Multiple Hormone Deficiencies Research Articles

Growth Hormone Therapy in Chronic Heart Failure: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Guideline-directed medical therapy of heart failure (HF) primarily targets neurohormonal activation. However, growth hormone (GH) has emerged as a potential treatment for the multiple hormonal deficiency syndrome, which is associated with worse outcomes in HF. This study evaluates the efficacy and safety of GH therapy in HF. A systematic search was conducted in PubMed, Cochrane Library, and ClinicalTrials.gov, according to PRISMA guidelines. Randomized, placebo-controlled trials studying GH therapy in adult HF patients were included. Of the 1,184 initially identified records, 17 studies (1.4%) met the inclusion criteria. Two independent authors conducted the search, with any disagreements resolved by a third author. Study quality was assessed using predefined criteria, including randomization, blinding, and the presence of a placebo group. A random-effects model was applied due to heterogeneity across studies. GH therapy significantly improved left ventricular ejection fraction (3.34%, 95% CI: 1.09% to 5.59%, p=0.0037), peak oxygen consumption (2.84 mL/kg/min, 95% CI: 1.32 mL/kg/min to 4.36 mL/kg/min, p=0.0002), and New York Heart Association class (-0.44, 95% CI: -0.08 to -0.81, p=0.023). GH therapy also reduced the composite of death, worsening HF or ventricular tachycardia by 41% (95% CI: 0.39-0.90, p=0.013). Subgroup analyses indicated that patients with ischemic cardiomyopathy, baseline ejection fraction ≥30% and longer treatment duration experienced greater benefits. GH therapy may improve cardiac function, exercise capacity, and HF symptoms, with a trend towards improvement in hard endpoints, such as worsening HF. Event-driven trials are necessary to validate these findings.

Circulating thyroid hormones and clinical parameters of heart failure in men

Heart failure (HF) is a multiple hormonal deficiency syndrome which includes alterations in the serum concentration of thyroid hormones (TH). This cross-sectional study enrolled 215 male patients hospitalised for acute HF. Data on cardiovascular risk factors, chronic medications, cardiac function assessed by echocardiography, and clinical parameters of HF were prospectively collected. The independent predictive association of TH with all investigated parameters of the HF severity were assessed. The patient’s mean age was 74.4 years, 57.2% had arterial hypertension, 54.0% were consuming alcohol, and 42.3% were diabetics. Multivariate analysis revealed that total triiodothyronine (TT3) was an independent predictor of greater left ventricular ejection fraction (LVEF; β = 0.223, p = 0.008), less progressed left ventricular diastolic dysfunction (LVDD; β = − 0.271, p = 0.001) and lower N-terminal pro-brain natriuretic peptide (NT-proBNP; β = − 0.365, p < 0.001). None of the TH other than TT3 was associated with LVDD or NT-proBNP, whereas free triiodothyronine (β = − 0.197, p = 0.004), free thyroxine (β = − 0.223, p = 0.001) and total thyroxine (β = − 0.140, p = 0.041) were inversely associated with LVEF. The present study suggests that, among TH, serum TT3 level is most closely associated with echocardiographic, laboratory and clinical parameters of the severity of HF in men.

Pituitary function at presentation and following therapy in patients with non-functional pituitary macroadenomas: a single centre retrospective cohort study

BackgroundNon-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function.ObjectivesTo assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up.MethodsAll patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected.ResultsIn total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001).ConclusionNFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.

Pituitary stalk interruption syndrome (PSIS) presenting in a Jordanian male patient with short stature and delayed puberty: a case report

