of prognostic assessment, targeted surveillance and individualised management.

BACKGROUND:Lower testosterone concentrations in older men are associated with poorer health outcomes. OBJECTIVE:We examined whether, on a background of lifestyle intervention, testosterone treatment modulates leucocyte telomere length, a postulated marker of biological ageing, in overweight men with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (T2D). PARTICIPANTS AND METHODS:We conducted a secondary analysis of a randomised, placebo-controlled trial in 50- to 74-year-old men with waist circumference ≥ 95 cm and dysglycaemia (ACTRN12612000287831). All men received a background lifestyle program, and were randomised to 2 years treatment with intramuscular testosterone undecanoate (1000 mg) every 3 months or placebo. Leucocyte telomere length was assayed by multiplex quantitative polymerase chain reaction and expressed as relative telomere length (rTL), a ratio of telomeric DNA to β-globin, a single-copy control gene (T/S ratio). RESULTS:There were 720 participants, aged 60 ± 6 years (mean ± SD), 38% had BMI 30-34.99 kg/m2 and 44% ≥ 35 kg/m2. Mean rTL at baseline was 1.63 ± 0.27 in testosterone-treated men (N = 375) and 1.61 ± 0.28 in placebo-treated men (N = 345). At 2 years, mean rTL was 1.61 ± 0.28 and 1.58 ± 0.29, respectively. Change in rTL after 2 years treatment was -0.02 ± 0.15 in testosterone-treated and -0.03 ± 0.12 in placebo-treated men. Adjusting for baseline values there was no effect of testosterone treatment on rTL at 2 years (mean difference 0.01 [95% CI, -0.01 to 0.03], p = 0.24). Results were similar for rTL change at 2 years from baseline. CONCLUSIONS:There was no effect of testosterone treatment on telomere length in this group of men. Larger studies with longer treatment durations are merited.

Disclosure: J. Lockett: None. E. Brooks: None. S. Bhaumik: None. J. Sorbello: None. W.J. Inder: None. V.L. Clifton: None. Introduction: Glucocorticoids act via the glucocorticoid receptor (GR) to exert pleiotropic effects on all tissues, with heterogeneity in cellular response, aimed at regulating cellular and metabolic homeostasis. Recent advances in our mechanistic understanding of the GR demonstrate a more complex interplay of functions than traditionally considered. Multiple splice variants and translational isoforms of GR have been elucidated which contribute to cellular glucocorticoid sensitivity and may have diverse functions. The aim was to assess the GR isoform expression in PBMCs of individuals with varying states of glucocorticoid exposure. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of healthy volunteers (HV), patients with endogenous Cushing syndrome (CS), adrenal insufficiency (AI) and treated with exogenous glucocorticoids for other conditions (GC). GR protein isoforms were measured via western blot. RNA was extracted from PBMC aliquots and RNA-Seq libraries prepared using Illumina Ribo-Zero plus and sequenced using NovaSeq X. Results: PBMC were collected from 42 HV (15 male, 12 pre-menopausal and 15 post-menopausal females), 10 CS, 10 AI and 16 GC. The cohort were 50 ± 1.8 years old, with the GC group being older, and had a mean BMI 27.2 ± 0.8 kg/m2 (which was significantly greater in the CS group). GR isoforms GRα-A, α-C, α-D1-3, -A and -P were identified in both the cytoplasm and nucleus of PBMCs across all groups. Isoforms GRα-C and D3 were the most frequently expressed (n = 69). Cytoplasmic expression of GRα-C (p = 0.005), GR-P (p = 0.01), and GR-A (p = 0.009) were lower in the GC group. After adjusting for age, BMI and sex/menopausal status, the lower cytoplasmic expression in of GR-P (p = 0.002) and GR-A (p = 0.03) in GC remained significant. No other differences were detected between groups, while nuclear isoform expression was also similar. Preliminary data suggest that isoform expression is correlated with both shared and unique gene expression, in pathways consistent with published in vitro studies. Genes correlated with GRα-A were enriched in pathways involving functions associated with extra-cellular matrix, metabolism, immune function and GR-P correlated genes were enriched in pathways associated with stem cell proliferation/differentiation, coagulation and platelet function, cell adhesion, TLR signalling, and RAS-MAPK pathway activation. GRα-D1, -D3 and GR-A gene correlations were enriched in pathways associated with ATP production, mitochondrial function, and ribonucleotide synthesis. Conclusion: Previously described GR isoforms are present in PBMC of humans regardless of glucocorticoid exposure state. There appears to be an in vivo difference in gene regulatory function of individual isoforms which may contribute to the variation in clinical sequelae of glucocorticoid perturbations. Presentation: Sunday, July 13, 2025

