Endocrines, Volume 3, Issue 1 (March 2022) – 14 articles

In this review, we describe genetic mutations affecting metabolic pathways of calcium and phosphorus homeostasis. Calcium and phosphorus homeostasis has tight hormonal regulation by three major hormones: vitamin D, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). We describe the physiology and pathophysiology of disorders, their biochemical profile, clinical characteristics, diagnostics, and treatments. Full article

Background: Peroxiredoxin 4 (PRDX4), a secreted antioxidant enzyme, can protect against hepatocellular carcinoma and lung adenocarcinoma, but its role in papillary thyroid carcinoma (PTC) is still unclear. In this study, we investigated the association of the PRDX4 expression with the prognosis of patients with advanced PTC. Methods: We conducted a retrospective case-control study at Kanazawa Medical University Hospital. We selected PTC patients over 55 years of age who received surgery from 2006 to 2014. The PRDX4 expression was immunohistochemically analyzed in paraffin-embedded tumor specimens of 70 patients with stages Ⅱ–Ⅳ advanced PTC. We also investigated the key roles of PRDX4 in a human PTC cell line (K-1) in vitro. Result: The weak expression of PRDX4 was found to be significantly associated with recurrence. In a multivariate analysis, the weak expression of PRDX4—rather than other pathological features of high invasiveness—predicted a poor prognosis. In vitro, the viability of human PTC cells was significantly suppressed after PRXD4 plasmid transfection. Conclusion: The weak expression of PRDX4 can predict recurrence with a potential poor prognosis in advanced PTC. 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

Congenital or monogenic hyperinsulinism (HI) is a group of rare genetic disorders characterized by dysregulated insulin secretion and is the most common cause of persistent hypoglycemia in children. Knowledge of normal glucose homeostasis allows for a better understanding of the underlying pathophysiology of hyperinsulinemic hypoglycemia, facilitating timely diagnosis and management. The goal of management is to prevent cerebral insults secondary to hypoglycemia, which can result in poor neurologic outcomes and intellectual disability. Responsiveness to diazoxide, the first-line pharmacologic therapy for persistent hypoglycemia, is also the first step to distinguishing the different genotypic causes of monogenic hyperinsulinism. Early genetic testing becomes necessary when monogenic HI is strongly considered. Knowledge of specific gene mutations allows the determination of a clinical prognosis and definite therapeutic options, such as identifying those with focal forms of hyperinsulinism, who may attain a complete cure through surgical removal of specific affected parts of the pancreas. However, the lack of identifiable cause in a considerable number of patients identified with HI suggests there may be other genetic loci that are yet to be discovered. Furthermore, continued research is needed to explore new forms of therapy, particularly in severe, diazoxide-nonresponsive cases. Full article

Two endocrine disorders, congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH), when untreated, can have devastating, irreversible and fatal outcomes. Permanent cognitive impairment, growth failure and dysmorphic appearance are seen in congenital hypothyroidism (CH) and early infant death in males with salt wasting CAH (as most females are discovered by presence of atypical genital appearance, while males appeared normal). Newborn screening (NBS) for CH was developed with broader engagement of centers, and was more rapidly adopted throughout the US and other large or developed countries, while NBS for CAH was pioneered by relatively few and was not fully adopted in the US until the initiation of Universal Expanded Newborn Screening Panel in 2005. Advances in genetic understanding of CH and CAH continue with NBS. Cost–benefit analysis, showing CH NBS as more successful than CAH NBS, may not fully recognize the cost of a life saved with CAH NBS. Early treatment of CH is much simpler with taking a pill a day unlike CAH requiring multiple medication doses, and possibly surgery apart from enteral and parenteral stress doses during adrenal crisis. CAH management outcomes with gender identity matters in persons with atypical genital appearance and androgen effects are still being studied. 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

