Hormones-International Journal of Endocrinology and Metabolism最新文献

Purpose: Disorders of sex development (DSD) have complex pathogenesis, and evidence suggests an association between MAMLD1 defects and DSD. MAMLD1 is expressed in gonadal tissues and affected males exhibit hypospadias, steroid hormone abnormalities, or gonadal underdevelopment. We performed genetic testing on a newborn patient with severe hypospadias and an elevation of 17-hydroxyprogesterone (17α-OH) for the diagnosis of DSD.

Methods: Genetic testing of the proband and parents was conducted using whole-exome and Sanger sequencing. The identified variant was transfected into HEK293T cells to assess mutant protein expression using western blot (WB) and into steroidogenic NCI-H295R cells to assess MAMLD1 and CYP17A1 transcript levels using qPCR. Molecular dynamics simulations were performed to construct a structural model and analyze potential biological implications.

Results: A novel heterozygous variant was identified in the proband's MAMLD1, NM_005491.5: c.1619_1637del (p.Gln540Alafs*72), inherited from the mother. In transfected cells, the wild-type and mutant proteins were 86.2 and 68.3 kDa, respectively, indicating the formation of a truncated protein. While MAMLD1 transcription was not affected, CYP17A1 transcription levels decreased with the variant compared to wild-type, suggesting an impact on the transactivation of CYP17A1. The truncated protein exhibited enhanced hydrophobicity, owing to the absence of the C-terminal structural portion, resulting in a looser protein structure.

Conclusion: Severe hypospadias in the proband may be attributed to a novel MAMLD1 variant, whereas the 17α-OH elevation might be related to interference with CYP17A1 transcriptional activation. This study expands the spectrum of MAMLD1 variants and underscores the critical role of genetic testing in the diagnosis of DSD.

Thyroid eye disease (TED) is an autoimmune orbital inflammatory disease which ranges from mild to severe. Tissue remodeling, fibrosis and fat proliferation cause changes in the orbital tissues which can affect esthetics and visual function. In its severe form, it is sight threatening, debilitating, and disfiguring and may lead to social stigma, the embarrassment about which has an impact on the quality of life of those affected and the family members. The pathogenesis of TED, which is influenced by genetic, immunological, and environmental factors, is complex and not fully elucidated. However, it remains unknown what factors determine the severity of the disease. Recent research has revealed a number of diagnostic and prognostic biomarkers of this disease. In this overview of TED, we focus on new insights and perspectives regarding biological agents that may provide a basis for new treatment modalities.

Purpose: We explored the alternative of using overnight fold change in gonadotropin levels by comparing the last-night-voided (LNV) and first-morning-voided (FMV) urine concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as a conceptual analogy to the invasive gonadotropin-releasing hormone (GnRH) stimulation test setting.

Methods: We investigated the nocturnal changes in the immunoreactivity levels of urinary gonadotropins between early and late prepubertal stages as well as between early and late pubertal stages in FMV and LNV urine samples from 30 girls, of whom those who were prepubertal were further investigated through follow-up visits within the 1-year period from the start of the study.

Results: ROC analysis revealed that the FMV total U-LH and FMV U-FSH concentrations at or above 0.3 IU/L and 2.5 IU/L, respectively, were excellent predictors of forthcoming onset of puberty within 1 year (100% sensitivity, 100% specificity, AUC: 1.00, and n = 10, for both). FMV total U-LH concentration at or above 0.8 IU/L represented the cut-off for clinical signs of puberty. FMV/LNV total U-LH and FMV/LNV U-FSH ratios at or below 4.11 and 1.38, respectively, were also good predictors of the onset of clinical puberty within 1 year. An overnight increase (FMV/LNV ratio) in total U-LH concentrations and in the U-LH/U-FSH ratio at or below 1.2-fold in pubertal girls was associated with the postmenarcheal pubertal stage.

Conclusion: FMV total U-LH and U-FSH above 0.3 IU/L and 2.5 IU/L, respectively, can be used as cut-off values to predict the manifestation of the clinical signs of puberty within 1 year. FMV total U-LH concentrations 0.3-0.8 IU/L and 0.6 IU/L may represent the range and the threshold, respectively, that reflect the loosening of the central brake on the GnRH pulse generator. An overnight increase of 20% or less in total U-LH concentrations and in the U-LH/U-FSH ratio in an early pubertal girl may serve as an indicator of imminent menarche, a presumed timing of which can be unraveled by future longitudinal studies.