OBJECTIVE:Increased frequency of neuroimaging has led to enhanced identification of small nonfunctioning pituitary adenomas (NFPAs) leading, in many cases, to extensive follow-up. However, the value of ongoing monitoring of these incidental lesions remains unclear. The study aims to determine the need for surgical intervention and assess the risks of developing new endocrinopathies during follow-up in patients with conservatively treated micro-NFPAs. DESIGN:A systematic review and individual participant data (IPD) meta-analysis. METHODS:We conducted a bibliographical search of PubMed and EMBASE to identify relevant studies. Authors of eligible studies were invited to share IPD. Cohort studies including patients with conservatively treated micro-NFPAs with at least 1 follow-up magnetic resonance imaging were considered eligible. Fourteen studies met inclusion criteria. Six authors provided IPD (N = 647). Data were reanalyzed for verification. In cases of discrepancies the original authors were contacted for authentication. RESULTS:Risk estimates were reported as number of events per 100 person-years (PYs). Estimates were pooled using the 2-step approach. Overall probability of surgery was 0.2/100 PYs (95% CI: 0.0-0.4; I2 = 28%). Probability of surgery due to visual impairment was 0.1/100 PYs (95% CI: 0.0-0.2; I2 = 0%). Both were independent of baseline tumor size (≥6 or <6 mm), sex, or age (P values >.40). Risk of developing a new endocrinopathy was 1.0/100 PYs (95% CI: 0.4-1.6; I2 = 0%). Data for classical meta-analysis were available for 7 studies (N = 1089) and supported the IPD results. CONCLUSIONS:These data suggest that routine follow-up of micro-NFPAs can be reduced significantly and that available guidelines should be revisited.

Context The combined effects of testosterone treatment and lifestyle intervention on sexual function in men at high risk of type 2 diabetes are unclear.Objective To assess the effect of testosterone treatment with a lifestyle intervention in men aged 50 to 74 years at high risk of, or newly diagnosed with, type 2 diabetes (via oral glucose tolerance test).Design A secondary analysis of the Testosterone for the Prevention of Type 2 Diabetes trial, a double-blind, placebo-controlled trial conducted across 6 Australian centers.Interventions Intramuscular testosterone undecanoate (1000 mg) or placebo, 3 monthly for 2 years alongside a community-based lifestyle program.Main outcomes Sexual function measured using the International Index of Erectile Function (IIEF)-15 questionnaire.Results Of 1007 participants, 792 (79%) had complete International Index of Erectile Function-15 data. Baseline domain scores were inversely related to age and waist circumference, but unrelated to serum testosterone or estradiol levels. Testosterone treatment improved all 5 International Index of Erectile Function-15 domain scores, with stronger effects on sexual desire and orgasmic function in older men, and sexual desire in men with higher depression scores. Testosterone had no impact on depression. Independent of treatment, reductions in waist circumference were associated with improved erectile function, and reductions in depression scores correlated with better sexual function. Clinically significant improvement in erectile function and sexual desire occurred in 3% and 10% of men, respectively, and was inversely related to baseline function. Clinically significant improvement improvements in erectile function and sexual desire were greater in younger and older men respectively.Conclusion Testosterone treatment enhanced sexual desire and, to a lesser extent, erectile function, particularly in older men and those with higher waist circumference or depressive symptoms. Reduced waist circumference and depression independently improved sexual function.

