Editor’s Choice Articles

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

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

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

Adrenocortical carcinoma (ACC) and pheochromocytoma (PCC) are malignancies originating from distinct layers of the adrenal gland. ACCs arise from the adrenal cortex, are often detected at advanced stages and are associated with poor prognosis. PCCs are mostly benign, arise from the adrenal medulla and have a variable prognosis, with 10% of PCCs resulting in metastasis. Genetic background strongly influences metastasis of PCCs, and no reliable biomarkers that predict metastatic behavior exist to date. Current therapeutic strategies for both ACCs and PCCs are overall limited. Thus, novel preclinical models and drug screening approaches need to be established to aid in the identification of more promising drugs and treatment schemes. In this review, we summarize the currently available human and murine cell lines for both tumor entities. Full article

This study investigated the impact of intensive endurance exercise on circulating androgenic steroid hormones in women. Fifteen normally menstruating athletic women participated. They completed intensive endurance exercise (treadmill running) until volitional fatigue in their follicular phase, with blood samples collected at pre-exercise, volitional fatigue, 90 min and 24 h into recovery. The steroid hormones (total, free testosterone, dehydroepiandrosterone [DHEA], and DHEA-sulfate [DHEA-S], cortisol) were analyzed in blood sera. Non-parametric statistics were used to assess changes across exercise and recovery. At volitional fatigue, all hormones, except free testosterone, were significantly (p < 0.05) increased compared to pre-exercise levels. Most hormones remained elevated through 90 min of recovery, with DHEA, DHEA-S, and total testosterone changes being significant (p < 0.05). At 24 h of recovery, hormonal levels were reduced; specifically, DHEA, DHEA-S, and total testosterone compared to baseline (p < 0.01 to 0.06). Increases in cortisol levels at volitional fatigue and 90 min of recovery were correlated with reductions in total testosterone, DHEA, and DHEA-S observed at 24 h of recovery (rho > −0.62, p < 0.05). In conclusion, in menstruating women performing intensive endurance exercise during their follicular phase, their androgenic steroid hormones remain elevated during early recovery but are suppressed at 24 h of recovery. The latter finding indicates that establishing a resting endocrine equilibrium requires a longer recovery period than 24 h. Full article

Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient’s circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec’s efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (>180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management. Full article

Most patients with non-alcoholic steatohepatitis (NASH) have insulin resistance, and there is a near-universal association between NASH and insulin resistance. Insulin resistance induces lipid accumulation in the liver, leading to the development of metabolic syndrome. However, most NASH rodent models fail to develop metabolic syndrome. LEW.1WR1 rats that are 23 weeks old showed increased body mass, epididymal fat, and liver mass, suggesting obesity-driven metabolic dysfunction. We have characterized steatosis, inflammation, Mallory–Denk body formation with hematoxylin and eosin (H&E), and fibrosis with Trichome blue staining. The presence of hepatic fibrosis with other features of NASH described above is one of the major strengths of this model since most of the currently available NASH models do not develop microvesicular steatosis or fibrosis. Together with the other important features of NASH described above, we confirm that male LEW.1WR1 rats develop NASH and insulin resistance with a standard diet. Full article

GHRH regulates the secretion of GH from the anterior pituitary gland, previously associated with cancer progression and inflammation. An emerging body of evidence suggests that GHRHAnt support endothelial barrier function, but the mechanisms mediating these events are not completely understood. In the present study, it is demonstrated that the GHRHAnt JV-1-36 counteracts barrier dysfunction due to LPS or LTA treatment in HUVECs, utilizing the Dextran–FITC assay. Moreover, it is shown in BPAECs that these bacterial toxins increase ROS generation, and that this effect is counteracted by JV-1-36, which reinstates the redox balance. The possible involvement of NEK2 in the beneficial activities of GHRHAnt in IFN-γ- and LPS-triggered hyperpermeability was also assessed, since that kinase is involved in inflammatory responses. NEK2 was increased in the inflamed cells, and JV-1-36 counteracted those endothelial events. Our data support the beneficial effects of GHRHAnt in toxin-induced endothelial injury. Full article

