Endocrines, Volume 6, Issue 2 (June 2025) – 15 articles

Precocious puberty, defined as the onset of secondary sexual characteristics before age 8 in girls, presents a diagnostic challenge in distinguishing between normal variants and pathological conditions requiring intervention. Central precocious puberty (CPP) results from early activation of the hypothalamic–pituitary–gonadal axis, whereas peripheral precocious puberty (PPP) arises from excess sex steroid production independent of gonadotropins. Benign variants, including premature thelarche and premature adrenarche, require careful differentiation to prevent unnecessary treatment. This review explores the physiological mechanisms governing puberty, the epidemiological trends influencing its early onset, and the genetic and environmental factors contributing to its variability in female children. A structured diagnostic approach incorporating clinical evaluation, hormone assessments, imaging studies, and genetic insights is discussed. Management strategies vary depending on the etiology, with gonadotropin-releasing hormone analogs recommended for CPP and targeted therapies for PPP. In contrast, benign variants often necessitate observation and periodic follow-up. Given the increasing prevalence of early puberty, further research is essential to refine diagnostic thresholds and optimize treatment protocols. Early and accurate identification of precocious puberty ensures appropriate intervention, mitigating potential risks associated with early maturation, including compromised adult height and psychosocial challenges. Full article

Mini-puberty refers to the transient activation of the hypothalamic–pituitary–gonadal (HPG) axis during early infancy, lasting up to six months in boys and 12–24 months in girls. This phase represents the second activation of the HPG axis, following its initial activation during the second half of fetal life. At birth, the removal of the suppressive effect of placental estrogens on the HPG axis prompts a rise in both gonadotropins and sex steroid hormones, resulting in distinct clinical and laboratory markers of mini-puberty. While the clinical significance of mini-puberty remains partially understood, emerging evidence underscores its essential role in several aspects of human growth and development. In boys, testosterone influences penile growth, increases Sertoli cell numbers in the testes, and lays the foundation for future spermatogenesis. In girls, the increase in estradiol levels promotes follicular maturation and stimulates breast and uterine growth. Beyond the gonadal effects, mini-puberty appears to impact body composition, affecting body weight and promoting accelerated growth. Additionally, it may affect early psychosomatic and neural maturation, playing a role in several key aspects of the infantile brain. This narrative review examines recent findings on the physiology of the activation of the HPG axis before and after birth along with its significance in various aspects of human growth and development. In addition, mini-puberty-unique features in specific groups, such as preterm and small-for-gestational-age infants, are presented. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent chronic liver condition strongly linked to Type 2 Diabetes Mellitus (T2DM) and obesity. Globally, MASLD is the most common cause of chronic liver disease. The bidirectional relationship between MASLD and T2DM underscores the pivotal role of insulin resistance in disease progression, which contributes to hepatic steatosis, oxidative stress, and inflammation, forming a vicious cycle. MASLD is also associated with heightened risks of cardiovascular and chronic kidney diseases, necessitating comprehensive treatment approaches. While lifestyle interventions and weight loss remain the cornerstone of management, their sustainability is challenging. This review highlights the evolving pharmacological landscape targeting MASLD and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Currently, Resmetirom is the only FDA-approved drug for MASH. Current and investigational therapies, including insulin-sensitizing agents like peroxisome proliferator-activated receptor (PPAR) agonists, glucose-lowering drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), drugs that target intermediary metabolism such as Vitamin E, de novo lipogenesis inhibitors, and emerging agents targeting the gut-liver axis and oxidative stress, are explored. These therapies demonstrate promising effects on hepatic steatosis, inflammation, and fibrosis, providing new avenues to address the multifaceted pathophysiology of MASLD. Full article

