EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Bone quality, mineral density, and fractures in heart failure.

BACKGROUND: The trabecular bone score (TBS) indirectly estimates bone quality and predicts low-impact fractures independently of bone mineral density (BMD). However, there is still a paucity of data linking bone and heart diseases, mainly with gaps in the TBS analysis. METHODS: In this cross-sectional study, we evaluated TBS, BMD, and fractures in patients with heart failure with reduced ejection fraction (HFrEF) and in sex-, BMI- and age-matched controls, and we assessed the fracture probability using the FRAX tool, considering active search for fractures by vertebral fracture assessment (VFA) and the adjustment for the TBS. RESULTS: TBS values were 1.296 ± 0.14 in 85 patients (43.5% women; age 65 ± 13 years) and 1.320 ± 0.11 in 142 controls (P = 0.07), being reduced (< 1.31) in 51.8% and 46.1% of them, respectively (P = 0.12). TBS was lower in patients than in the controls when BMD was normal (P = 0.04) and when the BMI was 15-37 kg/m2 (P = 0.03). Age (odds ratio [OR] 1.05; P = 0.026), albumin (OR 0.12; P = 0.046), statin use (OR 0.27; P = 0.03), and energy intake (OR 1.03; P = 0.014) were associated with reduced TBS. Fractures on VFA occurred in 42.4% of the patients, and VFA and TBS adjustment increased the fracture risk by 16%-23%. CONCLUSION: Patients with HFrEF had poor bone quality, with a better discriminating impact of the TBS assessment when BMD was normal, and BMI was suitable for densitometric analysis. Variables related to the prognosis, severity, and treatment of HFrEF were associated with reduced TBS. VFA and TBS adjustment increased fracture risk.

Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease.

Objective: This study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine agonist cabergoline in patients with Cushing's disease (CD). Study design: This is an open-label, multicenter, non-comparative, Phase II study comprising 35-week core phase and an optional extension phase. All patients started with pasireotide, and cabergoline was added if cortisol remained elevated. Eligible patients had active CD, with or without prior surgery, were pasireotide naïve at screening or had discontinued pasireotide for reasons other than safety. Primary endpoint was proportion of patients with a mean urinary free cortisol (mUFC) level not exceeding the upper limit of normal (ULN) at week 35 with missing data imputed using last available post-baseline assessments. Results: Of 68 patients enrolled, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received pasireotide plus cabergoline during the core phase. Thirty-four patients (50.0%; 95% CI 37.6-62.4) achieved the primary endpoint, of whom 17 (50.0%) received pasireotide monotherapy and 17 (50.0%) received combination therapy. Proportion of patients with mUFC control remained stable during the extension phase up to week 99. Treatment with either mono or combination therapy provided sustained improvements in clinical symptoms of hypercortisolism up to week 99. Hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%) were the most frequent adverse events. Conclusion: Addition of cabergoline in patients with persistently elevated mUFC on maximum tolerated doses of pasireotide is an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01915303, identifier NCT01915303.

Safety of long-term use of daily and long-acting growth hormone in growth hormone-deficient adults on cancer risk.

Daily injections of recombinant human growth hormone (rhGH) have been used in clinical practice for almost four decades as a replacement therapy in adult patients with GH deficiency (GHD). Long-term adherence to daily injections of rhGH is a clinical concern that may result in reduced therapeutic efficacy, and long-acting GH (LAGH) formulations have been developed in an attempt of overcoming this problem. Long-term safety issues of rhGH are the other side of the coin that has been carefully monitored over the years, particularly related to the proliferative actions of GH that could increase the risk of tumor recurrence or induce the development of new benign and malignant tumors. In this review, we present what is currently known about the cancer risk in GHD adults treated with daily rhGH injections and we discuss the major concerns and responses needed from future surveillance studies regarding the safety of LAGH preparations.

2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

The science behind the relations among cancer, height, growth patterns, and growth hormone axis.

The association between growth hormone (GH) and carcinogenesis has long been postulated. The rationale for this association is that several components of the GH axis play an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis and have been tested as targets for cancer therapy. Epidemiological and clinical studies have examined the association between height, growth patterns, and insulin-like growth factor 1 (IGF1) levels with the most common types of malignancies, while genome-wide association studies have revealed several height-associated genes linked to cancer and/or metastasis-driving pathways. In this context, a permissive role of the GH-IGF signaling system in the link between height and cancer risk has also been investigated. In animal and human models, genetic defects associated with GH deficiency or resistance are associated with protection from tumor development, while the risk of malignancies in acromegaly or in patients exposed to recombinant GH therapy has long been a matter of concern and scrutiny. In this review, we present a narrative and historical review covering the potential relations among height, growth patterns, GH axis, and cancer.