Context:The diagnosis and differential diagnosis of Cushing syndrome (CS) is often challenging. Objective:To evaluate the 4-mg intravenous dexamethasone suppression test (IVDST) to differentiate CS from normal subjects and subjects with low probability of CS (LPC), and define the cortisol responses in pituitary, adrenal, and ectopic adrenocorticotropin (ACTH) CS. Methods:Data from 140 patients with surgically confirmed Cushing disease (CD), 5 with ectopic ACTH syndrome (EAS), 26 with adrenal CS (AC), and 97 with LPC, from 4 tertiary hospitals between 1995 and 2024 were retrospectively evaluated. Thirty-two controls (normal and overweight/obese participants with or without type 2 diabetes) were previously studied. Dexamethasone was infused at 1 mg/h for 4 hours. Plasma cortisol and ACTH were measured at -60 minutes, -5 minutes, +3 hours, +4 hours, +5 hours and on Day 2 (+23 hours and +23.5 hours). Main outcome measures were the sensitivity and specificity of the IVDST for the diagnosis of CS. Results:Controls showed marked cortisol suppression across Days 1 and 2. In 17 of 97 patients with LPC, Day 2 cortisol overlapped with CS. Day 2 cortisol level of >130 nmol/L diagnosed CS with 97% sensitivity and 87% specificity. Conclusion:The IVDST is a highly sensitive second-line diagnostic test for CS. False negative results occurred when IVDST is performed during an eucortisolemic phase of cyclic CD. The specificity of 87% emphasizes the importance of long-term follow-up of LPC. The small number of EAS cases is a major limitation in the use of IVDST to differentiate ACTH-dependent CS.

Objective We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect.Design Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357).Methods Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) >= 11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.Results Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c >= 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant's absolute risk of type 2 diabetes.Conclusions Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c >= 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.

OBJECTIVE:To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS:Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS:Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES:Self-reported measures of HR-QOL/psychosocial function. RESULTS:Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION:In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Abstract Disclosure: M. Umapathysivam: None. S. Nawaz: None. K. Robledo: None. C.A. Allan: None. K. Bracken: None. M. Grossmann: None. D.J. Handelsman: None. W.J. Inder: None. D. Jesudason: None. B. Stuckey: None. B. Yeap: None. A. Januszewski: None. A. Jenkins: None. A. Conway: None. B. Hastoy: None. G.A. Wittert: Consulting Fee; Self; I-Nova. Grant Recipient; Self; Lawley pharmaceuticals, Bayer, Weight Watchers, Eli Lilly & Company. Speaker; Self; Bayer, Inc., Amgen Inc, Besin Health Care. Background: In the Testosterone for the prevention of type 2 diabetes (T4DM) Study, treatment with testosterone (T)-undecanoate (1000 mg IM 3 monthly) vs placebo decreased fat mass and reduced the risk of T2D by 40% after 2 years. However, the mechanism(s) by which T therapy prevents or reverts T2D remain unclear. Aim: To assess (1) the impact of T treatment on insulin resistance (IR) and beta-cell function in the T4DM study and (2) the in-vitro effect of graded T exposure on glucose stimulated insulin secretion (GSIS) from the human beta-cell line EndoC-βH1. Methods: (1) T4DM study: Men (n= 1007) from the T4DM study aged, 50-74 years, waist circumference (WC) >95cm, with prediabetes, or newly diagnosed T2D (by OGTT) and serum testosterone (T) ≤ 14 nmol/L (chemiluminescent assay) treated with T-undecanoate (1000 mg IM 3 monthly) or placebo for 2 years. Men were included if they had fasting bloods at baseline, weeks 18, 66, and 102 (N=743). We compared the change in glycated albumin, and derived measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA-IR) using fasting glucose and c-peptide in T and placebo treated men using linear regression models.(2) EndoC-βH1 were incubated with T 5nM, 10nM and 15nM for 20 min and 15nM T for 2-days. Insulin secretion and content were measured at baseline (1mM glucose) and after 20 min exposure 20mM glucose. Results: Treatment with T compared to placebo reduced glycated albumin (-3.4 umol/L; 95%CI:1.4-5.4, p<0.001) maximally at week 66, along with C-peptide (corrected for baseline C-peptide and change in fasting glucose) (-0.12 nmol/L;-0.22,-0.02; p=0.01), HOMA2-B (-6.1; 95%CI: -16, 3.7; p=0.2) and HOMA-IR (-0.20; 95%CI: -0.59,0.20; p=0.3). In-vitro, acute exposure of EndoC-βH1 to 5nM and 10nM of T had no effect on GSIS, and 15nM T reduced GSIS (<20%, p=0.002). T, at 15nM for 2 days was without effect on GSIS. EndoC-βH1 insulin content was not altered at any concentration or timeframe of T exposure. Conclusion: In men with pre-diabetes or early T2D, T treatment reduces glycemia without evidence either in vivo or in-vitro of an affect to increase insulin secretion. Presentation: 6/1/2024

