Endocrines

Background: Osteoporotic fractures are a common clinical sign of Cushing syndrome (CS). However, Cushing diagnosis can occur years after this clinical manifestation. Methods: Herein, we present the case of a 45-year-old woman who was referred to our department for further diagnosis and treatment. Results: The patient was already under treatment for arterial hypertension and osteoporosis and was recently diagnosed with dyslipidemia and type 2 diabetes. She reported several previous fractures starting already 8 years before presentation. An adrenal CS was diagnosed, and the patient was treated with laparoscopic adrenalectomy, with a subsequent complete remission of her hypercortisolism. This case report presenting a particularly long time gap between initial osteoporosis signs and the final diagnosis underlines the need for an investigation into secondary osteoporosis in low-energy fractures also in the peripheral skeleton. In this context, we performed a literature review, including case reports with fragility fractures that were attributed to endogenous CS. Conclusions: In summary, a delayed diagnosis of CS in patients with a previous accumulation of such fractures is a worrisome observation and should be considered in everyday clinical practice in order to improve the timely diagnosis and treatment of CS. Full article

Background: The ketogenic diet (KD), characterized by high-fat content, virtually no carbohydrates, and adequate protein intake, induces a metabolic state resembling fasting, as the absence of carbohydrates forces the body to rely on the energetic supply from hepatically produced ketone bodies using free fatty acids as substrate. While the KD is clinically used in pharmacologically refractory epilepsy and specific genetic conditions such as GLUT1 deficiency, recent research suggests that, due to its “fasting mimicking” properties, the KD may also beneficially affect obesity and obesity-associated metabolic diseases. Results: Here, we present a narrative review discussing completed and ongoing nutritional studies in human volunteers specifically addressing the potential of the ketogenic diet as an anti-obesity approach and, from a larger perspective, as an intervention to ameliorate the metabolic state in conditions such as type 1 and 2 diabetes and polycystic ovary syndrome (PCOS). Published studies as well as ongoing clinical trials will be discussed. Efficacy and safety considerations will be discussed, as well as the potential physiological mechanisms mediating the effects of the KD in humans in the context of the (i) energy balance model (EBM) and (ii) carbohydrate–insulin model (CIM) of body weight control. Conclusion: Ketogenic diets may be beneficial to attenuate obesity and improve obesity-related metabolic disease, and here, we try, based on current evidence, to define the boundaries of the KD’s nutritional and clinical usefulness. Full article

Over the past few years, we have witnessed many advances in the understanding of diabetes and its management. Greater insight into pathogenesis has led to the approval of the first immunopreventative therapy for T1DM. We are using non-insulin agents more for nephro- and cardioprotection than glucose-lowering effects while leaning on advancing technology to use insulin more safely. We now recognize that over half of T1DM is diagnosed in adulthood, the prevalence of obesity in patients with T1DM matches that of the general population, and rates of pediatric T2DM have dramatically risen amongst marginalized youths in recent years. Diabetes is now considered more of a heterogenous disease state than ever before, and practitioners will need to be familiar with these endotypes as personalized medicine replaces standardized treatment approaches. To this end, this article aims to summarize recent findings in an easily digestible manner so that providers may be more familiar with this ever-growing complex disease state. Full article

Background: Granulosa cells are somatic cells within the ovarian follicle. As the primary site of estradiol production, they are critical regulators of several aspects of female reproduction. This review aims to provide an overview of the physiology of mammalian granulosa cells and their importance for female fertility. Methods: the literature about the function and regulation of granulosa cells was reviewed. Results: a comprehensive summary and discussion of the role of granulosa cells on ovarian steroidogenesis and folliculogenesis, as well as factors that control granulosa cells function, are presented. Conclusion: The functions of granulosa cells are regulated by a plethora of intra- and extra-ovarian factors via autocrine, paracrine, and endocrine pathways, which creates a complex regulatory network. A comprehensive understanding of granulosa cells’ physiology is vital for the development of innovative strategies to enhance reproductive outcomes in several species. Full article

