Effects of Levothyroxine Treatment on Fertility and Pregnancy Outcomes in Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Subclinical hypothyroidism, defined by elevated thyrotropin (TSH) and normal free thyroxine levels, is associated with adverse pregnancy outcomes, including preterm birth, pre-eclampsia, and small for gestational age. Despite the uncertainty regarding the effectiveness of levothyroxine (LT4) treatment on pregnancy outcomes in subclinical hypothyroidism, LT4 is widely administered with a pre-treatment threshold TSH level of 2.5 mU/L. The aim of this study is to investigate the efficacy of periconceptional LT4 treatment for subclinical hypothyroidism, including TSH levels >2.5 mU/L, and identify the characteristics of subclinical hypothyroidism that can benefit from LT4 treatment. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials from inception to February 2023. We analyzed the pooled effects of LT4 on subclinical hypothyroidism before and during pregnancy. The main outcomes before pregnancy were live birth, pregnancy, and miscarriage. The main outcomes during pregnancy were live birth, miscarriage, and preterm birth. We conducted subgroup analyses to compare the effects of LT4 on subclinical hypothyroidism with TSH levels of 2.5-4.0 and >4.0 mU/L. Results: Of the 888 studies identified, 27 full-text articles were screened for eligibility. Five studies on pre-conception treatment with 768 participants and eight studies on treatment during early pregnancy with 2622 participants were analyzed. One of the two studies on pre-conception treatment in subclinical hypothyroidism with TSH >4.0 mU/L had high risk of bias and the other was composed of 64 participants. Pre-conception LT4 treatment had no significant effect in improving rates of live births and pregnancies, or reducing miscarriages (risk ratio [RR], 95% confidence interval): 1.41 (0.84-2.36), 1.73 (0.88-3.39), and 0.46 (0.11-2.00), respectively. LT4 treatment during pregnancy was not significantly associated with higher rates of live births (RR 1.03, 0.98-1.09) nor decreased miscarriage rates (RR 1.01, 0.66-1.53). The effect of LT4 treatment on preterm birth during pregnancy was significantly different depending on the TSH values (p = 0.04); a positive effect was shown in the subclinical hypothyroidism subgroup with TSH >4.0 mU/L (RR 0.47, 0.20-1.10), while no significant effect was observed in the subgroup with TSH 2.5-4.0 mU/L (RR 1.35, 0.79-2.31). Conclusions: Pre-conceptional LT4 treatment for subclinical hypothyroidism does not improve fertility or decrease the incidence of miscarriages. However, further well-designed studies are needed for pre-conceptional treatment, especially in TSH >4.0 mU/L. LT4 treatment during pregnancy had a positive effect on preterm birth; nevertheless, this was only applicable to subclinical hypothyroidism with TSH >4.0 mU/L.

Comparisons of heart rate variability responses to head-up tilt with and without abdominal and lower-extremity compression in healthy young individuals: a randomized crossover study.

Introduction: Abdominal and lower-extremity compression techniques can help reduce orthostatic heart rate increases. However, the effects of body compression on the cardiac autonomic systems, which control heart rate, remain unclear. The primary objective of this study was to compare heart rate variability, a reflection of cardiac autonomic regulation, during a head-up tilt test with and without abdominal and lower-extremity compression in healthy young individuals. The secondary objective was to conduct a subgroup analysis, considering participant sex, and compare heart rate and heart rate variability responses to head-up tilt with and without compression therapy. Methods: In a randomized crossover design, 39 healthy volunteers (20 females, aged 20.9 ± 1.2 years) underwent two head-up tilt tests with and without abdominal and lower-extremity compression. Heart rate and heart rate variability parameters were measured during the head-up tilt tests, including the Stress Index, root mean square of successive differences between adjacent R-R intervals, low- and high-frequency components, and low-to-high frequency ratio. Results: Abdominal and lower-extremity compression reduced the orthostatic increase in heart rate (p < 0.001). The tilt-induced changes in heart rate variability parameters, except for the low-frequency component, were smaller in the compression condition than in the no-compression condition (p < 0.001). These results were consistent regardless of sex. Additionally, multiple regression analysis with potentially confounding variables revealed that the compression-induced reduction in Stress Index during the head-up tilt position was a significant independent variable for the compression-induced reduction in heart rate in the head-up tilt position (coefficient = 0.411, p = 0.025). Conclusion: Comparative analyses revealed that abdominal and lower-extremity compression has a notable impact on the compensatory sympathetic activation and vagal withdrawal typically observed during orthostasis, resulting in a reduction of the increase in heart rate. Furthermore, this decrease in heart rate was primarily attributed to the attenuation of cardiac sympathetic activity associated with compression. Our findings could contribute to the appropriate application of compression therapy for preventing orthostatic tachycardia. This study is registered with UMIN000045179.