Treatment of non-functioning pituitary adenoma with cabergoline: a systematic review and meta-analysis.

PURPOSE: To make a systematic review and meta-analysis of studies evaluating the effect of cabergoline (CBG) in the treatment of non-functioning pituitary adenomas (NFPAs). METHODS: The primary outcome was tumor shrinkage, using as cut-off a reduction of at least 20% of the NFPA size from baseline. The secondary outcomes were prevention of tumor progression, clinically required additional interventions and adverse events (AE). Search strategies were applied to MEDLINE, EMBASE, LILACS and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Random meta-analysis for the proportion of tumor shrinkage, prevention of tumor progression, clinically required additional interventions and frequency of AE were conducted. RESULTS: Five studies were included. The meta-analysis of proportion was 19% for tumor shrinkage (95% CI 8-38%, 4 studies, 108 participants), 50% for prevention of tumor progression (95% CI 35-64%, 5 studies, 187 participants), 14% for clinically required additional interventions (95% CI 6-30%, 4 studies, 128 participants) and 2% for adverse events (95% CI 1-6%, 3 studies, 157 participants). CONCLUSIONS: Effect of CBG to promote tumor shrinkage in NFPAs was low, while prevention of tumor progression after surgery was seen in half of the cases, with a low frequency of adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020206778.

Prevalence of sarcopenia in women at stable weight phase after Roux-en-Y gastric bypass.

Objective: Evaluating the prevalence of sarcopenia in women submitted to bariatric surgery - Roux-en-Y gastric bypass. Design: Observational, cross-sectional study. Subjects and methods: Women (18-65 years old) who underwent bariatric surgery (BG) ≥ 2 years and reached stable weight ≥ 6 months, were investigated. Control group (CG) comprised non-operated matched women with obesity. Body composition was determined through dual-energy X-ray absorptiometry. Low lean mass (LLM) was defined as appendicular lean mass index (ALM kg/height m2) < 5.5 kg/m2. Physical strength was assessed through dynamometer and sit-to-stand test (SST), whereas performance was assessed through 4-m gait speed and Short Physical Performance Battery Tests (SPPB). Sarcopenia was diagnosed in the presence of LLM and low strength. Results: One-hundred and twenty women (60 in each group, 50 ± 9.7 years old) were investigated. All anthropometric and body composition parameters were lower in BG than in CG, whereas strength and performance were similar between groups. Women with reduced strength presented high total fat mass and low physical activity level (p < 0.005). LLM was observed in 35% of BG and in 18.3% of CG (p = 0.04), whereas sarcopenia was diagnosed in 28.3% of BG and in 16.6% of CG (p = 0.12). Sarcopenic women in BG had better performance both in SST (p = 0.001) and SPPB (p = 0.004). Total lean mass (OR:1.41, 95% CI [1.18; 1.69], p < 0.001) and obesity (OR: 38.2 [2.27; 644.12], p < 0.001) were associated with sarcopenia in the multivariate analysis. Conclusion: Despite great weight loss, sarcopenia prevalence did not increase in BG and its presence was influenced by total lean mass and obesity.

Prevalence of sarcopenia in women at stable weight phase after Roux-en-Y gastric bypass