Retinoic acid (RA) exerts biological effects through RA receptors (RARs) to regulate transcription. RA also elicits rapid, RAR-independent (noncanonical) activities mediated by Cellular RA Binding Protein 1 (CRABP1) to modulate cytosolic signaling. CRABP1 functions by forming protein complexes, named CRABP1 signalosomes, to modulate signal propagation in a cell type-specific manner. This review summarizes multiple CRABP1 signalosomes and their physiological functions. CRABP1 knockout (CKO) mice develop multiple phenotypes progressively throughout the lifespan. These include altered brain function, obesity, and insulin resistance starting at young adult stages, increased vulnerability to heart failure and altered serum exosome profiles in midlife, and motor deterioration and thyroid dysfunction (hypothyroidism) in later life. The mouse Crabp1 gene is tightly regulated by multiple epigenetic mechanisms, whereas human CRABP1 gene dysregulation is associated with multiple human diseases in which age is an important factor. Further, CRABP1 expression in human and mouse thyroid glands gradually increases with aging. This underscores the clinical relevance of CRABP1 signalosomes in maintaining health and the functions of certain cells/organ systems, especially in the thyroid and during the aging process. The CRABP1 sequence is highly conserved, likely due to its functional constraint in forming various signalosomes; its tight regulation ensures proper expression of CRABP1 required for the forming of various signalosomes critical to the health and functions of multiple cell types/organ systems. Finally, CRABP1-specific (without activating RARs) signaling pathway-selective compounds have been designed. It may be an attractive therapeutic strategy to exploit these CRABP1-specific compounds to modulate selective signaling pathways in certain disease conditions, such as thyroid dysfunction, to maximize efficacy while minimizing retinoid toxicity. Full article

Background/Objectives: The association between sexual dysfunction and diabetes is well known, but few studies have investigated its prevalence in type 1 diabetes (T1D). The aim of this study was to evaluate the prevalence of sexual dysfunction in a group of women with T1D, regardless of their age, and to compare its different prevalences in women treated with different insulin regimens. Methods: The population included 77 women affected by T1D, of which 16 were on Multiple Daily Injections (MDI) and 61 on Continuous Subcutaneous Insulin Infusion (45 on Advanced Hybrid Closed Loop System with catheter and 16 on patch pump). All participants completed the Female Sexual Function Index (FSFI), a questionnaire that evaluates several aspects of sexual function. Another questionnaire that evaluated general features, diabetes-specific features and sexual-specific features was proposed to every participant. Results: The overall prevalence of female sexual dysfunction was 49.3%. A correlation was demonstrated between the prevalence of female sexual dysfunction and age; another correlation was found between the prevalence of female sexual dysfunction and dyadic status. No correlation between glycemic control and sexual dysfunction was found. Conclusions: Women with T1D presented a high prevalence of sexual dysfunction, independently from glycometabolic disease control and insulin regimens; on the other hand, a significant correlation was demonstrated with age and dyadic status. Evaluation of sexual function in women with T1D appears to be important in clinical settings independently from disease control. Full article

Lipedema is a chronic disease of the subcutaneous adipose tissue that mostly affects women. The etiopathogenesis of the disease is still poorly understood. Lipedema typically develops after major hormonal changes, such as puberty, pregnancy, and menopause. Alongside genetic susceptibility, the pathophysiological mechanism involving hormonal changes is mostly linked to aberrantly expressed estrogen receptors in adipose tissue. Lipedema has no known cure, and current therapies aim primarily to reduce symptoms, avoid complications, and slow the disease progression. Achieving or maintaining a healthy body composition, preserving or regaining mobility and functionality, preventing the progression of disease, and reducing pain and other symptoms are all possible outcomes of proper nutrition and weight management. Since nutrition may provide a long-term solution to control almost constant inflammation, it should be a major part of lipedema treatment. Despite the lack of a specific, scientifically supported diet for lipedema patients, several dietary approaches have been suggested. In this comprehensive narrative review, supported by published revisions and peer-reviewed studies following scrutiny of digital medical databases, the current state of knowledge and theories regarding the hormonal etiopathogenesis of lipedema are presented, as well as the role of nutritional intervention in reducing its symptoms and progression. Full article