BackgroundPituitary stalk interruption syndrome is a rare congenital pituitary anatomical defect manifested with wide and various clinical presentations. Short stature and delayed puberty are present in most cases and may be combined with extra pituitary malformations. Magnetic resonance imaging is considered the key factor for reaching the definite diagnosis as it reveals the different radiological presentations of this syndrome.Case presentationA 17-year-old male patient from Jordan was presented to the radiology department for pituitary MRI. The patient presents with multiple pituitary hormonal deficiency, short stature, and under-developed secondary sexual characteristics. The bone age of the patient was significantly less than the chronological age. MRI pituitary gland showed hypoplasia of the anterior pituitary, absence of the pituitary stalk and ectopic posterior pituitary gland located posterior to the optic chiasm. These findings were consistent with pituitary stalk interruption syndrome.ConclusionsConsidering uncommon incidence of pituitary stalk interruption syndrome, magnetic resonance imaging of the pituitary should be considered while examining a patient with pituitary deficiency for prompt diagnosis and treatment. Hormone replacement medication is the primary treatment for pituitary stalk interruption syndrome and should be started as soon as feasible. Thus, early diagnosis and monitoring of individuals are crucial.

MEHMO syndrome: complexity of verifying the diagnosis

MEHMO syndrome (OMIM: 300148; ORPHA: 85282) is a disease appears by mental retardation, epilepsy seizures, hypogonadism, microcephaly, and obesity. Pathology is associated with mutations in the EIF2S3 gene located on the X chromosome and leads usually to serious disability of patients. The article presents a clinical observation of the case of the syndrome in two male cousins with microcephaly, manifested by a complex of endocrinopathies (hyperinsulinemic hypoglycemia, multiple adenohypophysis hormone deficiency) and accompanied by severe neurological abnormalities (epilepsy, spastic tetraparesis, optic nerve atrophy). The complexity of the diagnostic due to the rarity of this syndrome, is described.

Long-term hepatic and cardiac health in patients diagnosed with Sheehan's syndrome.

Sheehan's syndrome (SS) is characterised by chronic pituitary insufficiency following a vascular insult to the pituitary in the peripartum period. There is a lack of substantial evidence on the long-term hepatic and cardiac consequences in these patients, following hormone replacement. Patients with a diagnosis of SS were recruited for the study. Detailed clinico-biochemical and radiological evaluation were performed in all patients (n = 60). Hepatic and cardiac complications were assessed using fibroscan and echocardiography (2D speckle-tracking) respectively, in a subset of patients (n = 29) as well as age-and BMI-matched controls (n = 26). Controlled attenuation parameter (for steatosis) and liver stiffness measurement (for fibrosis) were used to define non-alcoholic fatty liver disease (NAFLD). Diastolic cardiac function was evaluated using standard criteria and systolic function by ejection fraction and global longitudinal strain (GLS). The mean age of the cohort was 42.7 ± 11.6 years. Multiple (≥ 2) hormone deficiencies were present in 68.8% of patients, with hypothyroidism (91.4%), hypocortisolism (88.3%), and growth hormone (GH) deficiency (85.7%) being the most common. At a mean follow-up of 9.8 ± 6.8 years, NAFLD was present in 63% of patients, with 51% having severe steatosis, which was predicted by the presence of GH deficiency and higher body mass index. Though the ejection fraction was similar, increased left ventricular GLS (18.8 vs. 7.7%) was present in a significantly higher number of patients versus controls. NAFLD, especially severe hepatic steatosis, is highly prevalent in SS. Subclinical cardiac systolic dysfunction (impaired GLS) is also more common, but of mild intensity.

Abstract 58: Favourable outcomes with therapeutic glucocorticoid regimen compared to replacement glucocorticoid regimen in primary hypophysitis

