Endocrines, Volume 3, Issue 4 (December 2022) – 20 articles

Endometrial receptivity array (ERA)—an objective tool used in assisted reproductive technology—is used for personalized embryo transfer in in vitro fertilization. Hydrosalpinx affects implantation through various mechanisms. However, its effects on ERA are not well established. In this case report, we present the diagnosis and treatment of a 34-year-old nulligravida woman with infertility for two years, obesity, double uterus with unilateral hydrosalpinx and right kidney deficiency. Based on ERA results, endometrial microbiome metagenomic analysis (EMMA), analysis of infectious chronic endometritis (ALICE), and CD138 immunostaining, the patient was treated with hormonal replacement cycle and amoxicillin/clavulanic acid. After one week of amoxicillin/clavulanic acid administration, the vitirified-warmed 4AA blastocyst was transferred to the left uterus—which was absent of hydrosalpinx and easily accessible to transfer and pregnancy was achieved. To the best of our knowledge, this case study is the first one in which we found that there were no differences between the left and right uterus in ERA, EMMA, ALICE, and CD138 immunostainings. Hence, we suggest that hydrosalpinx does not necessarily cause endometrial changes in all cases. Further research to evaluate the effects of hydrosalpinx on implantation with ERA and EMMA/ALICE is warranted. 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

Diabetic ketoacidosis (DKA) is the most common hyperglycemic emergency and causes the greatest risk for death that could be prevented in patients with diabetes mellitus. DKA occurs more commonly among patients with type-1 diabetes with a thirty percent of the cases take place in patients with type 2 diabetes. DKA is characterized by sever hyperglycemia, metabolic acidosis and ketosis. Proper management of DKA requires hospitalization for aggressive replacement and monitoring of fluids, electrolytes and insulin therapy. Management of DKA has been updated with guidelines, to help standardize care, and reduce mortality and morbidity. The major precipitating factors for DKA include new diagnosis of diabetes, non-adherence to insulin therapy as well as infection in patients with diabetes. Discharge plans should include appropriate selection of insulin dosing and regimens as well as patient education to prevent recurrence of DKA. Further, definition and management of euglycemic DKA in patients prescribed sodium-glucose co-transporter 2 inhibitors are discussed. Special consideration is reviewed for specific patient population including pregnancy, renal replacement, acute pancreatitis, and insulin pump users as well as patients with COVID-19. Full article

Demand for minimally invasive surgery has driven the development of new gadgets and surgical techniques. Yet, questions about safety and skeptical views on new technology have prevented proliferation of new modes of surgery. This skepticism is perhaps due to unfamiliarity of new fields. Likewise, there are currently various remote-access techniques available for thyroid surgeons that only few regions in the world have adapted. This review will explore the history of minimally invasive techniques in thyroid surgery and introduce new technology to be implemented. 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

Background: This study assesses the long-term cost-effectiveness of this screening protocol from a healthcare system perspective. Methods: Australians presenting to private oral healthcare practices recruited to the iDENTify study were included as the study population. A Markov model preceded by a decision tree was developed to assess the intervention’s long-term cost-effectiveness when rolled out to all eligible Australians, and measured against ‘no-intervention’ current practice. The model consisted of four health states: normoglycaemia; pre-diabetes; type 2 diabetes and death. Intervention reach of various levels (10%, 20%, 30%, and 40%) were assessed. The model adopted a 30-year lifetime horizon and a 2020 reference year. Costs and benefits were discounted at 5% per annum. Results: If the intervention reached a minimum of 10% of the target population, over the lifetime time horizon, each screened participant would incur a cost of $38,462 and a gain of 10.564 QALYs, compared to $38,469 and 10.561 QALYs for each participant under current practice. Screening was associated with lower costs and higher benefits (a saving of $8 per person and 0.003 QALYs gained), compared to current standard practice without such screening. Between 8 and 34 type 2 diabetes cases would be avoided per 10,000 patients screened if the intervention were taken up by 10% to 40% of private oral healthcare practices. Sensitivity analyses showed consistent results. Conclusions: Implementing type 2 diabetes screening in the private oral healthcare setting using a simple risk assessment tool was demonstrated to be cost-saving. The wider adoption of such screening is recommended. 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