Background: The visceral adiposity index (VAI) is a composite marker designed to quantify visceral adiposity and its metabolic implications. It integrates anthropometric (such as waist circumference and BMI) and metabolic parameters (including triglyceride levels and HDL cholesterol), providing a more comprehensive assessment of visceral fat distribution than traditional measures alone. Higher VAI values are indicative of increased visceral adiposity and have been linked to heightened cardiovascular risk and metabolic disturbances. In recent years, understanding the complex interplay between metabolic factors and cardiovascular health has become increasingly important. Methods: This cross-sectional study delves into the influence of neck circumference (NC), blood pressure (BP), C-reactive protein (CRP), and insulin resistance on the VAI among outpatient cardiology patients, offering insights into sex-specific disparities and the utility of VAI as a diagnostic tool for assessing visceral adiposity and associated cardiovascular risks. Results: The sample comprised 268 outpatient cardiology patients (152 men, 116 women). Men, averaging 55.4 years old (SD = 14.4), exhibited significantly higher VAI values than women, with robust correlations found between VAI and markers of insulin resistance (Insulin: ρ = −0.167, p = 0.006; HOMA-IR: ρ = −0.163, p = 0.007). Analysis across VAI quartiles highlighted distinct patterns, revealing lower NC and elevated systolic blood pressure (SBP) values in higher VAI categories. Despite these associations, multiple linear regression controlling for age and sex demonstrated a limited predictive capacity of NC, BP, CRP, and lipid profiles on VAI (R2 range: 0.001–0.011). Conclusions: These findings underscore sex-specific disparities and suggest that VAI serves as a modest yet valuable tool in assessing visceral adiposity and associated cardiovascular risks. Full article

Precocious puberty (PP) requires appropriate management to prevent short adult height, psychosocial issues, and other adverse outcomes. Genetic diagnosis potentially improves the management of PP. Pathogenic NR0B1 variants, which typically cause X-linked adrenal hypoplasia congenita, can also affect gonadal function. While boys with NR0B1 variants usually exhibit hypogonadotropic hypogonadism during adolescence, previous reports have suggested that minipuberty, a physiological transient activation of the hypothalamic–pituitary–gonadal axis during infancy, occurs in these patients and can persist beyond a typical duration. In rare cases, NR0B1 variants cause PP. PP associated with NR0B1 variants has unique features such as early onset and high serum testosterone levels that are often disproportionate to testicular size. Three underlying mechanisms have been proposed for the association between PP and NR0B1 variants: (1) adrenocorticotropic hormone (ACTH)-dependent, (2) gonadotropin-dependent, and (3) ACTH- and gonadotropin-independent mechanisms. The factors contributing to PP vary among cases. Determining the underlying mechanisms is crucial for adopting appropriate therapeutic strategies to control PP. However, as the detailed molecular networks mediating these mechanisms are largely unclear, further research is needed to pave the way for a more effective and personalized management of patients with PP associated with NR0B1 variants. Full article

Background: Serum anti-Müllerian hormone (AMH) levels and antral follicle count are key in evaluating ovarian reserve (OR) for fertility. The performance of the Siemens Healthineers AMH assay was assessed on the ADVIA Centaur^® System. Methods: Analytical characteristics, clinical performance, and method comparison studies were performed in a prospective cohort of 532 women at fertility clinics. Serum AMH levels were determined using ADVIA Centaur, Beckman Access^®, and Roche Elecsys^® assays. Results: The limit of quantitation for the ADVIA Centaur AMH assay was 0.030 ng/mL. Repeatability was ≤2.9% CV, within-lab repeatability was ≤3.2% CV, and reproducibility was ≤4.4% CV. Results using serum or lithium heparin sample types were equivalent. Diagnostic sensitivity across assays ranged from 77.3% to 90.2% and specificity ranged from 51.0 to 71.0%; corresponding positive and negative predictive values ranged from 66.6% to 74.3% and 74.2% to 83.0%, respectively. Receiver operating characteristic analyses demonstrated that the assays have a high probability for discriminating between diminished–normal and high OR. ADVIA and Beckman assays agreed according to ADVIA = 1.00 × Beckman + 0.014 ng/mL, τ = 0.909, while a more modest correlation of ADVIA = 1.41 × Roche − 0.024 ng/mL, τ = 0.777 was observed with Roche assay. Conclusions: The ADVIA Centaur assay demonstrates acceptable analytical characteristics and clinical performance comparable to the Roche AMH assay and is essentially interchangeable with the Beckman AMH assay for reliable OR assessment. Full article

Introduction: During the formation of neural circuits, the developing brain demonstrates extraordinary plasticity, heavily influenced by hormones. These chemical messengers interact with specific receptors to regulate vital physiological functions. The thyroid gland plays a pivotal role in maintaining hormonal balance and guiding brain development. However, emerging threats like endocrine-disrupting chemicals (EDCs) can interfere with this intricate system. EDCs are exogenous substances that can mimic, enhance, or block the actions of endogenous hormones, disrupting hormonal signaling in the brain at various developmental stages. Exposure can impair cognitive function and behavior due to disruptions in thyroid function. Studies indicate that mixtures of EDCs negatively impact brain development, leading to lower IQ and behavioral problems. Reducing EDC exposure through regulations and public awareness is crucial, and further research is needed to elucidate their mechanisms. Conclusions: Protecting vulnerable populations, such as pregnant women and children, is essential through prompt regulatory measures. Full article

