Growth and endocrinopathies among children with ß-Thalassemia major treated at Dubai Thalassemia centre.

BACKGROUND: ß-Thalassemia major (BTM) is one of the most common hereditary anemias worldwide. Patients suffer from iron overload that results from repeated blood transfusion This in turn leads to multiple organ damage and endocrinopathies. This study aims to assess the prevalence of growth retardation, hypothyroidism, and diabetes mellitus in children and adolescents with BTM treated at Dubai Thalassemia Centre. METHODS: A total of 105 children and adolescents were included in this retrospective observational study. RESULTS: 39 children and 66 adolescents' data were analyzed. Females composed 51.3% (n = 20) of children and 53.0% (n = 35) of adolescents. Pretransfusion hemoglobin below 9 gm/dl was observed in 10.8% (n = 4) and 10.6% (n = 7) in children and adolescents, respectively. The mean age of menarche was 13.5 years. Among all study participants, 22.6% (n = 14) had normal height velocity whereas 37.1% (n = 23) had reduced height velocity in one year and 40.3% (n = 25) had reduced height velocity in two consecutive years. The proportion of children and adolescents showing reduced height velocity was significantly higher in females compared to the males (90.6% versus 63.3%, respectively, Chi-square = 6.597, p-value = 0.010). Although none of the study participants had diabetes mellitus, 26.1% (n = 12/46) had pre-diabetes. Elevated TSH was observed in 14.7% (n = 5) children and 8.1% (n = 5) adolescents while low FT4 was reported in one child and one adolescent. CONCLUSION: Of all endocrinopathies seen among children and adolescents with BTM, growth delay remains the main concern for this group of patients. Effective treatment is key to further reducing endocrinopathies. Although the sample size is limited, we postulate that the low percentage of endocrinopathies among children with BTM treated at Dubai thalassemia center and the low level of pretransfusion anemia reflect the effective transfusion and chelation at the center.

Endocrine Disruptor Chemicals and Children's Health.

We are all exposed to endocrine-disrupting chemicals (EDCs) starting from embryonic life. The fetus and child set up crucial developmental processes allowing adaptation to the environment throughout life: they are extremely sensitive to very low doses of hormones and EDCs because they are developing organisms. Considering the developmental origin of well-being and diseases, every adult organism expresses consequences of the environment in which it developed. The molecular mechanisms through which the main EDCs manifest their effects and their potential association with endocrine disorders, such as diabetes, obesity, thyroid disease and alteration of adrenal hormones, will be reviewed here. Despite 40 years having passed since the first study on EDCs, little is yet known about them; therefore, our purpose is to take stock of the situation to establish a starting point for further studies. Since there is plenty of evidence showing that exposure to EDCs may adversely impact the health of adults and children through altered endocrine function-suggesting their link to endocrinopathies-it is essential in this context to bear in mind what is already known about endocrine disruptors and to deepen our knowledge to establish rules of conduct aimed at limiting exposure to EDCs' negative effects. Considering that during the COVID-19 pandemic an increase in endocrine disruptor effects has been reported, it will also be useful to address this new phenomenon for better understanding its basis and limiting its consequences.

Autoimmune polyendocrine syndromes associated with autoimmune rheumatic diseases.

Autoimmune polyendocrine syndromes (APSs), also called autoimmune polyglandular syndromes, are a group of autoimmune diseases characterized by the co-occurrence of dysfunctions of several (at least two) endocrine glands. They develop under the influence of environmental factors in genetically predisposed people. Autoimmune polyendocrine syndromes may accompany autoimmune rheumatic diseases and worsen their course - APS-2 and APS-3 are the most common. The APS-2 includes the coexistence of, e.g. Hashimoto's disease, celiac disease and rheumatoid arthritis (RA). In APS-3, rheumatic diseases such as RA, systemic lupus erythematosus, and Sjögren's syndrome may coexist with Hashimoto's disease, type 1 diabetes and hypogonadism or other endocrinopathies. Undiagnosed endocrine diseases may be the reason for the intensification of metabolic disorders observed in the course of rheumatic diseases, cause the ineffectiveness of rheumatological treatment and also increase the frequency of bone fractures due to osteoporosis, cardiovascular complications and even miscarriages when coexistent, e.g. Hashimoto's disease with hypothyroiditis, which increases the risk of pregnancy loss. It is important to be able to conduct an extensive interview, paying attention to the symptoms of possible endocrinopathy as well as the features of other autoimmune disorders in the physical examination (e.g. vitiligo or darkening of the skin in Addison's disease). Depending on the history and physical examination, screening for various APSs is advised.

