Teriparatide as Treatment for Severe Osteoporosis in Lung Transplant Recipients.

Osteoporosis and osteopenia are common in lung transplant (LTx) recipients, with a significantly increased incidence compared to other non-lung solid organ transplant patients. Despite high fracture rates, including in patients treated with antiresorptive medications, there are limited data on the use of anabolic treatments in LTx recipients. We present clinical, biochemical and bone mineral density data for 3 patients with severe osteoporosis treated with teriparatide 20 micrograms daily for 18 months post-LTx. Prednisone doses ranged between 5 and 10 mg daily throughout the treatment period. All patients had previously received zoledronate (last dose 12-24 months prior to teriparatide). Bone turnover was monitored repeatedly during treatment in one patient. Following completion of teriparatide, all patients received consolidation treatment with 4 mg zoledronate. Bone density was measured prior and within 6 to 12 months after completion of teriparatide. All 3 patients experienced an increase in bone density at the lumbar spine (median +12%; range, 2%-14%) and total proximal femur (median +8%, range, 8%-10%). No adverse effects were observed. Given that severe osteoporosis is highly prevalent in LTx patients, teriparatide should be further studied as a treatment in this clinical setting. Our cases suggest it is safe and effective.

Effects of gender affirming hormone treatment in transgender individuals - a retrospective cohort study.

PURPOSE: Gender affirming hormone treatment (GAHT) results in measurable changes to anthropomorphic, biochemical and hormonal variables that are important to patients and their health care professionals to guide treatment. This study sought to quantify changes which occur in response to initiation of GAHT. METHODS: We performed a retrospective cohort study of outcomes in transgender and gender diverse (TGD) patients starting GAHT. The primary outcome was proportion of patients and time required to achieve optimal hormone levels after commencement of GAHT. Additional analyses were performed to assess whether clinical and biochemical factors were associated with likelihood of achieving target hormone levels. RESULTS: 345 patients were included. Among 154 transmasculine individuals, 116 (75%) achieved a testosterone level >10 nmol/L during follow-up at a median of 4-months (IQR 4-9). No clinical or biochemical factors were significantly associated with likelihood of reaching therapeutic testosterone concentrations in transmen. Among 191 transfeminine individuals, 131 (72%) achieved a testosterone level <2.0 nmol/L during follow-up at a median of 4-months (IQR 3-9). Factors associated with increased likelihood of testosterone suppression were use of subdermal estradiol implants as well as cyproterone acetate as an androgen antagonist. Changes in differing directions were observed during repeated measures of lipids, liver function, and blood count between transmasculine and transfeminine individuals, reflecting the important effects of testosterone and estradiol on biochemical tests ordered as part of routine clinical care. CONCLUSION: Most TGD patients achieve target testosterone levels within 9 months of GAHT initiation. Adverse effects of GAHT are rare, and are usually mild.

Early post-transplant hyperglycemia and post-transplant diabetes mellitus following heart transplantation.

INTRODUCTION: Heart transplantation is an important treatment for end-stage heart failure. Early post-transplant hyperglycemia (EPTH) and post-transplant diabetes mellitus (PTDM) are common following heart transplantation and are associated with increased morbidity and mortality. AREAS COVERED: This review summarizes the clinical characteristics, diagnosis, and treatment of EPTH and PTDM in cardiac transplant patients, incorporating findings from non-cardiac solid organ transplant studies where relevant due to limited heart-specific research. EXPERT OPINION: EPTH following heart transplantation is common yet understudied and is associated with the later development of PTDM. PTDM is associated with adverse outcomes including infection, renal dysfunction, microvascular disease, and an increased risk of re-transplantation and mortality. Risk factors for EPTH include the post-operative immunosuppression regimen, recipient and donor age, body mass index, infections, and chronic inflammation. Early insulin treatment is recommended for EPTH, whereas PTDM management is varied and includes lifestyle modification, anti-glycemic agents, and insulin. Given the emerging evidence on the transplant benefits associated with effective glucose control, and the cardioprotective potential of newer anti-glycemic agents, further focus on the management of EPTH and PTDM within heart transplant recipients is imperative.