Background/Objectives: There is a bidirectional relationship between major depressive disorder (MDD) and type 2 diabetes (T2D), as MDD increases the risk of T2D by 38% to 67%, and T2D increases the risk of MDD by 15% to 33%. Many factors contribute to the occurrence of comorbid MDD and T2D, including converging pathophysiological pathways like inflammation. The objective of this review was to comprehensively summarize available evidence on the relationship between MDD, T2D, and inflammation. Results: Although the precise mechanisms linking T2D and MDD are still not fully understood, shared inflammatory mechanisms likely contributes to the heightened risk of developing this comorbidity. To date, the evidence supports that chronic low-grade inflammation is a feature of both MDD and T2D and has been shown to interact with pathways that are relevant to the development of both chronic disorders, including the hypothalamic–pituitary–adrenal (HPA) axis, neuroplastic processes, gut microbiome, insulin resistance, and adipose tissue dysfunction. Through their impact on inflammation, dietary and physical activity interventions can play a role in the risk and management of MDD and T2D. Conclusions: Deepening our understanding of the mechanisms underlying the augmented inflammatory responses observed in individuals with the MDD and T2D comorbidity is essential for tailoring appropriate therapeutic strategies. Full article

Background: T1D is a severe metabolic disorder due to selective autoimmune pancreatic islet β-cell killing, which results in complete abrogation of endogenous insulin secretion. The affected patients, once the disease is clinically overt, must immediately undertake insulin supplementation according to intensive therapy regimens to prevent the onset of acute and chronic complications, some of them potentially lethal. Replacement of the destroyed β-cells with fresh and vital pancreatic endocrine tissue, either of the whole organ or isolated islets transplantation, started a few decades ago with progressively encouraging results, although exogenous insulin withdrawal was obtained in a minor cohort of the treated patients. The restricted availability of donor organs coupled with general immunosuppression treatment of recipients to avoid graft immune rejection may, at least partially, explain the limited success achieved by these procedures. Results: The introduction of pluripotent stem cells (either of human embryonic origin or adult cells genetically induced to pluripotency) that can be differentiated toward insulin secretory β-like cells could provide an indefinite resource for insulin-producing cells (IPCs). Conclusions: Because the use of human embryos may encounter ethical problems, employment of adult multipotent mesenchymal stem cells (MSCs) extracted from several tissues may represent an alternative option. MSCs are associated with strong immunoregulatory properties that can alter early stages of β-cell-directed autoimmunity in T1D, other than holding the potential to differentiate themselves into β-like cells. Lights and shadows of these new strategies for the potential cure of T1D and their advancement state are reviewed. Full article

Introduction: Thyroid nodules are extremely common and require complex management to prevent unnecessary surgical intervention and ensure that no malignant disease is overlooked. Several diagnostic tools and scoring systems are available to evaluate the risk of malignancy (ROM). The goal is to assess variables that can aid and support the clinical recommendations suggested by the updated Bethesda System for Reporting Thyroid Cytopathology (TBSRTC-2023), such as the ultrasonographic features of thyroid nodules, particularly for the indeterminate categories III (atypia of undetermined significance) and IV (follicular neoplasm). Methods: We retrospectively analysed the correlation of the demographic and ultrasonographic characteristics of thyroid nodules with the cytopathological and histopathological diagnoses of TBSRTC categories III (atypia of undetermined significance), IV (follicular neoplasm), V (suspicious for malignancy), and VI (malignant) in patients who underwent surgery in a single Portuguese centre over a 10-year period. Results: In total, 360 nodules were evaluated in 341 patients, and 57% were histopathologically malignant or borderline. The majority were included in the TBSRTC indeterminate categories III and IV, with ROMs of 44% and 43%, respectively. The ultrasonographic characteristics associated with a higher TBSRTC category and a greater ROM value were hypoechogenicity, the presence of microcalcifications, irregular margins, and the presence of cervical adenopathy. When correlating with a malignant histology, only adenopathy and the presence of microcalcifications were observed to be statistically significant. Discussion: The indeterminate categories of the TBSRTC have been the most challenging ones to manage. The new TBSRTC (2023) guidelines, as well as the ultrasonographic characteristics of a patient’s nodule, can be helpful in assessing the ROM and deciding on an appropriate course of treatment. Other resources, such as molecular tests, are also playing a more important role in the clinical decision process and may become crucial in the future. Conclusions: The worrisome ultrasound features that this study found to statistically correlate with a malignant histology were the presence of microcalcifications and adenopathy. The clinical management of thyroid nodules requires a careful analysis of clinical history and an evaluation of demographic details, personal and family history, ultrasonographic features, and the results of cytopathology, thyroid function, and molecular/genetic tests. Full article

Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds that interfere with the endocrine system, inducing harmful effects on organisms depending on the dose and period of exposure. Numerous studies have identified concerning amounts of EDCs in environmental and human samples. The thyroid gland is essential for thyroid hormone production and controls several body functions. Several EDCs have been classified as thyroid disruptors, impairing thyroid hormone production, synthesis, metabolism, transport, and/or actions. Notably, thyroid disorders are the second most prevalent endocrine disease worldwide, with incidence increasing significantly in recent years. Some studies have correlated this rise in thyroid dysfunctions and cancers with increased exposure to EDCs. Although many EDCs are linked to thyroid dysfunction, this review focuses on the deleterious effects of plasticizers, organochlorine pesticides, and per- and poly-fluoroalkyl substances on thyroid function. These contaminants are commonly found in food, water, and everyday products. Although the impact of human exposure to these EDCs is controversial, numerous epidemiological, in vivo, and in vitro studies have indicated their harmful effects on thyroid function. Given the critical role of thyroid function and hormone production in growth, metabolism, and development, this review summarizes the consequences of exposure to thyroid disruptors for human health. Full article

Background: Type 2 diabetes mellitus (DM) is an important disease with an impact on public health globally. Early assessment is necessary with accessible markers, such as the TG/HDL ratio, in predicting DM. Methods: A total of 11,653 subjects from the ELSA-Brazil were included in this analysis and were reevaluated after 3.9 ± 0.6 years of follow-up. Participants were classified according to the quartiles of the TG/HDL index, stratified by sex. ANOVA with Bonferroni correction and p-for-trend analysis were used to compare groups. Cox analysis was performed with adjustments for covariables. Kaplan–Meier curves are presented with the log rank pool and linear analysis. Results: From 11,653 participants (56% female; aged 50.5 ± 8.7 years), 866 (7.8%) were diagnosed with DM (7.2% in women and 7.8% in men). For both sexes, a worsening of the cardiometabolic profile was observed across the increase in TG/HDL quartiles (p < 0.001). Incidence rates of DM increased across TG/HDL quartiles for both men (from Q1 3.3% to Q4 12.8%) and women (from Q1 3.3% to Q4 12.4%). For the entire period, the incidence was highest in participants in the fourth quartile of TG/HDL (log rank analysis < 0.001 for both sexes). In the Cox regression analyses, for men, the HR (95%CI) for risk of DM was 2.4 (1.49–3.26) across the fourth quartile of the TG/HDL ratio, and in women it was 1.57 (1.11–2.22) for the third quartile and 2.08 (1.48–2.93) for the fourth quartile, compared to the first quartile after adjustments. Conclusions: Higher levels of the TG/HDL ratio were independently predictors of DM in both men and women. Full article

Acromegaly is a rare endocrine syndrome characterized by unrestrained growth hormone (GH) secretion from a GH-secreting pituitary neuroendocrine tumor (PitNET). Data on sleep disorders are scanty and mainly linked to Obstructive Sleep Apnea Syndrome (OSAS). This study aimed to evaluate the prevalence of insomnia and sleep quality in a cohort of patients with a low risk of OSAS before and after therapies for acromegaly. A total of 27 naïve acromegalic patients (mean age 55.15 ± 10.53 years) were submitted to a psychometric sleep evaluation and compared to a matched control group of 24 Non-Functioning Pituitary micro-Adenoma patients (mean age 51.08 ± 11.02 years). A psychometric sleep evaluation was carried out 4 years later, after achieving acromegaly control in all patients. The role of different therapies for acromegaly (somatostatin analogues, pegvisomant, or adenomectomy) was evaluated. At the initial evaluation, most untreated acromegalic patients had a higher rate of impaired sleep quality and clinical insomnia than NFPA patients (p = 0.001 ES = 1.381, p = 0.001 ES = 1.654, respectively). Patients treated with somatostatin analogues or pituitary adenomectomy had an improvement in insomnia parameters (p = 0.046 ES = 0.777, p = 0.038 ES = 0.913, respectively). Conversely, in patients treated with pegvisomant, sleep quality and insomnia worsened (p = 0.028 ES = 1.002, p = 0.009 ES = 1.398, respectively). In summary, therapies for acromegaly seem to have divergent effects on perceived sleep disorders. Concerning sleep, somatostatin analogues and adenomectomy seem to have favorable effects on the psychometric parameters of sleep. Full article