Background: Plastic pollution driven by human activities has become a critical global issue for human health. A growing literature demonstrates that micro- and nanoplastics (MNPs) contain endocrine-disrupting chemicals (EDCs) and other harmful compounds that enter the body easily, acting as agonists or antagonists for a wide range of hormonal receptors, and promoting endocrine toxicity. Endocrine disruption induced by MNPs occurs through the aberrant activation/inhibition of different signaling pathways that in addition to directly interfering with hormonal balances, trigger apoptosis, oxidative stress, and inflammation in endocrine cells. However, to date, the molecular mechanisms of these contaminants remain not completely elucidated. Furthermore, given the unanimous consensus on the negative impact of MNPs on human health, several methodologies have been developed to detect MNPs and contaminants not only in the environment but also in biological fluids and human tissues. Results: This review comprehensively summarizes the emerging experimental and clinical evidence explaining the mechanisms underlying the toxicity related to chronic plastic pollution in relation to the endocrine system. In addition, the review illustrates the new methodological approaches to detect MNPs in human biological samples, highlighting that employing complementary methods enables the precise characterization and quantification of MNPs. Conclusions: Future studies employing experimental, epidemiological, epigenetic, and multi-omics approaches are essential for understanding the short and long-term effects of MNPs on endocrine glands and developing effective strategies to mitigate their impact on human health. Full article

Background: Oncocytic adenomas (OAs) of the thyroid, previously referred to as Hürthle cell adenomas, are uncommon tumors, particularly in pediatric populations, where they represent a minority of thyroid nodules. Due to their rarity and the potential difficulty in distinguishing benign from malignant forms on cytology, these adenomas present unique diagnostic and management challenges. Here, we report a pediatric case of a large OA of the thyroid, managed with surgical resection following inconclusive fine-needle aspiration (FNA) results. Case Presentation: A 13-year-old girl presented with an enlarging thyroid nodule. An ultrasound examination showed a large (26 × 16 mm), solid, isoechoic nodule with a hypoechoic halo. The FNA findings were inconclusive, indicating a follicular neoplasm with oncocytic features, classified as Bethesda IV. The patient underwent a hemithyroidectomy, and a histopathological examination confirmed an encapsulated OA without evidence of capsular or vascular invasion. The postoperative recovery was uneventful, and follow-up assessments showed no recurrence. Conclusions: OAs in pediatric patients are rare and may pose diagnostic challenges. This case highlights the importance of a comprehensive approach, including surgical resection, for definitive diagnoses in cases where FNA results are inconclusive. Further studies are warranted to establish guidelines for the management of oncocytic thyroid neoplasms in pediatric patients, as well as to understand their clinical behavior in this population. Full article

Background: Vitamin D is essential for neonatal health, with maternal vitamin D status crucial in fetal development and neonatal outcomes. During pregnancy, vitamin D is transferred to the fetus via the placenta, forming an initial reserve. Postnatally, neonates rely on maternal levels and supplementation due to limited sunlight exposure and immature skin synthesis. Objectives: This review evaluates neonatal vitamin D deficiency’s causes and clinical consequences, emphasizing its impact on newborn and infant health. Results: Maternal vitamin D levels strongly correlate with neonatal 25(OH)D concentrations, influencing birth weight, bone development, and overall health. Supplementation during pregnancy reduces the risk of severe deficiencies and rickets, particularly in exclusively breastfed infants who require daily supplementation of 400 IU. Formula-fed infants typically meet requirements through fortified formulas. Preterm infants are at a higher risk of complications like osteopenia and rickets, with mixed evidence on the effectiveness of higher supplementation doses. Vitamin D is critical in skeletal development, immune function, and protection against respiratory infections such as bronchiolitis and pneumonia. Deficiency is associated with respiratory distress syndrome (RDS), atopic dermatitis, and impaired bone mineralization due to reduced placental calcium transport. Conclusions: Vitamin D deficiency during pregnancy and infancy has significant clinical implications, including impaired skeletal and immune development. Maternal and neonatal supplementations are critical to prevent deficiencies, particularly in high-risk groups such as preterm and breastfed infants. Targeted strategies are essential to improve neonatal health outcomes and prevent complications. Full article

