Endocrines, Volume 3, Issue 3 (September 2022) – 20 articles

Interleukin-1 antagonism is a proposed biomarker and potential therapy for the delay and/or treatment of type 1 diabetes (T1D). We evaluated the role of circulating interleukin-1 receptor antagonist (IL-1ra) in a prospectively monitored cohort of T1D patients. In order to determine a mechanistic association between IL-1ra and T1D, we performed co-localization analyses between serum IL-1ra protein quantitative trait loci and T1D genome-wide analysis studies. Adjusting for human leukocyte antigen (HLA) genotypes, first degree relative status, gender, and age, serum levels of IL-1ra were lower in subjects who progressed to T1D compared to the controls (p = 0.023). Our results suggest that females have higher levels of IL-1ra compared to males (p = 0.005). The 2q14.1 region associated with serum IL-1ra levels is not associated with a risk of developing T1D. Our data suggest that IL-1 antagonism by IL-1ra is not an effective therapy in T1D, but IL-1ra may be a biomarker for progression to T1D. Full article

X-linked hypophosphatemia (XLH) is a rare inherited disorder involving elevated levels of fibroblast growth factor (FGF) 23, and is caused by loss-of-function mutations in the PHEX gene. FGF23 induces renal phosphate wasting and suppresses the activation of vitamin D, resulting in defective bone mineralization and rachitic changes in the growth plate and osteomalacia. Conventional treatment with combinations of oral inorganic phosphate and active vitamin D analogs enhances bone calcification, but the efficacy of conventional treatment is insufficient for adult XLH patients to achieve an acceptable quality of life. Burosumab, a fully human monoclonal anti-FGF23 antibody, binds and inhibits FGF23, correcting hypophosphatemia and hypovitaminosis D. This review describes a typical adult with XLH and summarizes the results of clinical trials of burosumab in adults with XLH. Full article

The spread of severe acute respiratory syndrome—Coronavirus 2 (SARS-CoV-2) around the world has rapidly sparked the interest of the scientific community to discover its implications in human health. Many studies have suggested that SARS-CoV-2 is directly or indirectly involved in the male reproductive tract impairment. Some evidence supports the possible role of the virus in male infertility. Therefore, this review aims to summarize the relationship between the male urogenital tract, male fertility, and the gonadal hormone profile. The testis is one of the organs with the highest expression of the angiotensin-converting enzyme (ACE) 2-receptor that allows the virus to penetrate human cells. Orchitis is a possible clinical manifestation of COVID-19 and testicular damage has been found on autopsy in the testes of patients who died from the disease. SARS-CoV-2 infection can compromise the blood-testis barrier, favoring testicular damage and the production of anti-sperm autoantibodies. Some studies have detected the presence of SARS-CoV-2 in semen and a high percentage of patients with COVID-19 have altered sperm parameters compared to controls. Finally, lower testosterone levels, higher luteinizing hormone (LH) levels, and decreased follicle-stimulating (FSH)/LH and testosterone/LH ratios suggest primary testicular damage. In conclusion, further studies are needed to evaluate the exact mechanisms by which SARS-CoV-2 affects the male reproductive system and fertility and to evaluate the reversibility of its long-term effects. 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

The therapeutic management of premature lifelong ejaculation (PE) ranges from behavioral therapy to pharmacological and surgical treatments. Hyaluronic Acid (HA) injection into the glans penis is a non-surgical procedure, intended to reduce glans hypersensitivity, improving the intravaginal ejaculation latency time (IELT). HA injection can be performed through different techniques that, although safe and effective, rarely can cause local complications. In this pilot uncontrolled study, we tested the effectiveness of a new technique based on a single HA injection into the frenulum of the glans, to improve IELT in a sample of patients affected by PE. We observed a significant increase of the IELT after one (median 73.3, IQR 66.2–79.9 s) and two months (66.2, 63.1–73.9) that gradually decreased at three months, remaining still significantly higher than at baseline (34.8, 30.9–37.4). PEDT and IIEF questionnaires significantly improved compared to baseline in the first two months of follow-up (p < 0.001). In conclusion, the preliminary results emerging from this pilot uncontrolled study, highlight the effectiveness of this one-shot HA injection approach, although a larger sample and longer follow-up time are needed to standardize the procedure. Full article