Glucagon-like Peptide-1 Receptor Agonist Treatment With Semaglutide in Type 1 Diabetes.

The efficacy of glucagon-like peptide-1 receptor agonists in type 2 diabetes is well established, but their role in type 1 diabetes (T1DM) is less clear. A 36-year-old woman with a 27-year history of T1DM and undetectable c-peptide presented for review of weight management, with body mass index 29.3 kg/m2. A previous trial of dapagliflozin led to no improvement in weight or glycemic control. Semaglutide was introduced (0.25 mg weekly increased to 0.5 mg weekly) and was well tolerated. After 6 months, weight had decreased by 16 kg and insulin dose by 36%. Despite less insulin, hemoglobin A1c improved, with reduced glycemic variability and no increase in hypoglycemia. Semaglutide may exert significant metabolic benefits in patients with established T1DM, even where c-peptide is no longer detectable. This case supports the need for a dedicated trial examining potential benefits of semaglutide in T1DM.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

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.

Metabolic Sequelae of Everolimus Treatment After Cardiac Transplant: A Hypothesis-Generating Study.

BACKGROUND: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. METHODS: Post-hoc analysis to compare PTDM and other metabolic outcomes in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients (RADTAC1 study). RESULTS: There were 39 participants in the trial; mean follow-up was 6.4±1.5 years. There was a high rate of pre-existing diabetes (26%) and newly diagnosed PTDM (36%) during follow-up. Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). In the first 12 months there was a higher use of non-insulin treatment for diabetes in the everolimus-tacrolimus group compared to the standard tacrolimus group. CONCLUSIONS: This study suggests that treatment with everolimus may be associated with improved glycaemic control of PTDM relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials.

Sodium glucose co-transporter 2 inhibition with empagliflozin on metabolic, cardiac and renal outcomes in recent cardiac transplant recipients (EMPA-HTx): protocol for a randomised controlled trial.

INTRODUCTION: Cardiac transplantation (CTx) is a life-saving operation that can improve the quality and length of a recipient's life. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant complications include metabolic effects such as diabetes and weight gain, renal impairment, and cardiac disease such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of oral medication that increase urinary excretion of glucose. In patients with type 2 diabetes, SGLT2 inhibitors improve cardiovascular, metabolic and renal outcomes. Similar benefits have been shown in patients with heart failure and reduced ejection fraction irrespective of diabetes status. In patients with post-transplant diabetes mellitus, SGLT2 inhibitors improve metabolic parameters; however, their benefit and safety have not been evaluated in randomised prospective studies. This study will potentially provide a novel therapy to improve or prevent complications (diabetes, kidney failure and heart fibrosis) that occur with immunosuppressive medications. METHODS: The EMPA-HTx study is a randomised, placebo-controlled trial of the SGLT2 inhibitor empagliflozin 10 mg daily versus placebo in recent CTx recipients. One hundred participants will be randomised 1:1 and commence the study medication within 6-8 weeks of transplantation with treatment and follow-up until 12 months after transplantation. Demographic information, anthropomorphic measurements, pathology tests and cardiac magnetic resonance (CMR) scan will be recorded at baseline and follow-up. Patients will be reviewed monthly during the study until 12 months post-CTx and data will be collected for each patient at each study visit. The overall aim of the study is to assess the safety and efficacy of empagliflozin in CTx recipients. The primary outcome is glycaemic improvement measured as change in glycated haemoglobin and/or fructosamine. Key secondary outcomes are cardiac interstitial fibrosis measured by CMR and renal function measured by estimated glomerular filtration rate. ETHICS AND DISSEMINATION: This study has been approved by St Vincent's Hospital Human Research Ethics Committee (2021/ETH12184). The findings will be presented at national and international scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12622000978763.

Diabetes medication following heart transplantation: a focus on novel cardioprotective therapies-a joint review from endocrinologists and cardiologists.