Background/Objectives: Hyperprolinemia is a rare autosomal recessive disorder with two distinct types: I (HPI) and II (HPII). The clinical presentation varies widely, with some individuals remaining asymptomatic and others exhibiting neurological, renal, or auditory defects and seizures. However, it has never been associated with hypoglycemia. The present case report describes a 5-year and 6/12-month-old boy with HPII, with an episode of severe hypoglycemia and Pituitary Stalk Interruption Syndrome (PSIS) with isolated growth hormone (GH) deficiency (GHD). Results: The boy was presented to the Department of Pediatric Endocrinology for routine thyroid function assessment due to hypothyroidism. He was diagnosed with HPII at the age of 2 years old during an investigation for seizure episodes. Clinically, the boy exhibited attention deficit hyperactivity disorder (ADHD) and a reduction in growth velocity (1.6 cm/year). Hematological and biochemical analyses were within the reference range. Hormone profiling revealed lower-than-expected insulin-like growth factor-1 (IGF-1) concentrations, prompting a GH stimulation test, which, in turn, revealed GHD. Brain magnetic resonance imaging (MRI) showed features consistent with PSIS. Noteworthy is the occurrence of severe hypoglycemia during an episode of gastroenteritis, leading to hospitalization, eventually attributed to GHD. Following the exogenous administration of recombinant human GH, the boy exhibited increased growth velocity, with no adverse events over the follow-up period. Conclusions: Hyperprolinemia is a rare condition; in this context, the occurrence of severe hypoglycemia accompanied by a low growth velocity poses a challenge for the clinical pediatrician. Furthermore, the coexistence of hyperprolinemia and PSIS has never been reported in the literature thus far. Full article

This review examines the relationship between cholesterol and bone resorption. It seeks to elucidate the dependence of bone turnover on cholesterol metabolism by highlighting the common inhibitory effect of both statins and nitrogen-containing bisphosphonates on cholesterol biosynthesis and bone resorption as well as on bone density. Moreover, this paper also discusses the epidemiologic studies of the effects of nitrogen-containing bisphosphonates on all-cause and cardiovascular mortality using the latest publications to reinforce the relationship between bone resorption and cardiovascular disease. This review will also discuss the role of lipoproteins in supplying cholesterol to both osteoclasts and osteoblasts and the effects of doing so on both of these bone cells and their precursors. As inflammation is a major factor in both bone resorption and cardiovascular calcification, this article will also discuss the role of cholesterol in triggering inflammatory responses. Finally, this paper will raise questions unanswered to date that bear on the relationship between lipid metabolism, bone resorption, and cardiovascular disease. Full article

Background: This paper briefly reviews the most important endocrine features of primary ovarian insufficiency (POI) and shows their relevance for the diagnosis and treatment of this condition. Introduction: Endocrine disturbances in POI cause problems for both the fertility and general health status of the affected women. Both subfertility and infertility result from the depletion of growing ovarian follicles which, in its turn, is the causative factor of hypoestrogenism; this is responsible for most of the general health problems affecting women. Method: Search of literature. Results and conclusion: A combination of high-serum follicle-stimulating hormone (FSH) and low 17β-estradiol (E2) concentrations is a key feature characterizing POI and is the decisive element for POI diagnosis. However, an in-depth search for possible genetic and non-genetic causes is important for adequate counseling regarding prevention and early intervention. The treatment of general health problems, based on correcting hypoestrogenism through hormone replacement therapy (HRT), is relatively easy. On the other hand, resolving infertility is a much more difficult task, and oocyte donation is the only really efficient instrument. Fertility preservation is a suitable alternative in patients with early POI diagnosis, in whom some viable follicles are still present in the ovaries. In patients who refuse oocyte donation, intraovarian injection of autologous platelet-rich plasma and in vitro activation of dormant follicles may be considered. Other innovative treatments, such as stem cell therapies or nuclear transfer, are currently under investigation. Full article