Background: The prevalence of type 2 diabetes mellitus (T2DM) has been steadily increasing over the past few decades, largely due to the rise in obesity rates. Bariatric surgery is a gastrointestinal surgical treatment focused on achieving weight loss in individuals with obesity. A more recent and growing body of literature has shown that improvements in glycemic control and insulin sensitivity and even the remission of T2DM can be seen in patients with obesity and T2DM (“diabesity”), before significant weight loss is achieved, justifying the modification of the terminology from bariatric to metabolic and bariatric surgery (BMS). Main Results: This narrative review provides an overview of the latest literature on BMS for diabesity, discussing key publications and exploring controversial and diverging hypotheses. Robust scientific evidence supporting the use of BMS as a treatment for diabesity has been garnered and new venues are being explored, suggesting the novel and complementary role of the latest generation of incretin-based pharmacotherapy. Conclusions: BMS has emerged as a valuable treatment option for patients with diabesity, offering significant improvements in glycemic control, weight loss, and overall health. The limitations of the currently available and reviewed literature include the flawed knowledge of the mechanisms of action and long-term effects of BMS for the treatment of diabesity. Further studies are also warranted to refine the patient selection criteria and optimal surgical techniques and to evaluate the impact of surgery on T2DM outcomes in diverse populations. Lastly, there is a scarcity of studies investigating the efficacy of BMS against incretin-based pharmacotherapy. The non-systematic, narrative nature of this review and its implicit subjective examination and critique of the body of literature are to be considered additional and intrinsic limitations. Full article

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy. Full article

Endocrine disruptors are molecules that can interfere with the proper functioning of the endocrine system and lead to harmful effects in living organisms. This review focuses on the impact of synthetic fragrances, which are commonly found in personal care and household products, on the endocrine system. The article discusses the different types of hormones in the body and how they interact with receptors to produce signals. It also explores how endocrine disruptors can interfere with hormone signaling and transport, leading to adverse effects in the body. This work underscores the crucial need for further research into the impact of synthetic fragrances on the endocrine system and the importance of using safer alternatives in personal care and household products. Full article

Dysmenorrhea treatment with 0.5 mg dienogest tablets twice daily (1 mg/day) has proven useful, but its effect on premenstrual disorders has not yet been evaluated. This study aimed to evaluate the efficacy of 0.5 mg dienogest tablets in relieving premenstrual syndrome (PMS)-like symptoms during the treatment of dysmenorrhea in comparison with that of continuous low-dose estrogen–progestin (LEP/COC) drospirenone/ethinylestradiol combination, which is considered effective in treating premenstrual dysphoric disorder. During the standard course of dysmenorrhea treatment with dienogest or LEP/COC, PMS-like symptoms were scored based on patients’ reports, and the treatment effects were compared. As a result, the dienogest group experienced a significant improvement in PMS-like symptoms compared with the LEP/COC group over the 6-month study period (p < 0.01). Furthermore, dienogest was more effective in providing relief from PMS-like symptoms, with 89.7% of patients reporting a complete resolution of PMS-like symptoms at 6 months, compared with 47.1% in the LEP/COC group (p < 0.01). These results indicate that dienogest is effective in relieving PMS-like symptoms, similar to LEP/COC. Further studies are needed to determine whether 0.5 mg dienogest tablets, which are only available in Japan, are effective in treating premenstrual disorders diagnosed via standard methods. Full article

Growth hormone deficiency (GHD) is the most frequent pituitary hormone deficiency in childhood, with an incidence of 1 in 4000–10,000 live births. GHD can be congenital (genetic or due to hypothalamic/pituitary abnormalities) or acquired and can be isolated (IGHD) or associated with other pituitary hormone deficiencies, but most cases are idiopathic. GH stimulation testing is commonly used in the diagnostic workup of GHD, except for some clinical conditions that do not require GH stimulation tests for the diagnosis. Children with GHD receive replacement therapy with daily injections of recombinant human GH (rhGH). RhGH therapy is effective in increasing short-term height gain and adult height in patients with GHD. The safety of long term GH therapy has been confirmed in many large international studies. Recently, long-acting weekly GH formulations have been introduced, showing good efficacy and safety profiles. Full article