There is accumulating evidence that novel glucose-lowering agents infer potent cardiovascular and renal benefits. Therefore, it is imperative to reassess the management of post-transplant diabetes mellitus and consider the role of newer agents. With improved transplant-related survival and high prevalence of post-transplant diabetes, management of long-term complications such as diabetes are increasingly important. There are limited guidelines to assist in choice of appropriate agents after solid organ transplantation. Traditional therapies including insulin and sulfonylureas may still have a role; however, other agents should be considered prior. The evidence of novel glucose-lowering agents in post-transplant care is limited, and most studies have focused on kidney transplant recipients. While there are some parallels between renal and cardiac transplant recipients, the potential cardiovascular benefits, particularly on cardiac fibrosis are unique to cardiac transplantation. The treatment of diabetes, with a focus on additional cardiac and renal benefits, needs to be brought to the forefront of post-transplant care with incorporation of recent evidence outside of transplantation. The role for novel glucose-lowering agents in cardiac transplant recipients will be explored, with a summary of available evidence.

Immune Related Adverse Events of the Thyroid - A Narrative Review.

Immune checkpoints are small molecules present on the cell surface of T-lymphocytes. They maintain self-tolerance and regulate the amplitude and duration of T-cell responses. Antagonism of immune checkpoints with monoclonal antibodies (immune checkpoint inhibitors) is a rapidly evolving field of anti-cancer immunotherapy and has become standard of care in management of many cancer subtypes. Immune checkpoint inhibition is an effective cancer treatment but can precipitate immune related adverse events (irAEs). Thyroid dysfunction is the most common endocrine irAE and can occur in up to 40% of treated patients. Both thyrotoxicosis and hypothyroidism occur. The clinical presentation and demographic associations of thyrotoxicosis compared to hypothyroidism suggest unique entities with different etiologies. Thyroid irAEs, particularly overt thyrotoxicosis, are associated with increased immune toxicity in other organ systems, but also with longer progression-free and overall survival. Polygenic risk scores using susceptibility loci associated with autoimmune thyroiditis predict development of checkpoint inhibitor associated irAEs, suggesting potentially shared mechanisms underpinning their development. Our review will provide an up-to-date summary of knowledge in the field of thyroid irAEs. Major focus will be directed toward pathogenesis (including genetic factors shared with autoimmune thyroid disease), demographic associations, clinical presentation and course, treatment, and the relationship with cancer outcomes.

Association of Antithyroid Antibodies in Checkpoint Inhibitor-Associated Thyroid Immune-Related Adverse Events.

CONTEXT: The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown. OBJECTIVE: To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events. METHODS: A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients. RESULTS: A total of 122 patients were included-31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive TPOAb or TgAb at baseline was 97% and 100% specific for eventual development of a thyroid irAE, respectively. During ICI treatment, overt thyrotoxicosis, but not other subtypes of thyroid irAE, was associated with statistically significant increases in the titer of TgAb and TPOAb. Baseline IL-6 levels were not associated with thyroid irAE onset but statistically significantly increased during treatment in patients who developed overt hypothyroidism. CONCLUSIONS: TPOAb and TgAb positivity at baseline was more prevalent in patients who developed thyroid irAEs. Statistically significant increases or new antibody positivity was observed in association with overt thyrotoxicosis. TPOAb and TgAb positivity or increases during ICI treatment may be a useful biomarker to identify patients at increased risk of thyroid irAEs, particularly overt thyrotoxicosis.

Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment.

CONTEXT: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. OBJECTIVE: This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. METHODS: We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. RESULTS: A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. CONCLUSION: Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Hyperprolactinemia and association with prolactinoma in transwomen receiving gender affirming hormone treatment.