Context The recent WHO 2022 Classification of pituitary tumours identified a novel group of ‘plurihormonal tumours without distinct lineage differentiation (WDLD)’. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells. Objectives To determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours. Methods Retrospective evaluation of surgically resected pituitary tumours from St Vincent’s Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically “mature” types. Results On immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD. Conclusions Our study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.

The use and misuse of opioids are a growing global problem. Although the effects of these drugs on the human endocrine system have been studied for decades, attention on their related clinical consequences, particularly on the hypothalamic-pituitary system and bone health, has intensified over recent years. This Statement appraises research data related to the impact of opioids on the gonadal and adrenal function. Whereas hypogonadism is well recognized as a side effect of opioids, the significance of their inhibitory actions on the hypothalamic-pituitary-adrenal system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated. The often-inconsistent results of studies investigating how opioids affect the secretion of GH, prolactin, arginine vasopressin, and oxytocin are assessed. The accumulating evidence of opioid actions on bone metabolism and their negative sequelae on bone mineral density and risk of fracture are also reviewed. In each section, available data on diagnostic and management approaches for opioid endocrine sequelae are described. This Statement highlights a plethora of gaps in research associated with the effects and clinical consequences of opioids on the endocrine system. It is anticipated that addressing these gaps will improve the care of people using or misusing opioids worldwide. The Statement is not intended to serve as a guideline or dictate treatment decisions.

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.

Context The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%.Background The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described.Methods A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables.Results Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors.Conclusion We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU.