Impacts of subclinical reactive hypoglycemia on food ingestion are not well studied. In the present study, in obese/overweight males without diabetes (n = 34), continuous glucose monitoring and eating behavior were recorded for 6 days after the 75 g glucose challenge. In 50% of subjects, the minimal sensor glucose levels within 24 h post-challenge (CGMmin) were <70 mg/dL, while symptoms, if any, were subtle. Median eating and snacking frequencies were 3.45 and 0.45 times/day, respectively. In subjects with eating frequency > 3 times/day, CGMmin was significantly lower than CGMmin in those without. The receiver operating characteristic curve of CGMmin for detecting eating frequency > 3 times/day showed the area under the curve of 0.74 with the cutoff point of 65 mg/dL (p = 0.027). Eating frequency of subjects with CGMmin < 65 mg/dL was significantly higher than that of subjects with CGMmin ≥ 65 mg/dL (3.68 vs. 3.3 times/day, p = 0.047). When it was defined as reactive hypoglycemia that either the 2 h post-load blood glucose level, the minimal self-monitored blood glucose level within the 1st day, or CGMmin, was below their respective cutoff for detecting eating frequency > 3 times/day, eating frequency of subjects with the reactive hypoglycemia was significantly higher than that of the subjects without the reactive hypoglycemia (3.75 times/day vs. 3.15 times/day, p = 0.001). In addition, the median snacking frequency was 6 times higher in subjects with reactive hypoglycemia compared to those without it (0.9 times/day vs. 0.15 times/day, p < 0.001). In conclusion, in obese/overweight males without diabetes, subclinical reactive hypoglycemia is significantly associated with higher eating/snacking frequencies. Full article

The conventional treatment for X-linked hypophosphatemia (XLH), consisting of phosphorus supplementation and a biologically active form of vitamin D (alfacalcidol or calcitriol), is used to treat rickets and leg deformities and promote growth. However, patients’ adult height often remains less than −2 SD. Moreover, adverse events, such as renal calcification and hyperparathyroidism, may occur. The main pathology in XLH is caused by excessive production of fibroblast growth factor 23 (FGF23). Several studies have demonstrated that treatment with burosumab, a blocking neutralizing antibody against FGF23, is better than conventional therapy for severe XLH and has no serious, short-term side effects. Thus, treatment with burosumab may be an option for severe XLH. The present article reviews the conventional and burosumab therapies. In addition to the fact that the long-term efficacy of antibody-based treatment has not been demonstrated, there are other, unresolved issues concerning the burosumab treatment of XLH. Full article

Background: The American Joint Commission on Cancer on Tumor Node Metastasis (AJCC/TNM) staging system provides adequate information on the risk of differentiated thyroid cancer (DTC)-specific mortality in totally thyroidectomized patients, but its role in predicting persistence and relapse of disease is uncertain. The relatively new 2015 American Thyroid Association (ATA) guidelines recommend stratifying patients at the time of DTC diagnosis with its own risk classification system, in order to identify those at high risk of residual or recurrent morbidity who may benefit from post-operative radioiodine (RAI) administration and/or need additional work-up. Methods: To verify the prevalence proportion of persistence or relapse of disease, a consecutive cohort of 152 patients with a diagnosis of DTC, subjected to total thyroidectomy (+/− post-operative RAI administration as per guidelines indication) and to neck ultrasonography (US), as well as biochemical surveillance for a minimum of 2 years at the Endocrinology Unit of Mater-Domini Hospital (Catanzaro, Italy), was enrolled. The prognostic role of the AJCC/TNM stage and ATA risk classification system was analyzed by logistic regression. Results: At a mean of 9 years after surgical treatment, DTC was found to persist or relapse in 19 (12.5%) participants. The initial risk for these outcomes, based on the ATA classification, was mostly low (53.9%) or intermediate (39.5%). AJCC/TNM stages were predominantly stage I or stage II. Despite a small representation in this cohort, high-risk patients according to the ATA classification had 8-fold higher odds of persistence or relapse of disease than those of low-risk participants, while controlling for potential risk modifiers, including age at DTC diagnosis, male gender, and post-operative RAI administration (p = 0.008). In contrast, the AJCC/TNM stage was not associated with the disease status at the last follow-up visit (p = 0.068 for the 7th Edition; p = 0.165 for the 8th Edition). Furthermore, low-risk participants subjected to post-operative RAI administration had the same probability of persistence or relapse of DTC when compared to those who had undergone total thyroidectomy only. Conclusions: There is a need for the endocrine community to revise the current work-up of DTC. The initial ATA risk classification is a reliable tool for predicting the persistence or relapse of disease in long-term surveillance. Full article

Twenty-five years ago, a pathogenic variant of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene was identified as the cause of X-linked hypophosphatemic rickets (XLH). Subsequently, the overproduction of fibroblast growth factor 23 (FGF23) due to PHEX defects has been found to be associated with XLH pathophysiology. However, the mechanism by which PHEX deficiency contributes to the upregulation of FGF23 and the function of PHEX itself remain unclear. To date, over 700 pathogenic variants have been identified in patients with XLH, and functional assays and genotype–phenotype correlation analyses based on pathogenic variant data derived from XLH patients have been reported. Genetic testing for XLH is useful for the diagnosis. Not only have single-nucleotide variants causing missense, nonsense, and splicing variants and small deletion/insertion variants causing frameshift/non-frameshift alterations been observed, but also gross deletion/duplication variants causing copy number variants have been reported as pathogenic variants in PHEX. With the development of new technologies including next generation sequencing, it is expected that an increasing number of pathogenic variants will be identified. This chapter aimed to summarize the genotype of PHEX and related analyses and discusses the pathophysiology of PHEX defects to seek clues on unsolved questions. Full article