Multidisciplinary management of endocrinopathies and treatment-related toxicities in patients with Bloom syndrome and cancer.

The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a challenge. Bloom syndrome is one such disorder that is caused by a defect in DNA repair, predisposing to the development of early-onset age-related medical conditions and malignancies. We report on two patients with Bloom syndrome who responded well to chemotherapy despite significant alterations to standard protocols necessitated by hypersensitivity. Both patients experienced severe toxicities and exacerbation of endocrine comorbidities during chemotherapy. A multidisciplinary team of oncologists and endocrinologists is best suited to care for this patient population.

Adult complications of nephropathic cystinosis: a systematic review.

While nephropathic cystinosis is classically thought of as a childhood disease, with improved treatments, patients are more commonly living into adulthood. We performed a systematic review of the literature available on what complications this population faces as it ages. Nearly every organ system is affected in cystinosis, either from the disease itself or from sequelae of kidney transplantation. While cysteamine is known to delay the onset of end-stage kidney disease, its effects on other complications of cystinosis are less well determined. More common adult-onset complications include myopathy, diabetes, and hypothyroidism. Some less common complications, such as neurologic dysfunction, can still have a profound impact on those with cystinosis. Areas for further research in this area include additional study of the impact of cysteamine on the nonrenal manifestations of cystinosis, as well as possible avenues for new and novel treatments.

Emergency Presentations of Immune Checkpoint Inhibitor-Related Endocrinopathies.

BACKGROUND: Immune checkpoint inhibitors (ICI) are an important component of anticancer treatment, with indications across an increasing range of oncological diagnoses. ICIs are associated with a range of immune-mediated toxicities. Immune-related endocrinopathies pose a distinct challenge, given the nonspecific symptom profile and potentially life-threatening sequelae if not recognized. OBJECTIVES: To determine the frequency and clinical presentations of immune-mediated endocrinopathies in patients treated with ICIs presenting as emergencies. METHODS: A prospective observational cohort study was undertaken at a specialist oncology hospital in North West England from May 20, 2018 to May 19, 2020. Within the hospital, the Oncology Assessment Unit (OAU) acts as the receiving unit in which assessments are undertaken of all emergency presentations. All patients treated with ICIs presenting to the OAU were included. The primary outcome was diagnosis of an immune-mediated endocrinopathy. Length of inpatient stay, and 7- and 30-day mortality rates were examined. RESULTS: During the study period, 684 patients treated with ICIs presented to the OAU. Twenty-four (3.5%) patients had an acute immune-mediated endocrinopathy, of which 17 had hypophysitis, 4 diabetes mellitus, 2 thyrotoxicosis, and 1 adrenalitis. Median length of stay for patients with hypophysitis was 1 day. No patient with an immune-mediated endocrinopathy died within 30 days of presentation. CONCLUSIONS: Presentations to emergency settings with acute immune-mediated endocrinopathies are rare. Early recognition of immune-mediated toxicities is important, and particularly pertinent in ICI-related endocrinopathies, where even in life-threatening cases, the presentation can be vague and nonspecific.

The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies.

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells' differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies-type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

Relation of health-related quality of life to near final height and body composition in adolescents with chronic endocrinopathies during transition period.

INTRODUCTION: We evaluated sequelae of disease and therapy in adolescents with chronic endocrinopathies using a medical and psychological workup to record health-related quality of life (HRQoL), near final height (NFH) and body compositions during the transition period from paediatric to adult care. METHODS: Near final height, weight, body mass index (BMI), grip strength (GS), hip and waist circumference (HC; WC), skin folds (SF) and HRQoL T-scores by KIDSCREEN and DISABKIDS were assessed in 134 patients (70 females and 64 males) from May 2010 to March 2016 diagnosed with congenital adrenal hyperplasia (CAH; n = 22), multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 37), Turner syndrome (TS; n = 27), SGA-short stature (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). RESULTS: Median HRQoL T-scores for KIDSCREEN (50.6-56.5) and DISABKIDS (52.7-58.9) ranged within references with considerable variations but without significant deficit in any diagnosis. Median-corrected height SDS (CoH-SDS: NFH-SDS-TH [target height]-SDS) was >-1, except in KS (SDS + 1.3) and in TS (SDS - 1.9; P < .0001) without correlations with HRQoL. Median BMI was below 25 kg/m2 in all patients except MPHD (26.5 kg/m2 ; SDS 1.5; P = .006). BMI correlated negatively in CAH females with self-perception (rs  = -.64, P = .0338), physical well-being (rs  = -.8; P = .0086), social exclusion rs  = -.65; P = .031) and emotions (rs  = -.7; P = .0169). CONCLUSION: Health-related quality of life and body compositions were similar to those of healthy adolescents. Lower scores in HRQoL dimensions as self-perception, physical well-being, social exclusion and emotions were detected and correlated negatively with BMI. Treatment strategies and psychological support should consider HRQoL and adapted in specific treatment guidelines.

Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports.

BACKGROUND: The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION: We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS: Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.

Primary and secondary insulin resistance.

Insulin resistance (IR) is defined as insufficient insulin metabolic effect in target tissues, including glucose utilisation in skeletal muscle, suppression of hepatic glucose production and suppression of lipolysis in fat tissue. Primary IR originates as consequence of rare monogenetic defects of insulin receptor or molecules includes to post-receptor insulin signal cascade. Secondary IR originates mainly as a result of metabolic or hormonal changes, most commonly in visceral obesity by multifactorial postreceptor inhibition of insulin signal and it is associated with metabolic syndrome and type 2 diabetes mellitus. It is also present in endocrinopathies with overproduction of contraregulatory insulin hormones (cortisol, growth hormone, catecholamines) and using of some drugs (mainly steroids, immunosuppressive treatment). In practice IR is usually diagnosed by glycemic parameters with confirmation of prediabetic states and type 2 diabetes mellitus. The healthy life style and physical activity associated with weight loss are the most important for type 2 diabetes prevention. According to actual international guidelines metformin is only antidiabetic drug which is possible to use in prediabetic states with high risk of type 2 diabetes development, mainly in obese subjects with BMI > 35 kg/m2, age under 60 years and in women with history of gestational diabetes.

Endocrinopathies in paediatric-onset neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibody.

The involvement of the diencephalic regions in neuromyelitis optica spectrum disorder (NMOSD) may lead to endocrinopathies. In this study, we identified the following endocrinopathies in 60% (15/25) of young people with paediatric-onset aquaporin 4-Antibody (AQP4-Ab) NMOSD: morbid obesity ( n = 8), hyperinsulinaemia ( n = 5), hyperandrogenism ( n = 5), amenorrhoea ( n = 5), hyponatraemia ( n = 4), short stature ( n = 3) and central hypothyroidism ( n = 2) irrespective of hypothalamic lesions. Morbid obesity was seen in 88% (7/8) of children of Caribbean origin. As endocrinopathies were prevalent in the majority of paediatric-onset AQP4-Ab NMOSD, endocrine surveillance and in particular early aggressive weight management is required for patients with AQP4-Ab NMOSD.

Endocrinopathies and cardiopathies in patients with Turner syndrome.

Ovarian dysgenesis, short stature, and infertility are common features of Turner syndrome (TS). Endocrinopathies and cardiopathies are less common, but may induce significant complications, and are the leading cause of mortality in TS patients. Endocrine abnormality including osteoporosis occurs in up to 60% of patients, hypothyroidism at an incidence of 3.2%, and impaired glucose metabolism with variable incidence depending on the age group. Estrogen therapy and growth hormone therapy, alone or combined, improve height and bone mass in TS patients. Autoimmune hypothyroidism is prone in the X-isochromosome phenotypes in the first and second decades of TS women's life. Type 2 diabetes mellitus resulting from haploinsufficiency of Xp genes and quiescent ß-cell autoimmunity occurs with higher frequency in TS patients in different age groups. The prevalence of cardiopathies in TS patients is 23%, with coarctation of aorta and bicuspid aortic valve being the most common cardiovascular malformations. Multidisciplinary and long-term medical healthcare is needed for TS patients. The risks of cardiovascular defects require close ultrasonography monitoring through the patient's lifespan, especially during pregnancy. The goal of this review is to provide an overview of endocrinopathies and cardiopathies in patients with TS.

Adrenal Insufficiency In Pakistani Hiv Infected Patients.