Purpose: We present two cases of autoimmune hypothyroidism converted to Graves' disease (GD) and their medical management.

Methods: We tested thyroid function and thyroid antibodies and performed an ophthalmologic examination and neck ultrasound in two patients with autoimmune hypothyroidism converted to GD during a follow-up of several years.

Case reports: The first case is a 33 year-old woman with hypothyroidism due to Hashimoto's thyroiditis (HT). She developed signs and symptoms of hyperthyroidism after 7 years of treatment with the same dose of levothyroxine (LT₄). Even when LT₄ therapy was discontinued, she remained thyrotoxic, with mild Graves' ophthalmopathy (GO) and very high thyroid-stimulating hormone receptor antibodies (TRAb > 40 IU/L, reference range: <1.75 IU/L). Antithyroid medication was started on a titration regimen, without achievement of euthyroidism. She was switched to a block and replace regimen, using 20 mg of methimazole (MMI) and 75 mcg of LT₄ daily, with normalization of thyroid hormones and improvement of GO without steroids. The second case is a 57 year-old man with a 2-year positive medical history of HT and 6 months of LT₄ treatment. He developed hyperthyroidism and moderate-severe GO. Despite stopping LT₄ and initiating antithyroid medication in a titration regimen, he did not achieve euthyroidism and had active GO. Pulse glucocorticoid therapy and switching to a block-replace regimen was required to achieve euthyroidism and reduce ocular proptosis and diplopia.

Conclusion: Spontaneous autoimmune conversion of hypothyroidism to hyperthyroidism can occur at any time: it is important to promptly identify these cases so as to manage them effectively.

Purpose: The OPG/RANKL (osteoprotegerin/receptor activator of nuclear factor kappa-B) system, which plays a crucial role in bone metabolism, is also associated with vascular calcification. Acromegaly is characterized by excessive secretion of growth hormone and insulin-like growth factor, and studies have demonstrated an elevated risk of cardiovascular disease in individuals with acromegaly. In this study, our objective was to investigate the relationship between OPG/RANKL and various cardiovascular risk scoring systems.

Methods: We recruited 44 consecutive acromegaly patients and 41 healthy controls with a similar age and gender distribution for this study.

Results: While RANKL levels were significantly higher in the acromegaly group compared to the controls, OPG levels were not found to be significantly different between the two groups. Furthermore, within the acromegaly group, RANKL levels were significantly higher in patients with active acromegaly compared to those with controlled acromegaly. Osteoprotegerin levels showed a positive correlation with the Framingham risk score (FRS) in the acromegaly group. Linear regression analysis revealed an association of OPG with FRS (adjusted R² value of 21.7%).

Conclusion: OPG and RANKL may serve as potential markers for assessment of cardiovascular calcification and prediction of the cardiovascular risk status in acromegalic patients.

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of low-density-lipoprotein cholesterol (LDL-C), a major risk factor for cardiovascular (CV) disease. Since the hormone leptin has been suggested as having a role in CV risk regulation, possibly by modulating LDL receptor expression through the PCSK9 pathway, nutritional status may represent a potential regulator. Thus, evaluation of PCSK9 levels in human eating disorders appears to be of interest. In this report, we evaluate the lipoprotein profile, PCSK9, and leptin levels in subjects affected by anorexia nervosa (AN) to improve our understanding of the metabolic alterations in this disease.

Methods and results: We designed a case-control observational study, enrolling 20 anorexic adolescent females and 20 adolescent females without AN as the control group, age- and sex-matched. Subjects affected by AN showed lower BMI, total cholesterol, and LDL-C in comparison to the control group, with lipoprotein levels in the normal range. Furthermore, adolescent girls with AN show significantly higher PCSK9 (+24%, p < 0.005) and lower leptin levels (-43%, p < 0.01), compared to the control group.

Conclusions: The findings of increased levels of PCSK9 and reduced leptin levels among AN subjects warrant further research in order to unravel the role of the liver and adipose tissue in the management of PCSK9/LDL metabolism in adolescents affected by AN.