Binge eating disorder (BED) is the most common eating disorder categorized in the DSM-V, but it is often not diagnosed in patients with obesity because it can be difficult to detect in these patients who often have altered eating patterns. In this narrative review, we have highlighted the most recent findings in the screening, diagnosis, and treatment of patients with BED and obesity. The results of our search showed that many BED patients are not obese, and most people with obesity do not have binge behavior. In the diagnostic assessment of these patients, it is important to evaluate not only the clinical and nutritional status and the presence of medical comorbidities, but also the psychological signs and symptoms related to psychiatric comorbidities to define the appropriate diagnosis and the consequent level of treatment. Well-tolerated drugs with action on both body weight and binges can be useful as a second-line complement to cognitive behavioral therapy (CBT). Specific guidelines are needed to obtain consensus on appropriate recommendations in patients with obesity and BED approaching bariatric surgery, taking into account not only weight reduction and clinical data, but also eating behaviors. Identification of BED is important for targeting individuals at high risk of obesity, adverse metabolic patterns, and cardiovascular disease. The challenge is to also achieve lasting weight loss in patients with BED and concomitant obesity. Full article

Background: Tirzepatide (TZP) is a once-weekly glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic-polypeptide (GIP) receptor co-agonist approved for T2D. TZP provides promising evidence in improving glucose control and weight loss in T2D and obesity across preclinical and human studies, including data from the SURPASS program. Aims: The goal of this paper was to review the evidence on TZP in terms of glucose control, body weight, and the progression of chronic diabetes-related complications and comorbidities. Results: The mean change in HbA1c ranged from −1.6% to −2.06% over placebo, from −0.29% to −0.92% over each GLP-1RAs, and from −0.7% to −1.09% over basal insulins. In SURPASS-6, TZP was more effective than insulin lispro U100 added to basal insulin in reducing HbA_1c levels at the study end (−2.1% vs. −1.1%, respectively). Compared to placebo, TZP induces a significant weight loss: 7.5 (5 mg/week); 11 (10 mg/week); and 12 kg (15 mg/week). Compared to GLP-1RAs, TZP reduces body weight from −1.68 kg to −7.16 kg depending on the dose (5 to 15 mg, respectively). Compared to basal insulin alone rigorously titrated, TZP added onto basal-insulin results in the best strategy for the composite endpoint of improvement of glucose control and weight loss. In SURPASS-6, TZP compared to insulin lispro U100 in add-on to insulin glargine U100 reduced body weight by 9 kg in mean (versus weight gain in basal-bolus users: +3.2 kg). TZP has pleiotropic effects potentially dampening the individual cardiovascular risk, including a reduction in systolic arterial pressure by 4 to 6 mmHg and total cholesterol by 4–6% compared to baseline. A post hoc analysis of SURPASS-4 revealed that TZP, compared to glargine U100, delayed the rate of glomerular filtration decline (−1.4 mL/min vs. −3.6 mL/min, respectively), reduced the rate of urinary albumin excretion (−6.8% vs. +36.9%, respectively), and was associated with a lower occurrence of the composite renal endpoint (HR 0.58 [0.43; 0.80]). Conclusions: Consistent evidence indicates that TZP dramatically changes the clinical course of T2D in different clinical scenarios. The efficacy and safety of TZP on chronic diabetes-related comorbidities and complications seem promising, but ongoing trials will clarify the real benefits. Full article