Abstract Disclosure: G.A. Wittert: Advisory Board Member; Self; Bayer Schering Pharma. Speaker; Self; Bayer Schering Pharma, Besin. K. Robledo: None. M. Grossmann: None. B.B. Yeap: Advisory Board Member; Self; Bayer Schering Pharma. Grant Recipient; Self; Bayer Schering Pharma, Lawley. B.G. Stuckey: None. W.J. Inder: None. K. Bracken: None. D.R. Jesudason: None. C.A. Allan: None. D.J. Handelsman: None. Background: In T4DM (men aged 50 – 74 yrs., waist circumference (WC) ≥95cm cm, prediabetes, or newly diagnosed type 2 diabetes (T2D) and serum testosterone (T) ≤ 14 nmol/L), 2 years treatment with T-undecanoate (1000 mg IM 3 monthly) vs placebo while enrolled in a lifestyle weight management program, decreased fat mass, and reduced the risk of T2D by 40%. Aim: To determine baseline predictors and T treatment effects on sexual function (SF) over time, including interactions with changes in waist circumference (WC), blood pressure (BP), glucose and mood. Methods: Adjusting for baseline sociodemographic, clinical parameters and serum sex steroid (LCMS) concentrations, linear mixed effects models were fitted to assess T treatment effects on measures of SF (erectile function (EF), sexual desire (SD), orgasmic function (OF), intercourse satisfaction (IS) and overall satisfaction (OS) via questionnaire (IIEF)) completed by each participant at baseline and weeks 30, 54, 78, and 102, together with WC, BP, glucose, trough T, estradiol (E), T:E ratio and mood (Center for Epidemiologic Studies Depression Scale (CES-D) at weeks 0, 54 and 102. Results Among men on T (504) or placebo (503) at baseline, age was inversely associated with all SF scales (p <0.001), and WC and CES-D score inversely associated with EF (p=0.041) and SD (p=0.029). There was no effect of baseline T, E or T:E ratio on SF. T treatment improved all SF measures (p<0.001) peaking at 30-54 weeks). The T treatment effect on SD and OF (both p-int=0.014) was greater in older men. Increasing WC over time was inversely associated with EF (p=0.036) and SD (p=0.043) scores, with no interaction with T treatment. SF scores were unaffected by changes in glucose, BP, or trough T, E or T:E ratio. Increase in depression scores corresponded to decreases in all SF scores (p <0.001). T treatment increased SD more in those with higher depression scores (p int=0.026) while not affecting the CES-D scores. Conclusion: Baseline age, WC, and depression scores, but not T were inversely associated with SF measures which improved with T treatment regardless of baseline T, E, or T:E ratio. T treatment improved SD and OF more in older men, and SD in those with more depressive symptoms. Change in WC was inversely associated with EF and SD, independent of T treatment. A pharmacological effect of T treatment to improve SF, particularly in older and depressed men, coexists with benefits from reduced central adiposity. Presentation: Thursday, June 15, 2023

Abstract Disclosure: D.J. Handelsman: None. M. Grossmann: None. B.B. Yeap: Consulting Fee; Self; Bayer, Inc., Lawley. Research Investigator; Self; Lawley. B.G. Stuckey: Speaker; Self; Lawley. N. Shankara-Narayana: None. A.J. Conway: None. W. Inder: None. R.I. McLachlan: None. C.A. Allan: None. A. Jenkins: None. D.R. Jesudason: None. K. Bracken: None. K. Robledo: None. G.A. Wittert: Research Investigator; Self; Bayer, Inc., Lilly USA, LLC. The T4DM study randomized 1007 men (age 50-74 yr, waist ≥95 cm, serum T ≤14.0 nmol/L, no pathological hypogonadism) with impaired glucose tolerance or newly diagnosed type 2 diabetes to T undecanoate (1000 mg) or matching placebo injections every 12 weeks for 24 months with a lifestyle program. At study’s end, T treatment reduced OGTT diabetes diagnosis by 40% without change in HbA1C. After a median of 5 years since last injection, a follow-up email survey obtained 705 responses (70%) comprising 599 completed surveys (316 T, 283 P, 10 deceased, 95 declining). Participants in follow-up survey were similar to non-participants in 23 anthropometric and demographic variables at entry to T4DM, but more in follow-up study were randomized to T (53 vs 46%%, p=0.038), had lower entry weight (107 vs 109 kg, p=0.026) and older school leaving age (16.7 vs 16.5 years, p=0.026) but remaining well matched for work status (46% retired, 35% full-time work, p=0.60), alcohol intake (69% nil or light, 3% heavy; p=0.12) and smoking (3% smoking, p=0.61). At long-term follow-up, randomization to T treatment was associated with stronger belief in benefits during study (64% vs 49%, p<0.001) with less for post-study benefits (44% vs 40%, p=0.07) but overall high interest in future studies (surveys 93%, clinical 76%). At entry, 35% had sleep apnea, most (71%) diagnosed pre-study, with new diagnosis more frequent on T during (9% vs 1%, p=0.03), but not before or after, the study. After study, T treatment was prescribed at a higher rate for men who had study T treatment (6% vs 2.8%, p=0.03), mostly using T injections with 81% continuing at 24 months (median) on post-study T treatment. In the long-term, study T treatment did not influence self-reported new post-T4DM study diagnosis of diabetes (19%, p=0.65) or diabetes drug treatments (22%, p=0.31; oral 18%, injectable 2%, both 2%), prostate disease (p=0.49; cancer 3%, non-cancer 8%) or cardiovascular disease (p=0.95; heart disease 13%, stroke 1%). Both groups had similar weight maintenance (maintained 24%, lost 22%, gain 24%, up/down 30%, p=0.91) and further attempts to lose weight (76%, p=0.29; diet 68%, exercise 57%, drugs 6%, surgery 2%). We conclude that randomized T (vs placebo) treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism, was associated with higher rates of (a) self-reported benefits during, but not after the study, (b) of resuming T treatment after the study, consistent with androgen dependence due to withdrawal (androgen deficiency) symptoms and/or recalling perceived benefits of study T treatment, and (c) of sleep apnea diagnosis during, but not before or after the study. Five years after T treatment stopped, there was no difference in the long-term rates of self-reported new diagnosis of diabetes, prostate or cardiovascular disease nor change in weight maintenance or weight loss behaviors. Presentation: Friday, June 16, 2023