Reducing the gender gap in academic activities: a 10-year progress report by the Japan Endocrine Society Women Endocrinologists Association (JES-We-Can).

The Japan Endocrine Society (JES) has the largest ratio of female membership among societies associated with Internal Medicine in Japan; half of female members are in their 20s or 30s at present. In 2009, JES organized the "JES-We-Can" committee to promote women's career development. To evaluate the effectiveness of JES-We-Can, we investigated the gender balance of various activities at JES in fiscal 2009 and 2017. Significant gender-differences were not observed in the acquisition rate of board-certified endocrinologists (BCEs) aged <40 y in 2009 and 2017. However, the acquisition rate of BCEs among women aged ≥40 y was significantly lower than men in 2009. In 2017, the gender-difference among BCEs in this group (currently aged ≥50 y) has considerably improved, but is not resolved. The acquisition rate of certificated endocrine educators (CEEs) among women was still significantly lower than men at all ages in 2017. Since the ratio of women oral speakers or poster presenters at annual academic meetings have grown to equal or surpass the membership ratio, female members make efficient contributions to JES. The numbers of women chairpersons, symposiasts, lecturers and invited speakers have increased, but remain limited. JES-We-Can was found to be effective in reducing the gender gap in academic activities at JES, but JES-We-Can should support women more intensely to raise the rate of CEEs among all ages and BCEs currently over 50 y, and to promote more women into higher positions in JES in the future. These actions are expected to introduce new and diverse perspectives into academia.

Sex in basic research: concepts in the cardiovascular field.

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Acromegaly accompanied by Turner syndrome with 47,XXX/45,X/46,XX mosaicism.

A 33-year-old woman was hospitalized for examination of edematous laryngopharynx. She was acromegalic. A pituitary adenoma with elevated serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) was detected, indicating acromegaly caused by GH-secreting pituitary adenoma. Multiple pigmented nevi were also noted without overt short stature and cubitus valgus. Chromosome analysis revealed that she had contracted Turner syndrome with 47,XXX/45,X/46,XX mosaicism. Transsphenoidal resection of the tumor decreased serum GH and IGF-I levels, but the edema was not improved. Both premature ovarian failure and hypertension appeared after surgery. This case may indicate the important relationships between GH/IGF-I and Turner syndrome.

Long-term follow-up of patients with multiple endocrine neoplasia type 1.

Whether early surgical treatment of non-functioning pancreas islet cell tumor (NFPT) provides a favorable quality of life and life expectancy in patients with multiple endocrine neoplasia type 1 (MEN1) remains controversial. We analyzed the long-term clinical courses and surgical outcomes of 14 Japanese patients with MEN1-associated NFPTs. NFPTs smaller than 20 mm in diameter did not show any apparent growth over a long monitoring period. Furthermore, these small NFPTs did not metastasize to regional lymph nodes or the liver. On the other hand, the development of additional NFPTs or metastasis was found in five of six patients with large (35 mm or larger) NFPTs. Among the seven patients who underwent a partial pancreatectomy, six patients developed impaired glucose tolerance or diabetes. The accumulation of more prospective data is needed to clarify the optimal surgical indications for patients with NFPTs, especially among the Japanese population, which has a relatively low insulin secretion potency compared with non-Hispanic white and African-American populations.

Familial neuroendocrine tumor syndromes: from genetics to clinical practice.

Thanks to recent developments in molecular biology and cancer genetics, genetic testing has become widely available and useful in several kinds of familial tumor syndrome. However, the impact of genetic testing on medical management is not always straightforward. Clinicians have to consider the psychological impact and ethical complexities of communicating hereditary cancer risk information to families. This review notes some points on genetic counseling before and after genetic testing for familial neuroendocrine tumor syndromes.

Novel 14 base-pair deletion of the MEN1 gene in a patient with recurrent primary hyperparathyroidism.