BACKGROUND: Adrenal insufficiency (AI) is the most common endocrine complication among patients with AIDS/HIV infection and there are number of causes of AI in HIV patients. Human immunodeficiency virus directly as well as indirectly destroys adrenal glands. The estimates of its prevalence and severity vary. AI is the most life threatening but readily correctable endocrine complication that occurs in persons with HIV infection. This study was carried out to determine the frequency of Adrenal Insufficiency in HIV patients and their clinical features as proper diagnosis and timely treatment have been shown to improve quality of life and long-term mortality in AIDS patients. METHODS: It was a cross sectional survey conducted at HIV clinic and Jinnah Allama Iqbal Institute of Diabetes and Endocrinology, Jinnah Hospital Lahore. Sixty-four HIV positive patients, both male and female, aged above 15 years were included in the study. HIV patients who had recently taken steroids, ketoconazole or rifampicin, determined on history, were excluded from the study. The data was collected on a structured proforma and analysis was performed in SPSS-21.0. Frequency and percentages for adrenal insufficiency and its characteristics were calculated. Chi-square test was used with p<0.05 as statistically significant. RESULTS: In this study, 9 (14.06%) HIV patients were diagnosed with adrenal insufficiency, male to female ratio was 3.5:1 and AI was found statistically significantly associated with fatigue (p<0.008) and weight loss (p<0.001). CONCLUSIONS: Adrenal insufficiency was high among the patients with HIV, it was not gender specific but it was found to be associated with fatigue and weight loss.

Endocrinopathy and Aging in Ferrets.

Ferrets have become more popular as household pets and as animal models in biomedical research in the past 2 decades. The average life span of ferrets is about 5-11 years with onset of geriatric diseases between 3-4 years including endocrinopathies, neoplasia, gastrointestinal diseases, cardiomyopathy, splenomegaly, renal diseases, dental diseases, and cataract. Endocrinopathies are the most common noninfectious disease affecting middle-aged and older ferrets. Spontaneous neoplasms affecting the endocrine system of ferrets appear to be increasing in prevalence with a preponderance toward proliferative lesions in the adrenal cortex and pancreatic islet cells. Diet, gonadectomy, and genetics may predispose ferrets to an increased incidence of these endocrinopathies. These functional proliferative lesions cause hypersecretion of hormones that alter the physiology and metabolism of the affected ferrets resulting in a wide range of clinical manifestations. However, there is an apparent dearth of information available in the literature about the causal relationship between aging and neoplasia in ferrets. This review provides a comprehensive overview of the anatomy and physiology of endocrine organs, disease incidence, age at diagnosis, clinical signs, pathology, and molecular markers available for diagnosis of various endocrine disorders in ferrets.

Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment.

INTRODUCTION: Endocrinopathies and metabolic disorders-characterized ß thalassemic (ßT) patients and the prevention and treatment of these comorbidities are important targets to be achieved. The aim of the study was to analyze the diagnostic and prognostic role of ferritin for endocrinopathies and metabolic disorders in ßT patients. The ability of iron chelators to treat iron overload and to prevent or reverse metabolic disorders and endocrinopathies was also evaluated. PATIENTS AND METHODS: Seventy-two ßT patients were treated with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying endocrine dysfunction in thalassemic patients. Kaplan-Meier curves were generated to assess the incidence of endocrinopathy. Adjusted risk estimates for endocrinopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: High ferritin levels were observed in patients with hypothyroidism [1500 (872.5-2336.5) µg/L], hypogonadism [878 (334-2010) µg/L], and in patients with hypoparathyroidism or osteoporosis [834 (367-1857) µg/L]. A strict correlation between ferritin and T2* magnetic resonance imaging of heart (r = -0.64; P:0.0006) and liver (r = -0.40; P:0.03) values was observed. Patients with ferritin values above 1800 µg/L experienced a significantly faster evolution to hypothyroidism [log-rank (χ(2) ):7.7; P = 0.005], hypogonadism [log-rank (χ(2) ):10.7; P = 0.001], and multiple endocrinopathies [log-rank (χ(2) ):5.72; P = 0.02]. Ferritin predicted high risk of endocrine dysfunction independently of confounding factors (HR:1.23; P < 0.0001). The intensification of chelation therapy led to an amelioration of hypothyroidism. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to endocrine dysfunctions. Intensive chelation therapy allows the reversibility of hypothyroidism.

Endocrine Adverse Events Related To Immune Checkpoint Inhibitor Treatment: Relationship Between Antibodies and Severity of Thyroid Dysfunction.