OBJECTIVES:To (1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and (2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group.DESIGN:All IGF-1 measurements at Pathology Queensland between 1/12/2018-1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: (1) documentation of acromegalic features, (2) relevant comorbidities and medication use, and (3) further investigations to exclude pathological GH excess.PATIENTS AND MEASUREMENTS:There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI.RESULTS:There were significant differences in the frequency of dopamine agonist use (19/102 cases vs. 6/102 controls, OR = 3.66, 95% confidence interval [CI]: 1.45-9.29, p = .009) and chronic kidney disease (CKD) (14/102 cases vs. 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, p = .024).CONCLUSIONS:Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intraindividual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered.

Background: The objective effects of testosterone treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism are unknown. Methods: Secondary analysis of a 2-year, randomised controlled, testosterone therapy trial for prevention, or reversal of newly diagnosed, type 2 diabetes, enrolling men>50 years at high risk for type 2 diabetes from six Australian centres. Men received injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. Main outcomes were self-reported measures of HR-QOL/psychosocial function. Findings: Of 1007 participants randomised into T4DM, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and two years. Over 24 months, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and less depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. Interpretation: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.Trial Registration: This study was registered on the Australia and New Zealand Clinical Trials Registry (ACTRN12612000287831). Funding: The T4DM study was supported by grants from the National Health and Medical Research Council (NHMRC) Project Grant #1030123, Bayer, Lilly, and the University of Adelaide with in-kind support from Weight Watchers and Sonic Healthcare. Declaration of Interest: MG has received research funding from Bayer, Otzuka, and speaker’s honoraria from Besins Health Care and Novartis. DJH has served as an expert witness in antidoping and professional standards tribunals and for testosterone litigation. BGAS has received speaker fees (Besins, Astellas). BBY has received speaker honoraria and conference support from Bayer, Lilly and Besins Healthcare, and research support from Bayer, Lilly and Lawley Pharmaceuticals, and has held advisory roles with Lilly, Besins Healthcare, Ferring and Lawley Pharmaceuticals. GAW has received research funding for testosterone pharmacology studies (Lawley, Bayer, Lilly), speakers (Besins, Bayer) and consultancy (Elsevier) fees. JDZ has received speaker fees from Besins. CA has received speaker honoraria (Besins) and had advisory roles (Besins, Ferring). MD, MNTF, KB, WJI, KPR and DJ have nothing to disclose. Ethical Approval: The study received ethics committee approval to be conducted at each site.

Objective:Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective.Results:In 2004, pituitary tumours were classified as 'typical' or 'atypical', based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms 'typical' and 'atypical' were omitted, though the importance of proliferative markers Ki67 and mitotic count was acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well-differentiated tumours. Whilst 'high risk' tumour types have been identified, further work is still required to improve prognostication.Conclusions:Recent WHO classifications have marked significant progress in the diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.

'Pituitary tumours' is an umbrella term for various tumours originating from different regions of the hypothalamic-pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune-Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial-mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.