Chromosome 15q26-qter deletion syndrome is a rare disease that causes prenatal and postnatal growth retardation, microcephaly, developmental delay, and congenital heart diseases, mainly due to haploinsufficiency of IGF1R. In addition, patients with pathogenic variants of the IGF1R show similar symptoms. We report the case of a 5-month-old girl with prenatal and postnatal growth retardation, microcephaly, and congenital heart disease. At 5 months of age, her length was 54.7 cm (−4.3 SD), her weight was 4.4 kg (−3.1 SD), and her head circumference was 37.4 cm (−2.8 SD), thus presenting severe growth retardation. Repeated pre-feeding serum GH levels were abnormally high (26.1–85.5 ng/mL), and IGF-1 levels (+0.16 to +1.2 SD) were relatively high. The 15q sub-telomere fluorescence in situ hybridization analysis revealed a heterozygous deletion in the 15q terminal region. Whole-genome single nucleotide polymorphism microarray analysis showed a terminal deletion of 6.4 Mb on 15q26.2q26.3. This is the first report showing that fasting GH levels are high in early infancy in patients with IGF1R abnormalities. In addition to relatively high IGF-1 levels, elevated fasting GH levels in early infancy may contribute to the diagnosis of IGF1R abnormalities. Full article

Multiple endocrine neoplasia (MEN) is a group of heterogenous syndromes characterized by the occurrence of two or more endocrine gland tumors in a patient or related individuals in the same family. They are inherited in an autosomal dominant fashion and are highly penetrant. There are three types of MEN syndromes: MEN type 1 (MEN1), MEN type 2 (MEN2), and MEN type 4 (MEN4). MEN2 is further divided into MEN2A, MEN2B (formerly known MEN3), and familial medullary thyroid carcinoma (FMTC). Although MEN syndromes are rare, it is crucial to identify individuals at risk for potentially life-threatening neoplasias. This review article provides an update on each MEN syndrome, its genetics, diagnosis, and management in children. Full article

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature. Full article

Moxonidine is a centrally acting, anti-hypertensive medication that exerts additional metabolic properties. It is unknown whether its effects are mediated by neurotransmitters or sympathetic tone regulators, including Neuropeptide Y (NPY). In this study, we evaluated the effects of moxonidine administration on serum NPY in humans. Methods: Ninety individuals with mild or moderate arterial hypertension that required monotherapy were categorized in three age and gender-matched groups according to their Body Mass Index (BMI) as normal weight (n = 30), overweight (n = 30), and obese (n = 30). Moxonidine was administered in therapeutic doses of up to 0.6 mg daily for 12 weeks, and clinical, biochemical and hormonal parameters were recorded. Results: In all three groups, a decrease in systolic and diastolic blood pressure and heart rate was shown. After treatment, BMI, 24 h urine catecholamines and catecholamines’ metabolites, and serum total cholesterol were also reduced. Most importantly, we found a decrease in serum NPY levels in all study groups, with the largest mean decrease in the group of obese and overweight participants compared to normal weight. Conclusions: Moxonidine administration results in improvement in cardio-metabolic parameters, as well as a decrease in serum NPY levels, which therefore represents it being a potent agent against obesity-associated hypertension. Its involvement in energy balance regulation warrants further investigation. 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

Members of the pre-B-cell leukemia transcription factor (PBX) family of homeoproteins are mainly known for their involvement in hematopoietic cell differentiation and in the development of leukemia. The four PBX proteins, PBX1, PBX2, PBX3 and PBX4, belong to the three amino acid loop extension (TALE) superfamily of homeoproteins which are important transcriptional cofactors in several developmental processes involving homeobox (HOX) factors. Mutations in the human PBX1 gene are responsible for cases of gonadal dysgenesis with absence of male sex differentiation while Pbx1 inactivation in the mouse causes a failure in Leydig cell differentiation and function. However, no data is available regarding the expression profile of this transcription factor in the testis. To fill this knowledge gap, we have characterized PBX1 expression during mouse testicular development. Real time PCRs and Western blots confirmed the presence Pbx1 mRNA and PBX1 protein in different Leydig and Sertoli cell lines. The cellular localization of the PBX1 protein was determined by immunohistochemistry and immunofluorescence on mouse testis sections at different embryonic and postnatal developmental stages. PBX1 was detected in interstitial cells and in peritubular myoid cells from embryonic life until puberty. Most interstitial cells expressing PBX1 do not express the Leydig cell marker CYP17A1, indicating that they are not differentiated and steroidogenically active Leydig cells. In adults, PBX1 was mainly detected in Sertoli cells. The presence of PBX1 in different somatic cell populations during testicular development further supports a direct role for this transcription factor in testis cell differentiation and in male reproductive function. Full article

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations. Full article