Background: Primary hypophysitis (PH) is most commonly treated with glucocorticoids. But there is considerable variation in the treatment regimens.Aims and Objectives: We aimed to compare the outcomes of therapeutic versus replacement glucocorticoid regimens in PH. Therapeutic regimen (TR) comprised oral prednisolone (1mg/kg/d) for 6-12 weeks followed by tapering. Replacement regimen (RR) comprised standard hydrocortisone. Response was defined as complete recovery of all pituitary axes, without any requirement of hormonal replacement.Results: Mean age of the cohort (n=30) was 37.8 ± 10.4 years with a female preponderance (79.3%). Response to glucocorticoids was present in 23.3% of the cohort, all on TR. There was no difference between responders and non-responders in terms of age, gender, duration of symptoms or follow-up (p>0.05). Headache was more frequent in responders than non-responders (100% vs 57.1%, p<0.05). Secondary hypocortisolism (100% vs 71.4%), hypothyroidism (71.4% vs 52.4%), hypogonadism (71.4% vs 42.8%), hyposomatotropism (57.1% vs 25%) and hyperprolactinemia (85.7 vs 57.1%) were more common among responders (p<0.05). Diabetes insipidus was not different (42.3% vs 38%, p=0.56). Pituitary enlargement (100% vs 76.2%) and absent posterior pituitary bright spot (PPBS) (71.4% vs 57.1%) were more frequent among responders (p<0.05). Asymmetric enlargement was more common in non-responders (23.8% vs 0, p<0.05). Stalk thickening (80.9% vs 85.7%) and T2 parasellar dark intensity (28.5% each) were not different (p>0.05). The mass regressed in 85.7% in responders and 57.1% of non-responders at a mean follow-up duration of 4.6 ± 2.7 years.Conclusion: Response in PH is optimal with TR. Multiple hormone deficiencies, hyperprolactinemia, symmetric pituitary enlargement and absent PPBS portend favourable response, whereas asymmetric pituitary enlargement is more common among non-responders.

A Case of Persistent Hypoglycemia with Disorder of Sex Development

A Case of Persistent Hypoglycemia with Disorder of Sex Development

Evaluation of the periodontal status of a patient diagnosed with Sheehan syndrome: A case report

Aim: Some immunological changes occurring in mothers during pregnancy increase their susceptibility to infections, including periodontal infections. Sheehan syndrome (SS) is a disease that occurs because of severe postpartum hemorrhage causing ischemic pituitary necrosis. The presence of multiple hormonal deficiencies leads to the impairment of bone microarchitecture, which can cause osteopenia and even osteoporosis. Osteoporosis and periodontitis are both chronic diseases characterized by bone loss. Moreover, recent studies have shown that there is a relationship between menopause, osteoporosis, alveolar bone resorption, and tooth loss. This case report aims to evaluate the oral and periodontal status of a patient with SS and to raise awareness about dental and periodontal problems that may occur in such patients.&#x0D; Methodology: A 63-year-old female patient diagnosed with SS in the endocrinology clinic was referred to the periodontology clinic with complaints of multiple tooth loss, mobility in her teeth, and gingival bleeding. In the clinical and radiographic examination of the patient, it was determined that all teeth had horizontal bone resorption; moreover, there was mobility in the mandibular anterior teeth and hemorrhage in the gums. When the patient’s laboratory results were examined, it was seen that the basal plasma levels of free triiodothyronine (T3) and thyroxine (T4), growth hormone (GH), prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, and total testosterone values were significantly lower, and the anterior pituitary elevation was significantly decreased in pituitary magnetic resonance (MR) imaging.&#x0D; Conclusion: The periodontium is the target tissue of sex and other hormones. Hormonal changes may affect the inflammatory–immune tissue responses of periodontal tissues. Many studies have shown that thyroid and sex hormones affect oral and especially periodontal tissues. The degradation of hormonal hemostasis may induce a series of pathological events in the oral environment, resulting in inflammatory changes in gingival tissues, periodontal attachment losses, and destruction of the alveolar bone. Systemic diseases that affect hormonal conditions, such as SS, must be considered in the evaluation of oral health. Medical physicians should refer their patients to the dentist for consultation when evaluating patients’ hormonal status and planning their treatment.&#x0D; &#x0D; How to cite this article: Şen SC, Saygun NI, Or Koca A, Özcan E. Evaluation of the periodontal status of a patient diagnosed with Sheehan syndrome: A case report. Int Dent Res 2021;11(Suppl.1):308-11. https://doi.org/10.5577/intdentres.2021.vol11.suppl1.46&#x0D; &#x0D; &#x0D; Linguistic Revision: The English in this manuscript has been checked by at least two professional editors, both native speakers of English.&#x0D;

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

The necessity of magnetic resonance imaging in the evaluation of pediatric growth hormone deficiency: Lessons from a large academic center

