Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model.

Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.

Effect of intraperitoneal docetaxel on ovarian function in mice.

Taxanes are important chemotherapeutic agents used to manage breast cancer and gynaecological malignancies. However, ovarian toxicity induced by the taxane docetaxel (DOC) is of great concern. We investigated DOC-induced toxicity in the ovaries of female CD1 strain mice. The mice were divided into control (saline), DOC-5 (5 mg/kg DOC), and DOC-10 (10 mg/kg DOC) groups and administered saline or DOC on the first day of the study and two weeks later. Two weeks after the second dose, the ovaries were removed for analysis after inducing superovulation. Ovary weight, the number of secondary follicles, and the total number of follicles were reduced after DOC administration. Additionally, the expression levels of caspase-3 and the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) increased. Our findings suggest that high-dose DOC induces damage to growing follicles; however, it may not affect primordial follicles.Impact statementWhat is already known on this subject? Docetaxel (DOC) is one of the most effective chemotherapeutic agents used to manage various cancers. Some in-vitro studies have examined paclitaxel-induced ovarian toxicity; however, limited research on DOC is available.What do the results of this study add? We investigated DOC-induced ovarian toxicity in female CD1 strain mice at 5 mg/kg and 10 mg/kg. We found that DOC reduced ovary weight, the number of secondary follicles, and the total number of follicles, with the higher dose having a higher effect.What are the implications of these findings for clinical practice and/or further research? We believe that our study makes a significant contribution to the knowledge about the effect of DOC on ovarian function.

Effects of peripheral oxytocin administration on body weight, food intake, adipocytes, and biochemical parameters in peri- and postmenopausal female rats.

Recent studies have revealed that the administration of oxytocin has beneficial effects on the regulation of body weight, food intake, and metabolic functions, especially in obese individuals. Obesity is common in women after the menopause and drives many components of metabolic syndrome. Weight gain in menopausal women has been frequently reported. Although obesity and associated metabolic disorders are frequently observed in peri- and postmenopausal women, there are few medical interventions for these conditions. In this study, we evaluated the effects of chronic oxytocin administration on appetite, body weight, and fat mass in peri- and postmenopausal female rats. Sixteen naturally premenopausal or menopausal rats were intraperitoneally injected with oxytocin (1,000 µg/day) for 12 days. The daily changes in their body weight and food intake were measured at the same time as the oxytocin and vehicle injections. Intraperitoneally administering oxytocin for 12 days significantly reduced food intake, body weight, and visceral adipocyte size. In addition, oxytocin administration caused reductions in serum triglyceride and low-density lipoprotein-cholesterol levels, while it did not disturb hepatic or renal functions or locomotor activity. This is the first study to show the effects of oxytocin on the metabolic and feeding functions of peri- and postmenopausal female rats. Oxytocin might be a useful treatment for metabolic disorders caused by the menopause or aging.

Mental stress promotes the proliferation of endometriotic lesions in mice.

Endometriosis is a condition in which tissue similar to the womb lining begins to grow in other sites, such as the ovaries or fallopian tubes. Endometriosis can cause pelvic pain, adhesion formation, and infertility. Here, we investigated the relationship between deterioration of endometriosis and inflammation of intraperitoneal adipose tissue in mice. We created a mouse model of endometriosis, then subjected these mice to stress loading. In the experimental mice, we measured protein expression levels of prostaglandin-E2, monocyte chemoattractant protein-1, and tumor necrosis factor-α using ELISA kits. We used quantitative real-time polymerase chain reaction to measure mRNA expression levels of inflammation-related enzymes and cytokines in lesions and adipose tissues. This study sugest that endometriotic lesions may progress in the presence of psychological stress in the presence of endometriosis. In addition, inflammation of the adipose tissue around the uterus may be involved in the development of endometriosis. However, this needs further consideration. Reducing or avoiding stress as much as possible may prevent the progression of endometriosis.

Circulating dehydroepiandrosterone-sulphate decreases even with a slight change in oestradiol.