X-linked hypophosphatemia is an inheritable disease of renal phosphate wasting that results in clinically manifestations associated with rickets or osteomalacia. The various symptoms in the skeletal system are well recognized, such as short stature; lower limb deformities; and bone, joint, or muscle pain, and it is often difficult to control these symptoms, despite the use of medication therapy in growing children. In addition, lower limb deformities can lead to degenerative osteoarthritis and dysfunction of lower limbs at the skeletal maturity. To prevent from future manifestation of those symptoms, orthopedic surgeries are applicable to growing patients with severe skeletal deformities or without response to conventional medication. Bone deformities are treated by acute or gradual corrective osteotomies and temporally hemiepiphysiodesis using guided growth method. The clinicians should choose the right procedure based on age, symptoms and state of deformities of the patient. Full article

Turner syndrome (TS) is a chromosomal disorder characterized by a short stature and gonadal dysgenesis, the latter of which requires estrogen replacement therapy (ERT) to induce and maintain secondary sexual characteristics. Insufficient ERT is associated with compromised skeletal health, including bone fragility, in adults with TS. In particular, estrogen insufficiency during adolescence is critical because the acquisition of a defective bone mass during this period results in impaired bone strength later in the life. In addition to bone mass, bone geometry is also a crucial factor influencing bone strength; therefore, a more detailed understanding of the skeletal characteristics of both bone mass and geometry during childhood and adolescence and their relationships with the estrogen status is needed to prevent compromised skeletal health during adulthood in TS. Although a delay in the initiation of ERT is associated with a lower bone mineral density during adulthood, limited information is currently available on the effects of ERT during adolescence on bone geometry. Herein, we summarize the current knowledge on skeletal characteristics in children and adolescents with TS and their relationships with estrogen sufficiency, and discuss the potential limitations of the current protocol for ERT during adolescence in order to achieve better skeletal health in adulthood. Full article

Leydig cells produce androgens which are essential for male sex differentiation and reproductive functions. Steroidogenesis, as well as expression of several genes in Leydig cells, are stimulated by LH/cAMP and repressed by AMP/AMPK. One of those genes is Plau, which codes for the urokinase-type plasminogen activator (uPA), a secreted serine protease. The role of uPA and the regulation of Plau expression in Leydig cells remain unknown. Using siRNA-mediated knockdown, uPA was required for maximal cAMP-induced STAR and steroid hormone production in MA-10 Leydig cells. Analysis of Plau mRNA levels and promoter activity revealed that its expression is strongly induced by cAMP; this induction is blunted by AMPK. The cAMP-responsive region was located, in part, in the proximal Plau promoter that contains a species-conserved GC box at −56 bp. The transcription factor Krüppel-like factor 6 (KLF6) activated the Plau promoter. Mutation of the GC box at −56 bp abolished KLF6-mediated activation and significantly reduced cAMP-induced Plau promoter activity. These data define a role for uPA in Leydig cell steroidogenesis and provide insights into the regulation of Plau gene expression in these cells. Full article

Burn injury serves as an example of a condition with a robust systemic inflammatory response. The elevation of circulating interleukins (IL)-1β and -6 in children and adolescents with severe burn injury upregulates the parathyroid calcium-sensing receptor (CaSR), resulting in hypocalcemic hypoparathyroidism accompanied by urinary calcium wasting. This effect protects the body from the hypercalcemia that results from bone resorption, liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR upregulation in response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation, allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis, and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population. Full article

Despite the growing prevalence of central precocious puberty (CPP), most cases are still diagnosed as “idiopathic” due to the lack of identifiable findings of other diagnostic etiology. We are gaining greater insight into some key genes affecting neurotransmitters and receptors and how they stimulate or inhibit gonadotropin-releasing hormone (GnRH) secretion, as well as transcriptional and epigenetic influences. Although the genetic contributions to pubertal regulation are more established in the hypogonadotropic hypogonadism (HH) literature, cases of CPP have provided the opportunity to learn more about its own genetic influences. There have been clinically confirmed cases of CPP associated with gene mutations in kisspeptin and its receptor (KISS1, KISS1R), Delta-like noncanonical Notch ligand 1 (DLK1), and the now most commonly identified genetic cause of CPP, makorin ring finger protein (MKRN3). In addition to these proven genetic causes, a number of other candidates continue to be evaluated. After reviewing the basic clinical aspects of puberty, we summarize what is known about the various genetic and epigenetic causes of CPP as well as discuss some of the potential effects of endocrine disrupting chemicals (EDCs) on some of these processes. Full article