BackgroundCurrent guidelines indiscriminately recommend magnetic resonance imaging (MRI) of the pituitary gland in pediatric growth hormone deficiency (GHD). The relationship between abnormal MRI, most importantly a tumor, and peak GH levels is not well known. MethodsIn this retrospective chart review, pituitary MRI results of children, ages of 3–16 years with GHD were collected and divided into 3 groups according to peak stimulated GH levels; ≤5, 5–7.4 and 7.5–10 ng/mL, Groups A, B & C respectively. Clinical and MRI findings were compared between the groups. ResultsA total of 399 children were included. Abnormal MRI was found in 36.9% of group A subjects, compared to group B (16.7%) and group C (17.0%), both p values =0.0002. Children with multiple pituitary hormonal deficiencies (MPHD) had a higher rate of abnormalities than those with isolated GHD. Children with isolated GHD were more likely to have abnormal MRI with peak GH level < 5 ng/mL compared to those with levels, 5–7.4 & 7.5–10 ng/mL. 4 children in group A had a craniopharyngioma. ROC analysis comparing peak GH levels with abnormal MRI findings showed an area under the curve (AUC) of 0.614 and 0.728 for IGHD and MPHD, respectively. ConclusionAlthough abnormal MRI was found in all 3 study groups, it was more likely at GH level < 5 ng/mL and in children with MPHD. To avoid missing a tumor, the importance of imaging in children with GHD and peak GH levels <5 ng/mL cannot be overemphasized.

Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes

BackgroundTranssphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown.MethodsData from patients who underwent endoscopic TSS for a NFPMA (2009–2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes.ResultsOf 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004).ConclusionPre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency

Immune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

PSIS With Phenotypic Features of Prader Willi and Fragile X Syndrome

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect characterized by triad of interrupted or thin pituitary stalk, hypoplasia or aplasia of anterior lobe and absent or ectopic posterior pituitary on MRI. PSIS is known to have a heterogenous phenotype involving variable combination of pituitary hormonal deficiencies. [1] We present this case diagnosed with PSIS who had phenotypical features of Prader-Willi and Fragile X Syndrome but was negative on chromosomal array and analysis. Case Presentation: 19 yo M presented to clinic accompanied with his mother who provided most of the history. As per the mother, the patient was initially evaluated for hypogonadism due to lack of pubic and axillary hair with underdeveloped penis and testes, till the age of 17 years. Later on he was found to have hypothyroidism and was on replacement for the above. The patient was born through C-section at term, had developmental delays with respect to achieving milestones. On Examination, the patient had BMI of 35.5 (Weight: 105.2 kg, Height: 172 cm). Exam was significant for bilateral gynecomastia with glandular tissue, absence of facial hair, minimally palpable testes, phimosis, minimal pubic hair. He was noted to have enlarged ear lobes and helices with mild hypertelorism. On evaluation patient had learning disability, borderline IQ (nonverbal IQ of 74). Labs were significant for FSH: 0.344 (normal 1.5-12.4), LH; 0.1 (normal 1.70-8.60), Prolactin: 6.31 (normal 2.64-13.13), TSH: 3.80 (normal 0.30-4), T3: 156 (normal 82-179), fT4: 0.409 (normal 0.30-1.90), Testosterone < 0.025, IgF-1 <32, ACTH 14, cortisol 2.1 after cosyntropin test cortisol 13.3. He was started on replacement for secondary adrenal insufficiency. In view of the patient’s obesity, panhypopituitarism, questionable intellectual disability (non-verbal) IQ of 74), and enlarged ear lobes and helices, the patient was strongly suspected to have Prader Willi and Fragile X syndrome, however chromosomes and array were negative for both. MRI brain was recommended that was consistent with PSIS: hypoplastic enhancing pituitary soft tissue within Sella consistent with anterior lobe, ectopic posterior pituitary in region of hypothalamus and unidentifiable pituitary stalk. Conclusion: Pituitary stalk interruption syndrome is diagnosed radiologically and involves multiple pituitary hormonal deficiencies that can gradually progress requiring lifelong hormonal replacement therapy and follow up. It is associated with a wide phenotypic spectrum suggesting both hormonal deficiencies and coexisting developmental defects. Work still needs to be done to further explore the molecular etiology of this rare syndrome however due to wide phenotypical presentation of this syndrome it is imperative to evaluate for PSIS at an early age if there is suspicion of any isolated or combined hormonal deficiency in addition to abnormal morphology to identify individuals with PSIS as they need close monitoring for progression of syndrome and lifelong hormonal replacement eventually.