The aim of this study was to determine the effect of hormone replacement therapy (HRT) on changes in circulating dehydroepiandrosterone-sulphate (DHEA-S) with focus on the relationship between oestrogen level and change in DHEA-S. Forty-two women were enrolled in this longitudinal study. Nineteen women received oral oestradiol and twenty-three women received transdermal oestradiol continuously. Twenty women received progesterone continuously except for women who had undergone hysterectomy. Circulating oestradiol, follicle-stimulating hormone, luteinising hormone and DHEA-S levels before and at 3 months after commencement of HRT were measured. Circulating DHEA-S level was significantly decreased at 3 months (p < .001). Oestradiol level at 3 months ranged from 6.5 pg/ml to 159 pg/ml. There was no significant correlation of ΔDHEA-S (DHEAS level at 3 months-DHEA-S level at baseline) with Δoestradiol (r = 0.114, p = .471). Circulating DHEA-S level was significantly decreased at 3 months in all the four quartiles and divided according to Δoestradiol, and ΔDHEA-S did not show significant differences. In conclusion, circulating DHEA-S decreases even with a slight increase in oestradiol level. Impact statement What is already known on this subject: A transient increase in DHEA-S in women during the menopausal transition may be involved in the occurrence of menopausal symptoms and/or unfavourable metabolic changes. Hormone replacement therapy decreases circulating DHEA-S level. However, dose dependency of the change in DHEA-S on oestrogen has not been reported. What the results of this study add: Circulating DHEA-S decreases even with a slight increase in oestradiol level. What the implications are of these findings for clinical practice and/or further research: Adrenal function may respond to a small change in oestrogen.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 µg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 µg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

Changes of liver enzymes and triglyceride during the menopausal transition in Japanese women.

We examined detailed changes in liver enzymes as surrogate markers for metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) during the menopausal transition and the associations of liver enzymes with lipid profiles related to risk of metabolic syndrome and endocrinological hormones. We divided 393 women into seven stages by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of alanine aminotranferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, lipid parameters, glucose, and endocrinological hormones were measured. Both levels of AST and ALT increased towards early post-menopause. AST remained high in late post-menopause but ALT decreased. The AST/ALT ratio decreased towards late menopausal transition and very early post-menopause and increased thereafter. This ratio was negatively correlated with triglyceride. Significant changes in ALT and AST/ALT ratio during the menopausal transition, which were associated with triglyceride, might be involved in the occurrence of metabolic syndrome and NAFLD in Japanese women.

Association between early-term birth and hypoglycaemia in large-for-gestational-age neonates:A retrospective cohort study.

BACKGROUND: The effect of early-term birth on the development of hypoglycaemia in large-for-gestational-age (LGA) neonates is yet to be clarified. This study aimed to clarify the association between hypoglycaemia and early-term birth in LGA neonates. METHODS: This single-centre retrospective cohort study evaluated LGA neonates born at term at Tsurugi Municipal Handa Hospital, Japan. Blood glucose levels were measured immediately and at 1, 2, and 4 hours after birth. The association between early-term birth and hypoglycaemia was evaluated using logistic regression analysis. The prevalence of severe hypoglycaemia and hypoglycaemia according to its timing of development was analysed using Fisher's exact test. RESULTS: In total, 295 neonates were included. Among them, 113 neonates (38.3%) were born at early term and 91 infants (30.8%) had hypoglycaemia. Logistic regression analysis showed a significant association between early-term birth and hypoglycaemia (adjusted odds ratio [95% confidence interval]:2.691 [1.597 to 4.535]). However, there was no significant between-group difference among those with severe hypoglycaemia. CONCLUSIONS: Among LGA neonates, early-term birth is positively associated with neonatal hypoglycaemia. This indicates that among LGA neonates, those born at early term require more careful observation for hypoglycaemia than do those born at later term. J. Med. Invest. 70 : 476-482, August, 2023.

Intraperitoneal administration of activin A promotes development of endometriotic lesions in a mouse model of endometriosis.