Background: Combined oral contraceptives (COCs) work mostly by preventing the pre-ovulatory gonadotropin surge, but the action of COCs on spontaneous episodic and GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) release has been poorly evaluated. Oral contraceptives are known to act on the spontaneous hypothalamic–pituitary functions reducing both GnRH and gonadotropin release and blocking ovulation. Aim: To evaluate spontaneous and GnRH-induced LH release during both phases of the menstrual cycle or under the use of the contraceptive pill. Methods: A group of 12 women, subdivided into two groups, volunteered for the study. Group A (n = 6, controls) received no treatments, while Group B (n = 6) received a 21 + 7 combination of ethinyl-estradiol (EE) 30 µg + drospirenone (DRSP) 3 mg. Both groups were evaluated twice: Group A during follicular and luteal phases, Group B during pill assumption and during the suspension interval, performing a pulsatility test, GnRH stimulation test, and hormonal parameters evaluation. Spontaneous and GnRH-induced secretory pulses were evaluated, as well as the instantaneous secretory rate (ISR). Results: COC treatment lowered LH and FSH (follicle stimulating hormone) levels significantly if compared to the follicular phase of spontaneous cycles. During the suspension interval, hormone levels rapidly rose and became comparable to those of the follicular phase of the control group. The LH pulse frequency under COC administration during the suspension interval was similar to that observed during the follicular phase (2.6 ± 0.3 pulses/180 min and 2.3 ± 0.2 pulses/180 min, respectively). The GnRH-induced LH peaks were greater in amplitude and duration than those observed after ISR computation in both groups. The GnRH-induced LH release during the luteal phase of the control subjects was higher than in the follicular phase (51.2 ± 12.3 mIU/mL and 14.9 ± 1.8 mIU/mL, respectively). Conversely, subjects under COC showed a GnRH-induced LH response similar during COC and during the suspension interval. Conclusions: Our data support that the EE + DRSP preparation acts on both spontaneous pulsatile release and GnRH-induced LH release during the withdrawal period of the treatment, and that after 5–7 days from the treatment suspension, steroidal secretion from the ovary is resumed, such as that of androgens. This suggests that in hyperandrogenic patients, a suspension interval as short as 4 days might be clinically better. Full article

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors were once known as a class of glycemic-lowering agents to treat type 2 diabetes. As the evolving evidence from recent cardiorenal trials on these agents has shown—e.g., EMPA-REG OUTCOME, DECLARE-TIMI 58, CANVAS Program, DAPA-CKD—disclosing their benefits beyond glycemic management, SGLT-2 inhibitors have stimulated a shift in the management of T2DM and its comorbidities, specifically preventing cardiovascular events in people with ASCVD, preventing heart failure hospitalizations, and delaying the progression of chronic kidney disease. As a result, their usage beyond glycemic management has been included in clinical practice guidelines. Although SGLT-2 inhibitors have shown promising results in cardiorenal outcomes, patients have not had equal access to these agents, at least in the United States, suggesting a systemic issue of health inequity. This review article explores the mechanisms by which cardiorenal benefits are offered, the results of the landmark clinical trials for these agents, and their place in therapy. Full article

Leydig cells, located in the testis interstitial space, are the primary source of testosterone in males. Testosterone plays critical roles in both reproductive and metabolic functions and therefore is essential for male health. Steroidogenesis must be properly regulated since dysregulated hormone production can lead to infertility and metabolic disorders. Leydig cell steroidogenesis relies on the coordinated interaction of various factors, such as hormones and signaling molecules. While luteinizing hormone (LH) is the main regulator of Leydig cell steroidogenesis, other molecules, including growth hormones (GH), prolactin, growth factors (insulin, IGF, FGF, EGF), and osteocalcin, have also been implicated in the stimulation of steroidogenesis. This review provides a comprehensive summary of the mechanisms and signaling pathways employed by LH and other molecules in the stimulation of Leydig cell steroidogenesis, providing valuable insights into the complex regulation of male reproductive and metabolic health. Full article

Parathyroid carcinoma (PC) is a very rare endocrine cancer with aggressive behavior, a high metastatic potential, and a poor prognosis. Surgical resection of affected gland(s) and other involved structures is the elective therapy. Pre-operative and intra-operative differential diagnosis with benign parathyroid adenoma remains a challenge. The lack of a clear pre-operative diagnosis does not allow one, in many cases, to choose the correct surgical approach to malignant PC, increasing persistence, the recurrence rate, and the risk of metastases. An initial wrong diagnosis of parathyroid adenoma, with a minimally invasive parathyroidectomy, is associated with over 50% occurrence of metastases after surgery. Genetic testing could help in identifying patients at risk of congenital PC (i.e., CDC73 gene) and in driving the choice of neck surgery extension. Targeted effective treatments, other than surgery, for advanced and metastatic PC are needed. The pathogenesis of malignant parathyroid carcinogenesis is still largely unknown. In the last few years, advanced molecular techniques allowed researchers to identify various genetic abnormalities and epigenetic features characterizing PC, which could be crucial for selecting molecular targets and developing novel targeted therapeutic agents. We reviewed current findings in PC genetics, epigenetics, and proteomics and state-of-the-art therapies. Full article