MEN1 is the causative gene for multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome characterized by hyperplastic and neoplastic disorder of endocrine organs such as parathyroid, anterior pituitary and gastroenteropancreatic endocrine tissues. More than 300 germline mutations have already been reported in patients with MEN1. We here report a novel deletional mutation identified in a Japanese woman with apparently sporadic recurrent hyperparathyroidism. Genetic testing revealed a heterozygous deletion involving 14 bp in exon 6 (starting at amino acid codon 293) of MEN1, which results in early termination of the protein. This deletional mutation has not previously been described elsewhere.

Octreotide as a rapid and effective painkiller for metastatic carcinoid tumor.

Octreotide is one of the somatostatin analogue used for the treatment of endocrine tumors principally to suppress hormone secretion and to inhibit tumor growth. We experienced a case with multiple endocrine neoplasia type 1 who small amount of octreotide dramatically relieved the lumber pain caused by metastatic bone tumor. He had recurrent bronchial carcinoid tumors that metastasized to liver and bones. The spontaneous and radiated pain by bone tumors subsided within a few minutes after the initial injection of octreotide and the effect persisted for several hours. Combination therapy of octreotide and interferon alpha-2b significantly reduced the size of metastatic liver tumors and inhibited further growth of metastatic bone tumors for the last 27 months. The use of octreotide may be a good option for controlling pain by metastatic bone disease and combination therapy of octreotide and interferon alpha-2b is worth to try for patients with inoperable metastatic carcinoid tumor.

Multiple endocrine neoplasia type 1 with unusual concomitance of various neoplastic disorders.

A patient with multiple endocrine neoplasia type 1 (MEN1) who manifested various MEN1-unrelated tumors was reported. The patient was a 43-year-old woman who manifested typical features of MEN1 including primary hyperparathyroidism, prolactinoma, adrenal adenoma and visceral lipomas. During the course, she also manifested chondrosarcoma, B cell lymphoma and mesothelioma. The patient had no apparent family history of MEN1 or any other neoplastic diseases. Genetic analysis of DNA from peripheral mononuclear cells of the patient revealed no germline mutations in MEN1 gene. Genetic instability due to yet unidentified cause is the possible explanation of occurrence of multiple tumors. Careful periodic screening of endocrine and other disorders for her siblings and children as well as for the patient is warranted.

Clinical and genetic features of patients with multiple endocrine tumors who have neither family history nor MEN1 germline mutations.

Multiple endocrine neoplasia type 1 (MEN1) is an hereditary tumor syndrome that involves specific endocrine organs such as parathyroids, anterior pituitary gland, and endocrine pancreas. The responsible gene for this syndrome, MEN1, has been isolated and that enabled genetic diagnosis for patients with endocrine tumors and early detection of asymptomatic gene carriers in affected families. Nevertheless, there are a considerable number of patients with MEN1 who have neither family history nor germline MEN1 mutations. In this article, clinical features of such patients are described. Among 53 MEN1 patients we have seen during the last 20 yr, five patients who did not have either MEN1 germline mutation or family history were categorized as MEN1 phenocopy. During the same period, we have also experienced three patients who had primary hyperparathyroidism and adrenocortical tumor but had no apparent family history of endocrine tumors. These patients were considered as MEN1 phenocopy variants and included in the study. The mean age of MEN1 phenocopy patients (including variants) at diagnosis was 48 yr, which was not significantly different from that of probands of familial MEN1 (46 yr) who carry heterozygous MEN1 gene mutations. In the majority of MEN1 phenocopy patients, primary hyperparathyroidism was due to a single parathyroid adenoma. In contrast to a previous report, we found that MEN1 phenocopy patients are not necessarily older than probands of familial MEN1. Phenotypic expression of such patients is variable, thus differentiation of familial MEN1 and MEN1 phenocopy cannot be made based on age and clinical phenotype alone.

Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions.

The contribution of endothelin to resting pulmonary vascular tone and hypoxic pulmonary vasoconstriction in humans is unknown. We studied the hemodynamic effects of BQ-123, an endothelin type A receptor antagonist, on healthy volunteers exposed to normoxia and hypoxia. Hemodynamics were measured at room air and after 15 min of exposure to hypoxia (arterial PO(2) 99.8 +/- 1.8 and 49.4 +/- 0.4 mmHg, respectively). Measurements were then repeated in the presence of BQ-123. BQ-123 decreased pulmonary vascular resistance (PVR) 26% and systemic vascular resistance (SVR) 21%, whereas it increased cardiac output (CO) 22% (all P < 0.05). Hypoxia raised CO 28% and PVR 95%, whereas it reduced SVR 23% (all P < 0.01). During BQ-123 infusion, hypoxia increased CO 29% and PVR 97% and decreased SVR 22% (all P < 0.01). The pulmonary vasoconstrictive response to hypoxia was similar in the absence and presence of BQ-123 [P = not significant (NS)]. In vehicle-treated control subjects, hypoxic pulmonary vasoconstriction did not change with repeated exposure to hypoxia (P = NS). Endothelin contributes to basal pulmonary and systemic vascular tone during normoxia, but does not mediate the additional pulmonary vasoconstriction induced by acute hypoxia.