PURPOSE: This study aimed to investigate the effect of intraperitoneal administration of activin on the occurrence of endometriosis using a mouse model of endometriosis. METHODS: A mouse model of endometriosis was prepared by intraperitoneally administering endometrial tissue and blood collected from donor mice to C57BL/6J 7-8- week-old recipient mice. A total of 400 µg of activin A was intraperitoneally administered to model mice in the activin group for 5 days. Intraperitoneal endometriotic lesions were confirmed macroscopically and IL-6 and TNF-α levels in washed ascites were measured by ELISA. RESULTS: Endometriotic lesions were observed in all mice. In the activin group, the maximum diameter of endometriotic lesions was significantly larger than that in control group (4.7?1.3 vs 2.9?0.9 mm, p?0.01). The total area of the lesion was also significantly higher in the activin group than in the control group (21.1?9.9 vs 8.8?5.4 mm2,p?0.01). Furthermore, IL-6 and TNF-α levels in ascites were significantly higher in the activin group than in the control group (IL-6 : 85.8?15.3 vs 75.1?19.3 pg/ml, p?0.05 ; TNF-α : 629.8?15.4 vs 605.9?11.4 pg/ml, p?0.05). CONCLUSION: Activin promotes occurrence of endometriosis. Inflammatory cytokines are also elevated by activin administration,suggesting that they may contribute to progression of endometriosis J. Med. Invest. 66 : 123-127, February, 2019.

Lipopolysaccharide promotes early endometrial-peritoneal interactions in a mouse model of endometriosis.

PURPOSE: The aims of this study were to clarify the effects of lipopolysaccharide (LPS) on the early development of endometriosis and on the production of cytokines and chemokines in the murine peritoneal cavity. METHODS: Endometriotic lesions were induced in C57BL/6J adult female mice by intraperitoneal injection of endometrial fragments plus blood or endometrial fragments plus blood with LPS. On day 7, endometriotic lesions were assessed by gross and microscopic evaluations. Time-dependent changes in the secretion of TNF-α,IL-6,and CXCL2/MIP-2 in peritoneal lavage fluid after the intraperitoneal injection of LPS (50 µg/body) were measured by their respective enzyme-linked immunosorbent assays. RESULTS: The areas of endometriotic lesions in the LPS group (10.8 8.6 mm2) were significantly larger than those in the control group (3.1 3.7 mm2).The levels of TNF-α and IL-6 peaked within 2 hours and the level of MIP-2 reached a maximum on day 1 after the injection of LPS. CONCLUSIONS: LPS promotes development of the early stages of murine endometriotic lesions. J. Med. Invest. 66 : 70-74, February, 2019.

Increase in circulating sclerostin at the early stage of menopausal transition in Japanese women.

OBJECTIVE: We examined the change in circulating sclerostin level during the menopausal transition and we investigated the associations of sclerositin with hormones and bone turnover markers according to each menopausal stage in cross-sectional and longitudinal studies. METHODS: We conducted a cross-sectional study in 200 healthy Japanese women and divided them into 4 stages (reproductive, menopausal transition, early postmenopause and late postmenopause) by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of sclerostin, bone turnover markers and reproductive hormones were measured. In addition, we examined changes in sclerostin level from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in a longitudinal study. RESULTS: In the cross-sectional study, sclerostin level gradually increased with progression of menopausal stages and showed a significant change during the menopausal transition. Sclerostin levels significantly increased from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in the longitudinal study. A negative correlation of sclerostin with estradiol was found in early postmenopause. Sclerostin levels were negatively correlated with bone-specific alkaline phosphatase levels in the reproductive stage and menopausal transition and with tartrate-resistant acid phosphatase-5b in menopausal transition. CONCLUSION: The change in sclerostin has already occurred in the early stage of menopausal transition and sclerostin level increases with progression of menopausal stages. Elevated sclerostin levels during the menopausal transition may be involved in relative decline in bone formation against increase in bone resorption.

A case of pregnancy complicated with congenital dysprothrombinemia (prothrombin Tokushima).

We present the course of pregnancy and delivery in a patient with congenital dysprothrombinemia. The patient is a 29-year-old nulliparous woman. She was diagnosed with dysprothrombinemia at 10 years of ag. Her course of pregnancy was uneventful. She delivered after prophylactic lyophilized human blood coagulation factor IX complex 800 U was administered. The plasma prothrombin activity was at 24.0% of normal plasma clotting activity. Her postpartum course was uneventful. After 6 years, her course of pregnancy was the same as before. Prophylactic lyophilized human blood coagulation factor IX complex 800 U was administered. Her plasma prothrombin activity was at 26.7%, and she underwent an induced delivery. Her postpartum course was uneventful. It is beneficial to use prophylactic lyophilized human blood coagulation factor IX complex 800 U in pregnancies that are complicated by dysprothrombinemia. The goal of therapy is to maintain prothrombin levels at above 20%.