OBJECTIVE: The purpose of this study was to identify predictive and risk factors for the development of immune-related endocrinopathies and to analyze the incidence and characteristics of immune-related endocrinopathies in our population. DESIGN: A retrospective, single-centre cohort carried out at Gregorio Marañón Hospital between January 2018 -December 2019. METHODS: A total of 163 patients were enrolled. In January 2018 and December 2019, we treated patients who underwent ICI treatment in the Medical Oncology Department of General University Hospital Gregorio Marañón, a tertiary care public hospital in Madrid, as part of an observational, retrospective, single-center cohort study. RESULTS: Endocrinopathies were diagnosed in 19.5% of the patients (n = 32). The tumours with the highest incidence of endocrinopathies were non-small cell lung cancer (25,9%), kidney cell cancer (25%) and hepatocarcinoma (20%). Among the 32 patients who developed endocrinopathy, 18,8%, 19,13%, and 21,28% received anti-CTLA-4, anti-PD-1 and anti-PDL-1, respectively. Thyroid dysfunction was the most frequent endocrinopathy (12,8%). A higher percentage of patients with negative antiTPO and antiTG antibodies developed G1 hypothyroidism compared to patients with positive antibodies who developed a higher proportion of G2 hypothyroidism. The presence of an initial phase of thyrotoxicity was not related to greater severity. We observed longer progression-free survival in patients who developed thyroid dysfunction. CONCLUSION: Pre-existing antibodies were independently associated with endocrinopathies. Moreover, our study let us conclude that the presence of thyroid autoantibodies may be related to its severity. It is important to determine anti-thyroid antibodies prior to the start of immunotherapy as a risk factor for thyroid dysfunction, which in turn is a prognostic marker.

Markers of Fertility in Adolescents With Chronic Endocrinopathies at Transition From Paediatric to Adult Care.

OBJECTIVE: During the process of transition from paediatric to adult health care, counselling concerning fertility is an important issue and is based mainly on serum markers of gonadal function. Here, we analysed these markers in adolescents with various underlying endocrine diseases at the time of transition. METHODS: After reaching near adult height and late puberty (girls: bone age [BA] ≥14 years, and boys: BA ≥16 years), we assessed stages of puberty according to Tanner and measured testes or ovarian volumes and serum markers of gonadal function (anti-Mullerian hormone [AMH], inhibin B, 17ß-estradiol, testosterone). RESULTS: One hundred and ten patients (56 females and 54 males) were included from May 2010 to March 2016 with multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 35), Turner syndrome (TS; n = 27), short stature after being born small for gestational age (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). Female and male adolescents exhibited mature secondary sexual characteristics. The levels of serum inhibin B and AMH were lower in TS and female MPHD than in GHD and SGA, each independently (p < 0.05). The levels of serum AMH were higher whereas serum inhibin B were lower in male MPHD and KS (p < 0.05). Ovary volumes were significantly smaller in patients with TS, and testicular volumes were smaller in patients with KS. CONCLUSIONS: After current established treatments with sex steroids, the development of secondary sexual characteristics was mature. However, impaired markers of fertility have been identified in patients with TS, KS and MPHD, reflecting gonadal dysgenesis in TS and KS, but gonadal immaturity in MPHD as gonadal gonadotropin stimulation is lacking throughout development. Consequently, in patients with MPHD, these markers cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts.

Effects of acute hypothyroidism on plasma melatonin and Aanat and Asmt expression in the pineal gland and gonads of rats.

Introduction: The reproductive system is tightly regulated by environmental and physiological signals. Melatonin, known as the hormone of darkness, plays a crucial role in regulating both the circadian and reproductive systems in mammals. Hypothyroidism is a key endocrine disorder that harms the reproductive system. Despite many studies on melatonin's effects on the reproductive system, there is conflicting information regarding melatonin synthesis modulation in hypothyroidism. The objective of this study was to investigate the modulation of plasma melatonin levels and gene expression of Aanat and Asmt in the pineal gland and gonads of rats with hypothyroidism at different times of the day. Methods: Female and male Wistar rats were divided into control and hypothyroid groups. Hypothyroidism was induced using propylthiouracil (PTU) for 15 days, rats were euthanized six hours after lights on (ZT6), before lights off (ZT11.5), and six hours after lights off (ZT18). Free thyroxine (FT4) and melatonin were quantified in plasma, and gene expressions of melatonin synthesizing enzymes (Aanat and Asmt) were measured in pineal and sexual organs (testis and ovary). Also, morphological analysis was performed in sexual organs. Results: The results reveal some disparities between the sexes. Hypothyroidism reduced antral and primary follicles in the ovary, and reduced the weight of testis, epididymis, and prostate. In relation to gene expression, we observed a reduction in Aanat expression in the pineal gland during the light phase (ZT6), and in males, this reduction occurred during the dark phase (ZT18). Regarding Asmt expression, there was a decrease in females also during the dark phase (ZT18). In the gonads, there was an increase in expression in both sexes at ZT11.5. Additionally, it was interesting to observe the association between FT4 levels and Asmt expression in the gonads. Conclusions: This study showed that acute hypothyroidism can affect components of the melatonergic system in gonads, particularly gene expression of melatonin synthesis enzymes (Aanat and Asmt) contributing to changes in reproduction organs during disease progression. These findings enhance our understanding of melatonin synthesis in the reproductive system during hypothyroidism, showing distinct responses in male and female rats, and suggest that hypothyroidism affects the circadian rhythmicity of melatonin synthesis in a sex-dependent manner.