[Genetic testing and counseling for familial tumor syndromes].

Recent developments in molecular biology have increased our understanding of the genetics of familial tumor syndromes. Isolation of the responsible genes has made it possible to identify gene carriers before they manifest clinical symptoms, which enables early detection of disease and at times prophylactic surgery. Indications for genetic testing of susceptible family members, however, should be carefully considered. Genetic counseling must be provided to clients before genetic tests. Patients should be provided with the latest knowledge on the disease and appropriately informed of the benefits and possible problems associated with genetic test, as such information is essential for clients to decide whether they will undergo such tests. Genetic medicine is not sufficiently available at present in Japan. Establishment of genetic services that deal with genetic counseling, family support and ethical, social and legal issues is strongly desired.

Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth.

PURPOSE: To determine the effect of pigment epithelium-derived factor (PEDF) in a mouse model of ischemia-induced retinal neovascularization and on vascular endothelial growth factor (VEGF)--induced migration and growth of cultured microvascular endothelial cells. METHODS: Human recombinant PEDF was expressed in the human embryonic kidney 293 cell line and purified by ammonium sulfate precipitation and cation exchange chromatography. C57BL/6 mice were exposed to 75% oxygen from postnatal day (P)7 to P12 and then returned to room air. Mice received intravitreal injections of 2 microg PEDF in one eye and vehicle in the contralateral eye on P12 and P14. At P17, mice were killed and eyes enucleated for quantitation of retinal neovascularization. The mitogenic and motogeneic effects of VEGF on cultured bovine retinal and adrenal capillary endothelial cells were examined in the presence or absence of PEDF, using cell counts and migration assays. RESULTS: Two species of human recombinant PEDF, denoted A and B, were purified to apparent homogeneity. PEDF B appeared to comigrate on SDS-PAGE with PEDF from human vitreous samples. Changes in electrophoretic mobility after peptide-N-glycosidase F (PNGase F) digestion suggest that both PEDF forms contain N-linked carbohydrate. Analyses of the intact proteins by liquid chromatography-electrospray mass spectrometry (LC-ESMS) revealed the major molecular weight species for PEDF A (47,705 +/- 4) and B (46,757 +/- 5). LC-ESMS analysis of tryptic peptides indicated that PEDF A and B exhibit differences in glycopeptides containing N-acetylneuraminic acid (NeuAc) and N-acetylhexosamine (HexNAc). Intravitreal administration of either species of PEDF significantly inhibited retinal neovascularization (83% for PEDF A and 55% for PEDF B; P = 0.024 and 0.0026, respectively). PEDF A and B (20 nM) suppressed VEGF-induced retinal microvascular endothelial cell proliferation by 48.8% and 41.4%, respectively, after 5 days (P < 0.001) and VEGF-induced migration by 86.5% +/- 16.7% and 78.1% +/- 22.3%, respectively, after 4 hours (P = 0.004 and P = 0.008, respectively). CONCLUSIONS: These data indicate that elevated concentrations of PEDF inhibit VEGF-induced retinal endothelial cell growth and migration and retinal neovascularization. These findings suggest that localized administration of PEDF may be an effective approach for the treatment of ischemia-induced retinal neovascular disorders.

Pituitary adenomas in adolescent patients with multiple endocrine neoplasia type 1.

Two juvenile patients with multiple endocrine neoplasia type 1 (MEN1) who developed pituitary adenomas are reported. The first case, a 14-year-old girl, developed prolactinoma and manifested delayed puberty and growth arrest. The second case, a 16-year-old boy, was asymptomatic and a pituitary adenoma accompanied by mild elevation of PRL and GH was identified through family screening. His growth and pubertal development was not impaired. Medication with bromocriptine was started for both cases with good therapeutic responses. These cases emphasize relevance of early screening of endocrine disorders for members of families with MEN1.