We evaluated the hospital evolution of hyponatremia and inflammation markers in patients with coronavirus disease 2019 (COVID-19). The hospital evolutions of a cohort of adult patients with COVID-19 pneumonia and hyponatremia were retrospectively analyzed. Data of the admission day, 2nd–3rd and 7th–10th day of hospitalization, and of the discharge day were collected. Comparative and multivariate analyzes were developed, and Hazzard ratio (HR) with 95% confidence intervals (95% CI) were calculated. Of the 172 hospitalized patients with COVID-19, 49 of them (28.5%) had hyponatremia, which were analyzed. A total of 32/49 (65.3%) patients were male, and 22/49 (44.9%) euvolemic. Mean age: 69.9 ± 14.7 years. All patients had high inflammatory markers at admission. Of the total patients with hyponatremia at admission, only 26.2% remained hyponatremic at the 7th–10th day of hospitalization. Improvement in serum sodium (SNa) coincided with improvement in inflammatory markers during hospitalization, in both euvolemic and hypovolemic hyponatremic patients. A higher serum creatinine at admission was independently associated with mortality (HR: 12.23, 95% CI: 2 to 25.6) in hyponatremic COVID-19 patients. In conclusion, both hypovolemic and euvolemic hyponatremia in COVID-19 patients occurred in an inflammation status, and improved as inflammation decreased. 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

14-3-3s are a family of structurally similar proteins that bind to phosphoserine or phosphothreonine residues, forming the central signaling hub that coordinates or integrates various cellular functions, thereby controlling many pathways important in cancer, cell motility, cell death, cytoskeletal remodeling, neuro-degenerative disorders and many more. Their targets are present in all cellular compartments, and when they bind to proteins they alter their subcellular localization, stability, and molecular interactions with other proteins. Changes in environmental conditions that result in altered homeostasis trigger the interaction between 14-3-3 and other proteins to retrieve or rescue homeostasis. In circumstances where these regulatory proteins are dysregulated, it leads to pathological conditions. Therefore, deeper understanding is needed on how 14-3-3 proteins bind, and how these proteins are regulated or modified. This will help to detect disease in early stages or design inhibitors to block certain pathways. Recently, more research has been devoted to identifying the role of MicroRNAs, and long non-coding RNAs, which play an important role in regulating gene expression. Although there are many reviews on the role of 14-3-3 proteins in cancer, they do not provide a holistic view of the changes in the cell, which is the focus of this review. The unique feature of the review is that it not only focuses on how the 14-3-3 subunits associate and dissociate with their binding and regulatory proteins, but also includes the role of micro-RNAs and long non-coding RNAs and how they regulate 14-3-3 isoforms. The highlight of the review is that it focuses on the role of 14-3-3, actin, actin binding proteins and Rho GTPases in cancer, and how this complex is important for cell migration and invasion. Finally, the reader is provided with super-resolution high-clarity images of each subunit of the 14-3-3 protein family, further depicting their distribution in HeLa cells to illustrate their interactions in a cancer cell. 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

Obesity produces a systemic low-grade inflammation associated with many adverse health conditions and, as we recently learned, with complications of COVID-19. Functional studies in animal models have demonstrated that asperuloside, an iridoid glycoside found in many medicinal plants, has produced promising anti-obesity results. However, the safety profile and the anti-inflammatory properties of asperuloside remain unknown. Here, we confirmed the previously reported anti-obesity properties of asperuloside, and, importantly, we performed toxicity studies assessing cell viability providing a dose reference for future animal experiments. Asperuloside significantly reduced blood levels of leptin and the mRNA levels of orexigenic peptides, such as NPY and AgRP in mice consuming HFD, with no effect on mice eating a standard chow diet. In addition, our results indicate that ASP reduced both hypothalamic and hepatic mRNA levels of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α as well as the blood levels of plasminogen activator inhibitor-1 (PAI-1), which are known to play a major role in the development of insulin resistance and cardiovascular complications. Collectively, our findings suggest that asperuloside is a safe compound for long-term use in animal models and that it reduces the elevated levels of pro-inflammatory cytokines occurring in obesity. Full article

Microwave endometrial ablation (MEA) is a minimally invasive treatment for uterine myoma with hypermenorrhea, which can replace conventional hysterectomy. However, cases requiring additional treatment because of postoperative recurrence are often encountered. MEA cauterizes the endometrium and is not recommended for patients who wish to preserve fertility. We present the cases of a patient with myoma-related hypermenorrhea who underwent microwave ablation of the inflowing blood vessels to the uterine myoma under transvaginal ultrasound guidance. A 43-year-old woman was diagnosed with chronic myeloid leukemia and treated with dasatinib 2 years ago. Worsening hypermenorrhea was observed after treatment initiation. Ultrasound and pelvic magnetic resonance imaging revealed a uterine myoma. Therefore, she underwent MEA under transvaginal ultrasound guidance. Visual analog scale evaluation demonstrated considerable improvement in hypermenorrhea and dysmenorrhea; the myoma size showed reduction. The postoperative course was uneventful, and the patient was discharged on the day after surgery. No postoperative complications were observed. This patient is currently undergoing infertility treatment. The microwave ablation of myoma under transvaginal ultrasound guidance can effectively and safely reduce the myoma size. These findings suggest that this method is a novel treatment option for patients with myoma-related hypermenorrhea who wish to preserve their fertility and have children. Full article