ABSTRACT Objective: Evaluating the prevalence of sarcopenia in women submitted to bariatric surgery - Roux-en-Y gastric bypass. Design: Observational, cross-sectional study. Subjects and methods: Women (18-65 years old) who underwent bariatric surgery (BG) ≥ 2 years and reached stable weight ≥ 6 months, were investigated. Control group (CG) comprised non-operated matched women with obesity. Body composition was determined through dual-energy X-ray absorptiometry. Low lean mass (LLM) was defined as appendicular lean mass index (ALM kg/height m2) < 5.5 kg/m2. Physical strength was assessed through dynamometer and sit-to-stand test (SST), whereas performance was assessed through 4-m gait speed and Short Physical Performance Battery Tests (SPPB). Sarcopenia was diagnosed in the presence of LLM and low strength. Results: One-hundred and twenty women (60 in each group, 50 ± 9.7 years old) were investigated. All anthropometric and body composition parameters were lower in BG than in CG, whereas strength and performance were similar between groups. Women with reduced strength presented high total fat mass and low physical activity level (p < 0.005). LLM was observed in 35% of BG and in 18.3% of CG (p = 0.04), whereas sarcopenia was diagnosed in 28.3% of BG and in 16.6% of CG (p = 0.12). Sarcopenic women in BG had better performance both in SST (p = 0.001) and SPPB (p = 0.004). Total lean mass (OR:1.41, 95% CI [1.18; 1.69], p < 0.001) and obesity (OR: 38.2 [2.27; 644.12], p < 0.001) were associated with sarcopenia in the multivariate analysis. Conclusion: Despite great weight loss, sarcopenia prevalence did not increase in BG and its presence was influenced by total lean mass and obesity.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

Proposal of an obesity classification based on weight history: an official document by the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO).

Obesity is a chronic disease associated with impaired physical and mental health. A widespread view in the treatment of obesity is that the goal is to normalize the individual's body mass index (BMI). However, a modest weight loss (usually above 5%) is already associated with clinical improvement, while weight losses of 10%-15% bring even further benefits, independent from the final BMI. The percentage of weight reduction is accepted as a treatment goal since a greater decrease in weight is frequently difficult to achieve due to metabolic adaptation along with environmental and lifestyle factors. In this document, the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO) propose a new obesity classification based on the maximum weight attained in life (MWAL). In this classification, individuals losing a specific proportion of weight are classified as having "reduced" or "controlled" obesity. This simple classification - which is not intended to replace others but to serve as an adjuvant tool - could help disseminate the concept of clinical benefits derived from modest weight loss, allowing individuals with obesity and their health care professionals to focus on strategies for weight maintenance instead of further weight reduction. In future studies, this proposed classification can also be an important tool to evaluate possible differences in therapeutic outcomes between individuals with similar BMIs but different weight trajectories.

Proposal of an obesity classification based on weight history: an official document by the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO)

ABSTRACT Obesity is a chronic disease associated with impaired physical and mental health. A widespread view in the treatment of obesity is that the goal is to normalize the individual's body mass index (BMI). However, a modest weight loss (usually above 5%) is already associated with clinical improvement, while weight losses of 10%-15% bring even further benefits, independent from the final BMI. The percentage of weight reduction is accepted as a treatment goal since a greater decrease in weight is frequently difficult to achieve due to metabolic adaptation along with environmental and lifestyle factors. In this document, the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO) propose a new obesity classification based on the maximum weight attained in life (MWAL). In this classification, individuals losing a specific proportion of weight are classified as having "reduced" or "controlled" obesity. This simple classification - which is not intended to replace others but to serve as an adjuvant tool - could help disseminate the concept of clinical benefits derived from modest weight loss, allowing individuals with obesity and their health care professionals to focus on strategies for weight maintenance instead of further weight reduction. In future studies, this proposed classification can also be an important tool to evaluate possible differences in therapeutic outcomes between individuals with similar BMIs but different weight trajectories.

Acromegaly and pregnancy: a systematic review and meta-analysis.

PURPOSE: To evaluate the association between acromegaly and pregnancy in terms of disease activity, maternal and fetal outcomes. METHODS: This systematic review was conducted according to the Joanna Briggs Institute methodology for systematic reviews of etiology and risk. We focused on observational studies that included pregnant women with acromegaly. The outcomes were acromegaly activity, preterm birth, gestational diabetes, hypertension, eclampsia/preeclampsia, miscarriage, perinatal mortality, low birthweight, small for gestational age, and congenital malformations. Embase, Medline, LILACS, and CENTRAL were our source databases. To perform proportional meta-analyses, we used Stata Statistical Software 17. RESULTS: Nineteen studies were included encompassing a total of 273 pregnancies in 211 women with acromegaly. The overall frequency of control of acromegaly during pregnancy was 62%, and of tumor growth was 9%. No fetal or maternal deaths were reported. The overall frequency of worsening of previous diabetes or development of gestational diabetes was 9%, and of previous hypertension or preeclampsia/eclampsia was 6%. The overall frequency of premature labor was 9% [from 17 studies of 263 pregnancies; 95% confidence interval (CI), 5-13%]; of spontaneous miscarriage was 4% (from 19 studies of 273 pregnancies; 95% CI, 2-11%); of small for gestational age was 5% (from 15 studies of 216 newborns; 95% CI, 3-9%); and of congenital malformations was 1% (from 18 studies of 240 newborns; 95% CI, 0-7%). CONCLUSION: Pregnancy in women with acromegaly is frequently associated with disease control and is safe in relation to fetal and maternal outcomes, as in women without acromegaly.