Hypochondroplasia is an autosomal dominant genetic disorder due to a heterozygous pathogenic variant of the FGFR3 gene. The early diagnosis of hypochondroplasia is necessary, since growth hormone is effective for improving adult height. The genetic test for the FGFR3 gene could help the early diagnosis. The detailed characteristics of FGFR3 genotypes have not been widely investigated in Japan, except for a common pathogenic variant, p.Asn540Lys. This study retrospectively analyzed the FGFR3 genotypes of 35 patients from 30 families with hypochondroplasia (age, range 0–6 years, median 1 year) in Japan. The pathogenic variants of FGFR3 were identified in all the patients: p.Asn540Lys in 23 probands (76.7%), p.Lys650Gln in 2 (6.7%), p.Leu324His in 2 (6.7%), p.Leu324Val, p.Ser351Cys, and p.Lys650Thr in 1 each (3.2%). The median age at diagnosis, height SD score at diagnosis, or the severity of radiologic findings was not significantly different between probands with p.Asn540Lys and those with other variants. Intellectual disability or epilepsy was identified in seven patients with p.Asn540Lys, but none with other variants. The genetic test of FGFR3 can be useful for assessing the potential risk of neurological sequela in children with hypochondroplasia. Full article

Human growth hormone (hGH) has been used therapeutically to promote growth in children for over 60 years. Pituitary-extracted hGH has demonstrated positive growth promotion since the early 1960s. In 1985, prion-induced contamination of hGH triggered a global epidemic of Creutzfeldt–Jakob disease that was responsible for its discontinuation. Recombinant hGH immediately replaced pituitary hGH and, being available in large amounts, was used and licenced for therapy in GH-deficient children, followed by approval for non-GH deficient disorders such as Turner syndrome, short stature related to birth size small for gestational age, idiopathic short stature, SHOX deficiency, Prader–Willi syndrome and Noonan syndrome. RhGH therapy was refined by the use of growth prediction models; however, unmet needs, such as the variability in response and non-adherence resulted in the development of long-acting rhGH (LArhGH) molecules, which are currently in clinical trials and have shown non-inferiority in comparison with daily rhGH. It is likely that LArhGH will enter clinical practice in 2022 and 2023 and will need to demonstrate safety in terms of immunogenicity, IGF-1 generation, metabolic status and tolerability of potential injection pain and local reactions. Full article

X-linked hypophosphatemia (XLH) is the most common form of inherited disorders that are characterized by renal phosphate wasting, but it is a rare chronic disease. XLH presents in multisystemic organs, not only in childhood, but also in adulthood. Multidisciplinary team management is necessary for the care of patients with XLH. Although XLH has often been perceived as a childhood disease, recent studies have demonstrated that it is a long-term and progressive disease throughout adulthood. In the past 20 years, the importance of the transition from pediatric care to adult care for patient outcomes in adulthood in many pediatric onset diseases has been increasingly recognized. This review describes transitional care and team management for patients with XLH. 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

Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of longitudinal ligaments (OPLL), osteophytes around large joints, and enthesopathy in the Achilles tendons), early osteoarthritis, the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT), and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscesses. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets (ARHR1/2) due to mutations in PHEX, DMP1, and ENPP1 is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue, as many adult XLH patients suffer subsequent debilitating nervous symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of dosages by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, indications for this drug should be carefully considered, along with cost-effectiveness, guidelines or recommendations, and the health care system of each country. Full article

Kisspeptin is a peptide expressed mainly in the infundibular nucleus of the hypothalamus. Kisspeptin plays a crucial role in the regulation of reproductive functions. It is regarded as the most important factor responsible for the control of the hypothalamic–pituitary–gonadal axis, the onset of puberty, and the regulation of menstruation and fertility. Kisspeptin activity influences numerous processes such as steroidogenesis, follicular maturation, ovulation, and ovarian senescence. The identification of kisspeptin receptor mutations that cause hypogonadotropic hypogonadism has initiated studies on the role of kisspeptin in puberty. Pathologies affecting the neurons secreting kisspeptin play a major role in the development of PCOS, functional hypothalamic amenorrhea, and perimenopausal vasomotor symptoms. Kisspeptin analogs (both agonists and antagonists), therefore, may be beneficial as therapy in those afflicted with such pathologies. The aim of this review is to summarize the influence of kisspeptin in the physiology and pathology of the reproductive system in humans, as well as its potential use in therapy. Full article