(1) Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are a class of therapeutic agents that mimic the endogenous incretin hormone GLP-1. While this class of agents is not approved for Type 1 Diabetes (T1DM) due to concern of increased diabetic ketoacidosis (DKA) risk, long-acting GLP-1 medications are being commonly prescribed off label for T1DM in clinical practice. Several studies addressed the efficacy and safety of short-acting GLP-1 agonists therapy in patients with T1DM, but the data on long-acting agents are lacking. In our study, we aim to fill in this gap and help healthcare providers in their clinical decision making on the use of these agents for T1DM patients. (2) Methods: We conducted a retrospective chart review of T1DM patients on a long-acting GLP-1 for at least six months. Our retrospective chart review included information starting two years prior to starting GLP-1, and six or more months after starting GLP-1. Parameters collected included HbA1c, 14-day Continuous Glucose Monitor (CGM) and blood glucose (BG) data, and metabolic data (weight, systolic and diastolic blood pressure, and cholesterol levels). Statistical analysis was conducted using paired t-tests on R and Excel with α of 0.05. (3) Results: Our cohort consisted of 54 participants with T1DM on a long-acting GLP-1 (semaglutide, dulaglutide, exenatide extended-release [ER], albiglutide). Mean GLP-1 treatment duration was 23.85 ± 15.46 months. HbA1c values decreased significantly by an average of 0.71% percentage points (%-points, p = 0.002) comparing pre-therapy vs. on GLP-1 treatment. Similarly, for pre-therapy vs. on GLP-1 treatment values, CGM results were significant for increased time in range by 12.15%-points (p = 0.0009) showing a decreased average time in hyperglycemia (BG > 180 mg/dL) by a mean difference of 11.97%-points (p = 0.006), decreased 14-day mean BG by 19 mg/dl (p = 0.01), decreased 14-day BG standard deviation by 8.45 mg/dl (p = 0.01), decreased incidence of DKA hospitalization, and a decrease in weight by 3.16 kg (p = 0.007). (4) Conclusions: As more data emerges on cardiovascular and renal benefits of long acting GLP-1 in type 2 diabetes, there have been no reported outcomes in T1DM. Our study is the first to demonstrate glycemic and metabolic benefits of this class of medication as an adjunct therapy to insulin in T1DM, and safety of its use over an average of 1.5–2 years’ time. This study represents real life experience and the data warrants confirmation by additional prospective studies. Full article

Obesity affects over 40% of the adult population and is a major risk factor for morbidity and mortality due to cardiovascular disease. Black women have one of the highest prevalences of obesity, insulin resistance, hypertension, and cardiovascular events in the US. We previously found that free radical-mediated lipid peroxidation contributes to IL-6 production in dendritic cells leading to inflammation and hypertension. Thus, we hypothesized that F₂-isoprostanes (F₂-IsoPs), products and biomarkers of endogenous lipid peroxidation, contribute to increased inflammation and IL-6 production among obese Black women. We studied a total of 88 obese Black women of age 42.0 ± 9.8 years, weight 102 ± 16 kg, and body mass index (BMI) 37.68 ± 5.08. Systolic and diastolic blood pressure were 124 ± 14/76.2 ± 9.9 mmHg, heart rate was 68.31 ± 10.26 beats/min, and fasting insulin was 15.0 ± 8.7 uU/mL. Plasma F₂-IsoPs were measured using gas chromatography/negative ion chemical ionization mass spectrometry (GC/NICI-MS). Plasma cytokines, including IL-6, IL-8, IL-10, IL-1β, TNF-a, and C-reactive proteins were measured using multiplex Luminex technology. Anthropometric measurements were performed using dual-energy X-ray absorptiometry. Using Pearson’s correlation analysis, we found that BMI was positively correlated with plasma F2-IsoPs, while inversely correlated with insulin sensitivity in obese Black women. Further, F₂-IsoPs were positively correlated with inflammatory marker IL-6 levels while negatively correlated with anti-inflammatory marker IL-10. In addition, we found that plasma F₂-IsoPs levels were significantly associated with reduced insulin sensitivity. These results suggest that F₂-IsoPs may be associated with obesity-induced cardiovascular risk in Black women by increasing the production of inflammatory cytokine IL-6 and decreasing the production of anti-inflammatory IL-10. Full article