PURPOSE: Approximately 0.6% of the adult population identifies as transgender. Gender affirming hormone treatment (GAHT) is required by many to develop physical and psychological characteristics that align with their gender identity. Once started, GAHT is continued lifelong and at higher doses than conventionally used in the management of cis-gendered women. Hyperprolactinemia and pituitary lactotroph adenomas are a potential consequence of GAHT. METHODS: Case series of three transfeminine women with hyperprolactinemia during gender affirming hormone treatment. RESULTS: We report two new cases of prolactinoma and one new case of marked hyperprolactinemia without pituitary adenoma associated with GAHT in transwomen at different stages of hormonal transition. Novel aspects of our case series include the first report of a prolactinoma in a transwoman associated with spironolactone and the alternate progestin medroxyprogesterone acetate and documentation of the transient changes in prolactin from baseline (prior to feminizing hormones) in two transwomen which demonstrate that marked hyperprolactinemia develops early in the course of GAHT. CONCLUSIONS: Transgender women receiving GAHT may be at increased risk for prolactinoma. As the number of transwomen seeking GAHT continues to increase, hyperprolactinemia and GAHT-associated prolactinoma may become an increasingly important component of endocrine practice. Screening of prolactin levels in transwomen receiving GAHT could potentially prevent morbidity related to hyperprolactinemia and allow for early detection of prolactin secreting pituitary adenomas.

SEVERE HYPERTRIGLYCERIDEMIA ASSOCIATED WITH EVEROLIMUS TREATMENT AFTER HEART TRANSPLANTATION.

OBJECTIVE: Everolimus, a mammalian target-ofrapamycin (mTOR) inhibitor, is increasingly used post-transplantation due to favorable effects on renal function and malignancy risk when compared to other immunosuppressive treatments such as calcineurin inhibitors. However, it can confer adverse effects such as dyslipidemia, which is not underpinned by any long-term screening and management of dyslipidemia in heart transplant recipients treated with everolimus. METHODS: We report a case of severe hypertriglyceridemia which developed after commencement of everolimus in a heart transplant recipient with a background of Dunnigan-type familial partial lipodystrophy. RESULTS: The patient is a 36-year-old woman who underwent heart transplantation for dilated cardiomyopathy. About 11 weeks following commencement of everolimus as part of her antirejection medication regime, serum triglyceride level concentration peaked at 5,093 mg/dL (normal, 0.0 to 177.2 mg/dL). There were no clinical complications with triglycerides at this elevated level and it improved substantially following cessation of everolimus and initiation of a high dose intravenous insulin-dextrose infusion. CONCLUSION: This case highlights dyslipidemia as a potential complication of everolimus treatment and that appropriate screening is important as lipid lowering medication can effectively control levels and minimize adverse outcomes.

Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer.

Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.

Thyroid Peroxidase Antibody Positivity is Associated With Relapse-Free Survival Following Antithyroid Drug Treatment for Graves Disease.

OBJECTIVE: Graves' disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown. METHODS: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease. RESULTS: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse. CONCLUSION: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves' disease.

Efficacy and Safety of Empagliflozin in the Management of Diabetes Mellitus in Heart Transplant Recipients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent in patients undergoing heart transplant, and in those without preexisting T2DM, posttransplant diabetes mellitus may develop. Both T2DM and posttransplant diabetes mellitus have been associated with increased morbidity and mortality following heart transplantation. Empagliflozin is an effective glucose-lowering therapy that reduces the incidence of major cardiovascular events in patients with T2DM. The safety and efficacy of empagliflozin in transplant patients with diabetes mellitus has yet to be established. METHODS: Clinical outcomes were retrospectively examined in 22 heart transplant recipients treated with empagliflozin and compared with those of 79 heart transplant patients with diabetes mellitus receiving alternative glucose-lowering therapies. RESULTS: Three adverse events were recorded in empagliflozin-treated patients, leading to treatment discontinuation in 1. There were no genitourinary infections. Treatment with empagliflozin for 12 months was associated with reductions in weight, body mass index, glycated hemoglobin, and frusemide dose that were not seen in the control group. There were no large changes observed in blood pressure (systolic or diastolic) or renal function (serum urea, creatinine, or estimated glomerular filtration rate) after 12 months of treatment with empagliflozin or alternative glucose-lowering therapies. CONCLUSIONS: Empagliflozin appears safe and effective in the management of selected patients with diabetes mellitus following heart transplantation.