Primary hyperparathyroidism (PHPT), a relatively common disorder characterized by hypercalcemia with raised or inappropriately normal serum parathyroid hormone (PTH) concentrations, may occur as part of a hereditary syndromic disorder or as a non-syndromic disease. The associated syndromic disorders include multiple endocrine neoplasia types 1-5 (MEN1-5) and hyperparathyroidism with jaw tumor (HPT-JT) syndromes, and the non-syndromic forms include familial hypocalciuric hypercalcemia types 1-3 (FHH1-3), familial isolated hyperparathyroidism (FIHP), and neonatal severe hyperparathyroidism (NS-HPT). Such hereditary forms may occur in > 10% of patients with PHPT, and their recognition is important for implementation of gene-specific screening protocols and investigations for other associated tumors. Syndromic PHPT tends to be multifocal and multiglandular with most patients requiring parathyroidectomy with the aim of limiting end-organ damage associated with hypercalcemia, particularly osteoporosis, nephrolithiasis, and renal failure. Some patients with non-syndromic PHPT may have mutations of the MEN1 gene or the calcium-sensing receptor (CASR), whose loss of function mutations usually cause FHH1, a disorder associated with mild hypercalcemia and may follow a benign clinical course. Measurement of the urinary calcium-to-creatinine ratio clearance (UCCR) may help to distinguish patients with FHH from those with PHPT, as the majority of FHH patients have low urinary calcium excretion (UCCR < 0.01). Once genetic testing confirms a hereditary cause of PHPT, further genetic testing can be offered to the patients' relatives and subsequent screening can be carried out in these affected family members, which prevents inappropriate testing in normal individuals.

Objective: It is not clear whether response to initial treatment in papillary thyroid carcinoma (PTC) patients is best evaluated by measuring thyroglobulin (Tg) in the presence of levothyroxine (BTg) or when stimulated by elevated TSH (STg). The aim of this study was to evaluate whether response to therapy 1 year after initial treatment changes with the use of STg in relation to BTg in PTC patients treated with total thyroidectomy (TT) and radioiodine (¹³¹I), and, if observed, to assess which response is better associated with clinical course.

Subjects and methods: This is a retrospective study of 148 PTC patients submitted to TT and ¹³¹I. We analyzed the response to therapy (excellent, biochemical incomplete, or indeterminate) at 1 year after initial treatment, using BTg or STg, and compared which method was better associated with "excellent response at final evaluation."

Results: Twenty-eight patients (20.4%) presented change in response to therapy, with 17 of these (60.7%) presenting a worse response. Response using STg was 1.6 times better associated with proposed outcome [odds ratio (OR) = 4.61; confidence interval 95% (IC95%): 2.13-9.98] than with BTg (OR = 2.84; IC95%: 1.33-6.06).

Conclusion: Response to therapy at 1 year using STg was altered in approximately 20% of cases and therefore proved to be a better predictor of excellent response in the last evaluation.

Aim: To evaluate the response (titers of anti-COVID-19 antibodies) to COVID-19 mRNA vaccine of patients with Hashimoto's thyroiditis and normal individuals.

Patients and methods: Twenty-four patients with Hashimoto's thyroiditis and 51 normal individuals were studied after the third dose of the vaccine.

Results: Patients with Hashimoto's thyroiditis showed significantly higher immune response after the third dose of the COVID-19 mRNA vaccine compared with normal individuals (p = 0.020). After elimination of the four smokers with Hashimoto's thyroiditis, the immune response between the remaining 20 non-smoking patients compared with the response of the 23 non-smoking normal individuals was not different (p = 0.564). There was a significant positive correlation of the anti-COVID-19 antibodies with BMI (p = 0.029) but not with waist circumference in the patients with Hashimoto's thyroiditis (p = 0.054). Similar correlations were not found in normal individuals. Waist circumference could be considered as representative of visceral adipose tissue. In obese normal individuals (BMI ≥ 30), anti-COVID-19 antibodies were not different from those in lean normal individuals (BMI < 25). In obese patients with Hashimoto's thyroiditis, anti-COVID-19 antibodies were significantly higher compared to those in lean patients (p = 0.013). Median anti-COVID-19 antibody titer in obese patients with Hashimoto's thyroiditis was also significantly higher compared to that in obese normal individuals (p = 0.009).

Conclusions: Patients with Hashimoto's thyroiditis show significantly higher immune response after the third dose of the COVID-19 mRNA vaccine compared with normal individuals. Obese patients with Hashimoto's thyroiditis show additionally a significantly higher immune response compared with lean patients.