Evaluation of the Optimal Thyroxine Levels for Thyroxine Hormone Replacement in Patients With Central Hypothyroidism

Introduction: Central hypothyroidism results from pituitary or hypothalamic dysfunction. The evaluation of the adequacy of thyroxine replacement is difficult, due to the loss of thyrotropin (TSH) as an accurate feedback marker. This study aim to explore the potential metabolic and clinical effects of different free T4 (fT4) replacement targets in patients with central hypothyroidism. Method: This was a single center, prospective open-label crossover-like trial of 51 patients (mean age 56±12.9 years, 27 male) with hypopituitarism with multiple hormonal deficiencies including central hypothyroidism after excluding those with primary thyroid diseases, high risk for cardiovascular diseases (CVD) and known CVD. Dosage of levothyroxine (L-T4) was titrated to a targeted lower, middle and upper fT4 tertile and maintained for 24 weeks before assessment. Anthropometric and physiological measurements, metabolic and peripheral tissue markers, cognitive and quality of life assessments (SF-36 and Hong Kong Montreal Cognitive Assessment-5 [HK-MoCA-5]) were compared before and after each fT4 tertile change. This was followed by another 24-week cycle of L-T4 dosage adjustment to achieve fT4 in another tertile, with the same assessment as above. Results: We demonstrated that raising fT4 target from lower to upper tertile within the normal reference range resulted in significant decrease in body mass index (27.1±6.0 vs 25.7±5.6 kg/m2, P<0.01), waist circumference (89.5±12.7 vs 86.4±12.1 cm, p<0.01), diastolic blood pressure (79.1±12.9 vs 74.5±12.9 mmHg, p<0.05) and low density lipoprotein cholesterol (3.94±0.88 vs 2.90±0.71 mmol/L, p<0.01), apart from expected significant effect on tissue markers such as increased sex-hormone binding globulin (SHBG), increased ferritin and reduced creatinine kinase (CPK). The occurrence of metabolic syndrome (48.2% vs 29.0%, p <0.05) was significantly reduced with increasing fT4 from middle to upper tertile, without significant effect on glycemic indexes, heart rate, SF-36 and HK-MoCA-5. Conclusion: In this study, we demonstrated that raising fT4 target to the upper tertile of normal resulted in a favourable improvement in various metabolic indexes without a significant increase in adverse effects over a period of 48 weeks.

Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.

Recent evidence supports the occurrence of multiple hormonal and metabolic deficiency syndrome (MHDS) in chronic heart failure (CHF). However, no large observational study has unequivocally demonstrated its impact on CHF progression and outcome. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure) Registry has been specifically designed to test the hypothesis that MHDS affects morbidity and mortality in CHF patients. The T.O.S.CA. Registry is a prospective, multicentre, observational study involving 19 Italian centres. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydropianoandrosterone sulfate, insulin resistance, and the presence of diabetes were evaluated. A MHDS was defined as the presence of ≥2 hormone deficiencies (HDs). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Four hundred and eighty heart failure patients with ejection fraction ≤45% were enrolled. MHDS or diabetes was diagnosed in 372 patients (77.5%). A total of 271 events (97 deaths and 174 cardiovascular hospitalizations) were recorded, 41% in NO-MHDS and 62% in MHDS (P < 0.001). Median follow-up was of 36 months. MHDS was independently associated with the occurrence of the primary endpoint [hazard ratio 95% (confidence interval), 1.93 (1.37-2.73), P < 0.001] and identified a group of patients with a higher mortality [2.2 (1.28-3.83), P = 0.01], with a graded relation between HDs and cumulative events (P < 0.01). MHDS is common in CHF and independently associated with increased all-cause mortality and cardiovascular hospitalization, representing a promising therapeutic target. ClinicalTrials.gov identifier: NCT023358017.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2–/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4–/– and Dchs1–/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

Pituitary stalk interruption syndrome and liver changes: From clinical features to mechanisms.

Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. Although the etiology of PSIS is still unclear, gene changes and perinatal adverse events such as breech delivery may play important roles in the pathogenesis of PSIS. PSIS can cause multiple hormone deficiencies, such as growth hormone, which then cause a series of changes in the human body. On the one hand, hormone changes affect growth and development, and on the other hand, they could affect human metabolism and subsequently the liver resulting in nonalcoholic fatty liver disease (NAFLD). Under the synergistic effect of multiple mechanisms, the progression of NAFLD caused by PSIS is faster than that due to other causes. Therefore, in addition to early identification of PSIS, timely hormone replacement therapy and monitoring of relevant hormone levels, clinicians should routinely assess the liver function while managing PSIS.

Multiple Endocrine Deficiencies are Common in Hypoparathyroidism–Retardation–Dysmorphism Syndrome

The rare hypoparathyroidism-retardation-dysmorphism (HRD) syndrome (OMIM #241410) is caused by the mutated tubulin chaperone E (TBCE) gene. This gene encodes a critical protein in the microtubule assembly pathway. To evaluate the endocrine profile of patients with HRD. The study used a retrospective analysis of a large cohort of patients in a single university medical center. Sixty-three patients were diagnosed with HRD during 1990 to 2019; 58 of them had an endocrine evaluation. We investigated somatic growth parameters, the prevalence of hypoglycemia, growth hormone deficiency, hypothyroidism, hypogonadism, and cortisol deficiency. All patients were born small for gestational age, and severe growth retardation was found in all patients with mean height standard deviation score (SDS) of -8.8 (range: -5.1 to -15.1) and weight SDS -18 (range: -5.1 to -61.2). Serum insulin-like growth factor-1 concentrations were very low among the 21 studied patients: -2.32 SDS (range: -0.6 to -2.7). Four out of 14 (28%) investigated patients had growth hormone deficiency, and 55% of patients were hospitalized due to symptomatic hypoglycemia. Adrenal glucocorticoid insufficiency was diagnosed in 22% of those tested. Hypothyroidism was found in 36% of patients. Both hypogonadotrophic and hypergonadotrophic hypogonadism were observed. The main magnetic resonance imaging findings were small anterior pituitary gland, small hippocampus, brain atrophy, thin corpus callosum, Chiari type I malformation, and septo-optic dysplasia. Multiple endocrine abnormalities are common in patients with HRD syndrome. Periodic screening of thyroid and adrenal functions is recommended.

Managing Ipilimumab-Induced Hypophysitis: Challenges and Current Therapeutic Strategies.

Over the past years, progress has been made in cancer immunotherapy following the development of immune checkpoint inhibitors (ICI) that have been proved effective in the management of many malignancies. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), has been approved for the treatment of advanced melanoma but has been associated with the development of several endocrine immune-related adverse events (irAEs). Hypophysitis is the most common endocrine irAE related to ipilimumab with a reported incidence ranging from 1.8% to 17%. The mechanism underlying ipilimumab-induced hypophysitis implicates immune, inflammatory and genetic factors, but there are still some points that are not well understood and remain to be elucidated. The diagnosis is based mainly on clinical, biochemical and imaging data. The majority of patients display multiple hormone deficiencies that may recover or persist for a prolonged period of time with corticotroph deficiency usually being permanent. Immune-related hypopituitarism is treated with replacement of deficient hormones while in severe forms of hypophysitis treatment with high-dose glucocorticoids may be required. Proper evaluation and registration of patients in clinical trials and further investigation are needed to precisely clarify the pathophysiology of the ICI-related hypophysitis, define predictive factors and ameliorate the management and outcome of the disease.