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H₂O₂-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers. Full article

Diabetes-related distress (DRD) is defined as an emotional state experienced by people with diabetes (PWD) who are worried about their disease management, the emotional burden from the condition, and/or potential difficulties accessing care or support. The psychosocial aspect of diabetes management is a factor that directly influences patients’ well-being as well as the chronic management of the condition yet is not a primary clinical problem being addressed within the healthcare setting. This review advocates for a re-evaluation and subsequent adjustment of the current DRD screening methodology by implementing the five primary components (Intrapersonal, Interpersonal, Organizational, Community, and Public Policy) of the Socio-Ecological Model of Health (SEMH), bridging the gaps from a public-health perspective. We searched two electronic databases for studies published in the United States from 1995 to 2020 reporting the effects of social determinants of health (SDOH) on DRD. Articles that contained at least one of the five elements of the SEMH and focused on adults aged 18 years or older were included. SDOH, which include circumstances where individuals grow, work, and age, are highly influenced by external factors, such as the distribution of wealth, power, and resources. Current DRD screening tools lack the capacity to account for all major components of SDOH in a comprehensive manner. By applying the SEMH as a theory-based framework, a novel DRD screening tool addressing sex, ethnicity, and socioeconomic background should be implemented to better improve diabetes management outcomes. By exploring the relationships between each level of the SEMH and DRD, healthcare professionals will be better equipped to recognize potential stress-inducing factors for individuals managing diabetes. Further efforts should be invested with the goal of developing a novel screening tool founded on the all-encompassing SEMH in order to perpetuate a more comprehensive diabetes treatment plan to address barriers within the SDOH framework. Full article

This review aims at defining the neuroendocrine mechanisms underlying the sport-induced restrictions of the reproductive axis in female athletes. Episodic gonadotropin release was found to be compromised, presumably a result of impaired hypothalamic pulsatile GnRH release. Any deviation from optimal gonadotropin release may result in a suboptimal function of the ovaries, leading to disorders of the menstrual cycle and ovulation. A whole spectrum of menstrual dysfunctions ranging from ovulatory eumenorrhea to luteal phase defects and amenorrhea has been reported in sportive women. As essential neuroendocrine factors underlying these observations, activation of the adrenal axis and altered central nervous neurotransmitter activity have been identified to transfer metabolic, nutritional, and stress signals into the hypothalamic GnRH release. The degree by which the neuroendocrine axis governing reproduction is impaired critically depends on the intensity and duration of exercise and the state of training. Other decisive factors may be energy expenditure and availability, nutritional components, and the maturity of the hypothalamic-pituitary-ovarian (HPO) axis when sport activity was initiated. In conclusion, the gradual cessation of reproductive function observed in female athletes may be interpreted as an adaptive mechanism in response to physical and psychological endurance during sport. This sport-induced restriction of reproductive capacity may serve as protection (endogenous contraception) to preserve a woman’s health. Full article

Parathyroid carcinoma is a rare disease that needs an additional diagnostic tool and wide therapeutic options. The genomics and proteomics approach may help to find the tools to improve the prognosis of the disease by early detection and metastatic control. The findings from genomics were mainly CDC73, PRUNE2, CCND1, and genes related to PI3K/AKT/mTOR and Wnt pathways. CDC73, PRUNE2, and CCND1 were closely related to each other, and PRUNE2 and CCND1 genes are related to expression levels of parafibromin protein, which may aid in supporting the definite diagnosis of the disease. PI3K/AKT/mTOR and Wnt pathways could be a potential therapeutic target for the disease, which needs further basket trials to prove the concept. In this review, current findings from genomics and proteomics studies in parathyroid carcinoma were reviewed. Full article