Effectiveness of Medical Treatment of Cushing's Disease: A Systematic Review and Meta-Analysis.

Objective: The objective of this systematic review was to evaluate the effectiveness and safety of pasireotide, cabergoline, ketoconazole, levoketoconazole, metyrapone, osilodrostat, and temozolomide for the treatment of Cushing's disease (CD). Methods: The primary outcomes were the proportion of CD control, adverse events (AE), and reduction of urinary free cortisol. Search strategies were applied to Embase, Medline, and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Standardized mean difference was calculated with 95% confidence interval (CI) for continuous data (i.e., pre- and post-intervention). Random meta-analyses for the proportion of CD control and AE were conducted. Results: Twenty-nine controlled and non-controlled studies were included. No study with temozolomide and levoketoconazole and one study with osilodrostat fulfilled the inclusion criteria. The meta-analyses of proportion of CD control was 35% for cabergoline (95% CI: 27-43%, six studies, 141 participants), 44% for pasireotide (95% CI: 25-35%, eight studies, 522 participants), 41% for ketoconazole (95% CI: 36-46%, six studies, 450 participants), 66% for metyrapone (95% CI: 46-87%, four studies, 66 participants), and of 66.4% for osilodrostat (95% CI: 57.9, 74.3, 97 participants, one study). One study compared two different treatments (cabergoline vs. ketoconazole), and no statistical difference was observed in CD control (RR: 0.53, 95% CI: 0.15 to 1.87, 14 participants, very low certainty of evidence). The most frequent AE associated with pasireotide was hyperglycemia, dizziness and nausea with cabergoline and metyrapone, and elevated transaminases with ketoconazole. Conclusion: The superiority of one drug over another could not be determined due to lack of controlled studies, but the proportion of disease control identified in our meta-analysis may support clinical decision. New therapeutic options should be investigated due to the limited efficacy and tolerability of the currently available medical treatment for patients with Cushing's disease. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205567, identifier CRD42020205567.

Safety of growth hormone (GH) treatment in GH deficient children and adults treated for cancer and non-malignant intracranial tumors-a review of research and clinical practice.

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.

GH and IGF-I levels and tumor shrinkage in response to first generation somatostatin receptor ligands in acromegaly: a comparative study between two reference centers for pituitary diseases in Brazil.

PURPOSE: To compare biochemical and tumor response rates between two reference centers for pituitary diseases in Brazil after primary and adjuvant therapy with somatostatin receptor ligands (SRL) in acromegaly. METHODS: Patients were classified as non-responders (NR), partial responders (PR), and full responders (FR) to 12-month SRL therapy according to: [criteria A] normal IGF-I and random GH (rGH) < 1 ng/mL (FR); ≥ 50% decrease of IGF-I and/or rGH (PR); < 50% decrease of IGF-I and rGH (NR); [criteria B] normal IGF-I (FR); ≥ 50% decrease of IGF-I (PR); < 50% decrease of IGF-I (NR). Tumor shrinkage <20% defined poor responders (tPR) and ≥ 20% good responders (tGR). RESULTS: We studied 219 acromegaly patients (59% women, age 43.1 ± 13.9 years; 73 from Center I and 146 from Center II). After SRL therapy, the proportion of FR, PR, and NR by criteria A and B was 30.2 vs 49.1%, 52.8 vs 21.2% and 17 vs 29.7%, respectively (p < 0.001). Considering criteria A or B separately, there was no difference in the proportion of FR, PR and NR between two centers. However, when comparing criteria A and B, the Center I showed a difference of 30.9% in classification of FR in relation to 13.2% observed in Center II (p = 0.006). tGR were 51.4% of patients, with no differences between the centers. CONCLUSIONS: IGF-I alone significantly increased positive response rates to SRLs, whereas the inclusion of rGH levels into therapeutic decision might lead to a significant increment on the costs of acromegaly management.