Background/Objectives: Chronic somatic diseases are significant risk factors for the development of mental disorders. Type 1 diabetes mellitus (T1D) is the most common chronic endocrine pathology in children. Treatment requires nutrition management, physical activity, lifelong insulin therapy, and proper self-monitoring of blood glucose. It is complicated and therefore may result in a variety of psychosocial problems for children, adolescents, and their families. Considering the rapidly growing incidence of type 1 diabetes in the pediatric population of Latvia, it is important to detect and prevent the risks of anxiety and depression in families with children suffering from type 1 diabetes. Methods: This was a quantitative interdisciplinary cross-sectional study to determine the prevalence of anxiety and depression in adolescents with T1D and their parents. Two tools were used to detect the presence of symptoms of anxiety and depression: the Generalized Anxiety Disorder Scale-7 (GAD-7) and the Patient Health Questionnaire 9 (PHQ-9) scale. Results: A total of 812 respondents were eligible for screening. Anxiety and depression symptoms were seen significantly more frequently in the study group than in the control group. The study found negative effects of anxiety and depression on the compensation of diabetes. Conclusions: Adolescents with type 1 diabetes and their parents are more predisposed to anxiety and depression symptoms than somatic healthy children and their parents, thus worsening disease control and prognosis. Full article

Precocious puberty (PP) is characterized by the early onset of secondary sexual characteristics and accelerated growth, which often result in compromised adult height (AH). Central precocious puberty (CPP), a subset of PP, is treated with gonadotropin-releasing hormone analogs (GnRHa) to suppress premature hormonal activation and delay epiphyseal closure, thereby preserving height potential. The present review examined the effects of GnRHa on AH outcomes in girls with idiopathic CPP. Although AH is greater with GnRHa therapy than without it, the treatment does not consistently restore the patient’s genetic potential. The benefits of the treatment are most evident in girls in whom idiopathic CPP is diagnosed before 6 years of age and they achieve a height gain of 4.5–14.1 cm, which is unattainable without treatment. However, the treatment of older children (ages 6–8) shows conflicting results, with the AH outcome varying among previous reports. In particular, slowly progressive CPP is known to have a favorable height prognosis even without treatment. Another factor influencing the AH prognosis is the timing of GnRHa discontinuation; the best time to discontinue GnRHa therapy for the best AH outcome is reportedly the bone age of approximately 12 years. In conclusion, although GnRHa therapy significantly improves the AH, especially in early-onset CPP, its effectiveness is uncertain in borderline or late-onset cases. Further research is required to formulate more precise criteria for patient selection and treatment discontinuation to optimize height outcome in girls with idiopathic CPP. Full article

Background/Objectives: Understanding sex-based differences in both the pathophysiology and clinical presentation of diseases is necessary to improve health care towards precision medicine. The endocrine system is deeply involved in human health, and endocrine diseases may be influenced by steroidal hormone exposure. Thyroid nodular disease and differentiated thyroid cancer, in particular, show a high prevalence in the female sex; however, little is known about sex-related differences in risk factors and clinical presentation. This study aims to assess whether morphological differences, which can be detected by ultrasound examination, can be related to sex in order to refine diagnostic approaches and oncological risk classification. Methods: A retrospective observational study on 1355 ultrasound images of thyroid nodules obtained from 2017 to 2020 at a single university center was conducted. The images were reviewed by a single observer blinded to the patient’s sex and the cytological nature of the nodules. The qualitative description, size, anatomical location and oncological risk classification were assessed. Results: A taller-than-wide shape (anteroposterior/craniocaudal axis ratio > 1) was found to be more frequent in men than in women (6.7% vs. 3.6%, p = 0.027); the nodular volume was significantly larger in males (p << 0.01) than in females. Significant tropism for the upper lobe and isthmus was described in women (26% vs. 16.5%, p = 0.011) and for medium–lower thyroid lobes in men (83.5% vs. 73.8%, p = 0.011). Background thyroiditis was more common in women, while the number of cytological diagnoses of malignant or likely malignant nodules was higher than expected in men (9% vs. 6%, p = 0.01). Conclusions: Thyroid nodules show different distributions, in terms of a larger volume, more frequent taller-than-wide shape and lobular caudal location, in men vs. women. These results should be confirmed by further investigations, and the underlying mechanism should be clarified. However, our explorative research is of interest due to its novelty and possible future clinical implications. Full article