Short stature is a common reason for a child to visit the endocrinologist, and can be a variant of normal or secondary to an underlying pathologic cause. Pathologic causes include growth hormone deficiency (GHD), which can be congenital or acquired later. GHD can be isolated or can occur with other pituitary hormone deficiencies. The diagnosis of GHD requires thorough clinical, biochemical, and radiographic investigations. Genetic testing may also be helpful in some patients. Treatment with recombinant human growth hormone (rhGH) should be initiated as soon as the diagnosis is made and patients should be monitored closely to evaluate response to treatment and for potential adverse effects. Full article

Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement. Full article

X-linked hypophosphatemia (XLH) is the most common genetic form of rickets and osteomalacia and is characterized by growth retardation, deformities of the lower limbs, and bone and muscular pain. Spontaneous dental abscesses caused by endodontic infections due to dentin dysplasia are well-known dental manifestations. When dentin affected by microcracks or attrition of the enamel is exposed to oral fluids, oral bacteria are able to invade the hypomineralized dentin and pulp space, leading to pulp necrosis, followed by the formation of a periapical gingival abscess. Without appropriate dental management, this dental manifestation results in early loss of teeth and deterioration in the patient’s quality of life. Early specific dental intervention and oral management in collaboration with medical personnel are strongly recommended for XLH patients. Importantly, dental manifestations sometimes appear before the diagnosis of XLH. Dentists should be alert for this first sign of XLH and refer affected children to a pediatrician for early diagnosis. A humanized monoclonal antibody for FGF23 (burosumab) is a promising new treatment for XLH; however, the effects on the dental manifestations remain to be elucidated. The establishment of fundamental dental therapy to solve dental problems is still underway and is eagerly anticipated. Full article

Metabolic reprogramming is an emerging hallmark of cancer, involving the overexpression of metabolism-related proteins, such as glucose and monocarboxylate transporters and intracellular glycolytic enzymes. The biology of testicular germ cell tumors (TGCTs) is very complex, and although their metabolic profile has been scantily explored, some authors have recently reported that the metabolic rewiring of cancer cells resulted in an association with aggressive clinicopathological characteristics. In this study we have investigated, by immunohistochemical analysis, the expression of key proteins sustaining the hyperglycolytic phenotype in pure seminoma (SE, nr. 35), pure embryonal carcinoma (EC, nr. 17) tissues samples, and normal testes (nr. 5). GLUT1, CD44, PFK-1, MCT1, MCT4, LDH-A, and PDH resulted in more expression in EC cells compared to SE cells. TOM20 was more expressed in SE than in EC. GLUT1, MCT1, and MCT4 expression showed a statistically significant association with SE histology, while for EC, the association resulted in being significant only for GLUT1 and MCT4. Finally, we observed that EC resulted as negative for p53, suggesting that the GLUT1 and MTC overexpression observed in EC could be also attributed to p53 downregulation. In conclusion, our findings evidenced that EC exhibits a higher expression of markers of active aerobic glycolysis compared to SE, suggesting that the aggressive phenotype is associated with a higher glycolytic rate. These data corroborate the emerging evidence on the involvement of metabolic reprogramming in testicular malignancies as well, highlighting that the metabolic players should be explored in the future as promising therapeutic targets. Full article