Mixed Gangliocytoma-Pituitary Adenoma: A Systematic Review of Diagnostic Features, Clinical Management, and Surgical Outcomes.

OBJECTIVE: Mixed gangliocytoma-pituitary adenomas (MGPAs) are very rare sellar neoplasms. Contemporary understanding of their natural history, clinical characteristics, optimal management strategies, and prototypical outcomes remains poorly understood. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, EMBASE, Web of Science, and Cochrane were searched to include studies of patients with histologically confirmed Mixed Gangliocytomas (MGPAs). Clinical features, management strategies, and outcomes were analyzed. RESULTS: 33 studies reporting 78 patients met study criteria and were included. Median age at diagnosis was 47 years, with a female predominance (71%). Common presenting symptoms included headache (49%), acromegaly (43%), and visual disturbance (20%). Growth hormone (GH) and prolactin were the most commonly elevated hormones. Magnetic resonance imaging (MRI) identified local infiltration in 86% of patients, most frequently in the cavernous sinus. Transsphenoidal resection was the primary treatment strategy, which achieved a gross total resection (GTR) in 43%. Postoperative pituitary function was normal in 92%. Median follow-up was 21 months, during which time 14% of patients required secondary intervention for persistent hormonal hypersecretion. Following these secondary interventions and as of last follow-up, radiographic and/or biochemical control was confirmed in all patients, with an overall survival rate of 97%. CONCLUSION: MGPAs are rare, slow-growing tumors that present with a combination of endocrinological and neurological symptoms. MGPAs are optimally managed with transsphenoidal resection, which appears to achieve favorable rates of symptomatic relief and local control, despite the high incidence of local infiltration and relatively low attendant GTR rate.

Immune checkpoint inhibitors-related endocrinopathies exhibit increased severity in breast cancer patients: a real-world study.

PURPOSE: This study aims to systematically evaluate the incidence of immune checkpoint inhibitors (ICIs)-related endocrinopathies and their onset time in patients with breast cancer (BC) in a real-world setting. METHODS: An analysis was conducted on the medical records of 122 BC patients who underwent ICIs therapy at the Department of Breast Surgery, Guangdong Provincial People's Hospital, from April 2019 to September 2021. Follow-up data continued until October 2022. RESULTS: The research indicated that 60.66% of BC patients experienced ICI-related endocrinopathies. The endocrinopathies included pituitary injury (7.38%), primary thyroid dysfunction (34.43%), supranormal fasting blood glucose or glycohemoglobin levels (16.39%), and adrenal injury (2.46%). Subgroup analyses were further performed based on clinical characteristics, demonstrated variability in the incidence of ICI-related endocrinopathies. Notably, subpopulations harboring genetic mutations exhibited a markedly higher prevalence of hypophysitis, as evidenced by a statistically significant association (P = 0.022). Similarly, individuals with HER2 positivity were found to have a significantly increased incidence of pancreatic islet injury (P = 0.023). Moreover, the study documented that the median onset times of ICIs-related endocrinopathies in pituitary, thyroid, pancreatic, and adrenal damage were 264, 184, 99 and 141 days, respectively, which were substantially longer compared to previous reports involving other tumors. Remarkably, even after 500 days of initiating ICI therapy, new cases of ICI-related endocrine disorders continue to emerge, suggesting a situation of delayed onset of ICI-related endocrinopathies in BC patients. CONCLUSION: The retrospective analysis confirmed a higher incidence and longer median onset time of ICI-related endocrinopathies in BC patients compared to other cancers. These outcomes underscore the critical need for regular and extended monitoring of endocrine functions in BC patients receiving ICI therapy, advocating for personalized monitoring approaches based on individual clinical profiles.