BACKGROUND. Several studies have already investigated the relationship between IGF1 and semen parameters. However, clinical studies rarely concluded on the existence of a relationship between IGF1 and the sperm number, and whether the IGF1 serum levels have a practical value in the diagnostic work-up of patients with oligozoospermia is still unclear. OBJECTIVE. Molecular evidence reported that IGF1 and FSH belongs to the same molecular pathway. The aim of this study is to assess whether insulin-like growth factor-1 (IGF1)/follicle-stimulating hormone (FSH) ratio has an impact on testicular function and, specifically, on sperm number and testicular volume in a cohort of unselected men. METHODS. This is a cross-sectional study on 59 patients who attended the Seminology laboratory of the Division of Endocrinology of the University of Catania (Catania, Italy) for semen analysis. Data were analyzed to evaluate the relationships between IGF1 or IGF1/FSH ratio and sperm concentration, total sperm count (TSC), and testicular volume (TV). We also evaluated the occurrence of any difference in IGF1 and FSH serum levels and the IGF1/FSH ratio in patients with oligozoospermia and those with a TSC > 39 million/ejaculate. MAIN RESULTS AND ROLE OF CHANGE. Patients had a mean age of 31.0 ± 8.5 years. The mean FSH and IGF1 levels were 3.95 ± 2.55 mIU/mL and 232.59 ± 65.13 ng/mL, respectively. IGF1 serum levels did not correlate with sperm concentration, TSC, and TV. The IGF1/FSH ratio showed a positive correlation with sperm concentration (r = 0.408; p = 0.004), TSC (r = 0.468; p = 0.001), and TV (0.463; p = 0.002). Patients with oligozoospermia (Group 1, 23.7%, n = 14) had a significant lower IGF1/FSH ratio (57.9 ± 9.5 vs. 94.1 ± 8.7; p = 0.03) compared to those with TSC > 39 million/ejaculate (Group 2, 76.3%, n = 45). They did not differ significantly for neither IGF1 nor FSH serum levels. CONCLUSION. We found a positive correlation between the IGF1/FSH ratio and sperm concentration, TSC and TV. Furthermore, patients with oligozoospermia showed a significantly lower ratio compared to those with a normal TSC, while neither IGF1 nor FSH differed significantly in the two groups. Our results may reflect the existence of a molecular pathway to which IGF1 and FSH belongs. However, further studies are needed. Full article

Conventional hypocaloric diets, providing continuous energy restriction, are considered to be the cornerstone of dietary management of obesity. Although energy-restricted diets are overall safe, healthy, and modestly effective, their long-term adherence is difficult to accomplish. Intermittent fasting and ketogenic diets have emerged as attractive alternative dietary options for weight loss and improvement in cardiometabolic risk. Intermittent fasting is a unique dietary pattern characterized by periods of eating alternated with periods of fasting. Ketogenic diets are very low in carbohydrate, modest in protein, and high in fat. Several systematic reviews and meta-analyses of randomized controlled trials (RCTs) have reported beneficial but short-lived effects of intermittent fasting and ketogenic diets on various obesity-related health outcomes. Although for both diets, the current evidence is promising and steadily evolving, whether they are better than traditional calorie-restricted diets, whether they can safely lead to sustained weight loss and overall health benefits, and their effects on body composition, weight loss maintenance, energy intake and expenditure, diet quality, and cardiometabolic risk factors are still not unequivocally proven. The aim of the present review is to summarize the current state of evidence regarding the effects of these two popular modern diets, namely intermittent fasting and ketogenic diets. We describe the rationale and characteristics of different dietary protocols, we analyze the major mechanisms explaining their weight loss and cardiometabolic effects, and we provide a concise update on their effects on body weight and cardiometabolic risk factors, focusing on meta-analyses of RCTs. We also discuss knowledge gaps in the field of these diets, and we indicate directions for future research. Full article

Recombinant human growth hormone (rhGH) is prescribed to youth with growth hormone deficiency (GHD) to support normal growth and ensure healthy physical development, and to youth without GHD to address height concerns. Perceptions of youth involvement in rhGH treatment decisions have not been explored. This study aimed to examine perceptions of youth and parent roles in decisions around rhGH treatment. Youth (n = 22, 11.5 ± 2.0 years) who had undergone evaluation for short stature and their parents (n = 22) participated in semi-structured interviews after stimulation test results had been received. Interviews revealed the following themes: (1) parent provided youth with support; (2) parent facilitated youth’s decision-making involvement; (3) youth had no role or did not remember their role; and (4) youth did not remember conversations with their parents or providers. Parents facilitated their children’s involvement by sharing information and seeking their opinions. While some participants described youth as having a substantial decision-making role, not all youth felt they were involved, and some youth could not recall conversations about rhGH. Parents can bolster youth involvement by having conversations using developmentally appropriate language, which is critical to youth feeling empowered and developing efficacy over their own care. 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