Prediabetes, the precursor of type 2 diabetes (T2D), is on the rise among children and adolescents in the United States. The natural history of prediabetes is poorly characterized in children compared to adults. The available data indicate a phenotype of an accelerated β-cell failure in youth with prediabetes. Data from randomized controlled trials showed no benefit on β-cell preservation or A1c in youth with prediabetes from therapeutic agents such as metformin and insulin. As a result, the American Diabetes Association recommends only lifestyle intervention, but not therapeutic agents, for the management of prediabetes in children and adolescents. These recommendations for lifestyle modification in youth, largely derived from data in adults, lack the precision necessary for efficacy in youth. However, a recent 4-year real-world study on youth reported that adherence to nutrition visits was associated with a 4-fold reduction in the likelihood of progressing from prediabetes to T2D. The finding that this reversal is associated with reduced insulin resistance (IR) and not with decreased body weight is novel and provides the foundation for trialing investigational products that may protect β-cells and reduce IR and/or body weight. This study provides the much-needed foundation for further exploration of the impact of lifestyle modification in conjunction with other approaches for the reversal of prediabetes in youth. The systematization of the protocol for medical nutrition therapy for the reversal of prediabetes in youth will ensure optimal and consistent results from adherent patients. This communication provides updates on the pathobiology of prediabetes in youth and a clear direction for efficacious studies in the field. Full article

Subacute thyroiditis (SAT) is the most common cause of neck pain and thyrotoxicosis. Although this disease was recognized already by the end of the 18th century, new concepts regarding pathogenesis have emerged in recent years. Moreover, in the last two years, literature on SAT has increased significantly due to articles describing the possible connection with coronavirus disease 2019 (COVID-19). This integrative review depicts old and new concepts of this disease, proposing a detailed overview of pathogenesis, a practical approach to diagnosis and treatment, and a thorough description of the latest discoveries regarding the association of SAT with COVID-19. Full article

Background and study aims—Albuminuria, defined as an enhanced urine albumin/creatinine ratio (ACR) on a spot sample, is a validated biomarker of glomerular damage. However, it cannot always detect early renal failures in patients with type 2 diabetes (T2D), thus prompting the search for more sensitive and specific parameters. Herein, we investigated the differential role of plasma and urine neutrophil-gelatinase-associated lipocalin (NGALp,—NGALu) for the detection of diabetic kidney disease (DKD). Methods—Traditional glomerular (serum creatinine, cystatin C, ACR) damage biomarkers were evaluated in 84 patients with T2D and in 21 metabolically healthy controls. Diabetic patients were stratified into four groups based on T2D duration (less or more than 5 years) and presence and severity of DKD (early- or advanced-stage), as defined by the ACR and estimated glomerular filtration rate (eGFR). NGALp and NGALu were determined by ELISA methodology and compared among groups. Results—There was no difference in NGALp and NGALu levels between the metabolically healthy individuals and the age-matched, newly diagnosed diabetic patients in the absence of DKD. However, in contrast to NGALu, NGALp was found to be substantially increased in patients with long-standing diabetes without biochemical evidence of DKD, closely mirroring the modest, but still accelerated, decline in the eGFR typical of this chronic dysmetabolic condition, and remained overexpressed throughout the stages of DKD progression. Increased NGALu levels were, instead, rather specific in patients with biochemical evidence of DKD (i.e., marked by increased albuminuria), regardless of T2D duration. Spearman’s correlation and regression analyses showed that patient age and T2D duration could exert a strong positive impact exclusively on NGALp concentrations (ρ = 0.419, p < 0.001 for age; ρ = 0.581, p < 0.001 for T2D), and none on NGALu. Furthermore, receiver operating characteristic (ROC) analysis showed the best performance of NGALp compared to NGALu for the detection of DKD (AUC = 0.817 for NGALp, AUC = 0.711 for NGALu). Conclusions—Our data suggest a different pathophysiological and predictive role for urine and plasma NGAL in the context of T2D and DKD. Full article

The kisspeptin system includes the cleavage products Kiss1 precursor and kisspeptin receptor (Kiss1R). It was originally discovered and studied in cancer metastasis, but the identification of KISS1/KISS1R gene mutations causing hypogonadotropic hypogonadism (HH) revealed unexpected effects in reproduction. Nowadays, the kisspeptin system is the main central gatekeeper of the reproductive axis at puberty and adulthood, but it also has a widespread functional role in the control of endocrine functions. At the periphery, Kiss1 and Kiss1R are expressed in the testes, but the need for kisspeptin signaling for spermatogenesis and sperm quality is still unclear and debated. This brief manuscript summarizes the main findings on kisspeptin and male reproduction; upcoming data on sperm maturation are also discussed. Full article

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) encompass a variety of symptoms that occur during the luteal phase of the menstrual cycle and impair daily life activities and relationships. Depending on the type and severity of physical, emotional or behavioral symptoms, women of reproductive age followed for at least two prospective menstrual cycles may receive one of the two diagnoses. PMDD is the most severe form of PMS, predominantly characterized by emotional and behavioral symptoms not due to another psychiatric disorder. PMS and PMDD are common neuro-hormonal gynecological disorders with a multifaceted etiology. Gonadal steroid hormones and their metabolites influence a plethora of biological systems involved in the occurrence of specific symptoms, but there is no doubt that PMS/PMDD are centrally based disorders. A more sensitive neuroendocrine threshold to cyclical variations of estrogens and progesterone under physiological and hormonal therapies is present. Moreover, altered brain sensitivity to allopregnanolone, a metabolite of progesterone produced after ovulation potentiating GABA activity, along with an impairment of opioid and serotoninergic systems, may justify the occurrence of emotional and behavioral symptoms. Even neuro-inflammation expressed via the GABAergic system is under investigation as an etiological factor of PMS/PMDD. Pharmacological management aims to stabilize hormonal fluctuations and to restore the neuroendocrine balance. The rationale of suppressing ovulation supports prescription of combined hormonal contraception (CHC). Its effect on mood is highly variable and depends on biochemical characteristics of exogenous steroids and on type and severity of symptoms. Hormonal regimens reducing the estrogen-free interval or suppressing menstruation seem better choices. Psychoactive agents, such as serotonin reuptake inhibitors (SSRIs), are effective in reducing the symptoms of PMS/PMDD and may be prescribed continuously or only during the luteal phase. Novel therapeutic approaches include inhibition of progesterone receptors in the brain, i.e., with ulipristal acetate, reduced conversion of progesterone with dutasteride, and modulation of the action of allopregnanolone on the brain GABAergic system with sepranolone. Full article

The relationship between varicocele and hypogonadism becomes clearer everyday thanks to the most recent literature, particularly with regards to the impact of varicocele repair on serum testosterone level improvement in hypogonadal patients. We selected English articles published from 1964 to September 2021. The search terms “varicocele” and “hypogonadism” were used as filters. A total of 102 studies have been obtained. For the meta-analysis, the pooled mean differences (MDs) for continuous variables and the ln(OR) were used for data pooling observational studies. A total of 15 articles have been finally included: nine retrospective and six observational. Testosterone levels pre- and after surgery were reported in four studies. There was statistically significant heterogeneity in these studies (chi² = 267.09, I² = 72%; p = 0.01). Mean differences of total testosterone was statistically different in men pre- and after-surgery (mean difference = 106.76; p < 0.0001). It is indeed established that altered environments caused by varicocele cause pantesticular insult, but it has not been unequivocally determined whether men with varicocele are at increased risk for the development of clinical hypogonadal symptoms. Full article

The definition of primary hyperaldosteronism (PA) has shifted, as progress has been made in understanding the disease. PA can be produced by unilateral or bilateral cortical adrenal hyperproduction of aldosterone, due to hyperplasia, aldosterone-secreting cell clusters, aldosterone-producing macro or micro adenoma/s, and combinations of the above, or by an aldosterone-producing carcinoma. PA is a highly prevalent disease, affecting close to 10% of the hypertensive population. However, PA is clearly underdiagnosed. The purpose of this review is to address current knowledge of PA’s clinical manifestations, as well as current methods of diagnosis. PA is associated with a higher cardiovascular morbidity and mortality than essential hypertension with similar blood pressure control. Young hypertensive patients, those with a first-degree relative with PA or ictus, and/or those with apnea/hypopnea syndrome, moderate/severe/resistant hypertension, adrenal incidentaloma, and/or hypokalemia should be screened for PA. PA can induce atrial fibrillation (AF), and those patients should also be screened for PA. We propose the use of the Captopril challenge test (CCT), oral salt loading, or intravenous salt loading for PA diagnosis, given their availability in the majority of hospital centers. CCT could be first-line, since it is safe and easy to perform. Full article