Shigeo Yura

Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin

Excess or loss of body fat can be associated with infertility, suggesting that adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedly increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-deficient ob/ob mice. These findings suggest a role for leptin as an endocrine signal between fat depots and the reproductive axis, but the effect of hyperleptinemia on the initiation and maintenance of reproductive function has not been elucidated. To address this issue, we examined the reproductive phenotypes of female transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. With no apparent adipose tissue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterized by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonadotropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are associated with chronic hyperleptinemia, thereby leading to a better understanding of the pathophysiological and therapeutic implication of leptin.

A positive umbilical venous-arterial difference of leptin level and its rapid decline after birth☆☆☆★★★

OBJECTIVE We investigated the site of leptin production in the fetoplacental circulation. STUDY DESIGN We simultaneously determined plasma leptin levels in cord vessels and maternal peripheral veins of 38 healthy pregnant women. We also compared plasma leptin levels in 20 neonates at birth and on the fifth day after birth. RESULTS Leptin levels in cord vessels were significantly (p < 0.001) lower than those in maternal veins (mean 29.5 ng/ml). Leptin levels in umbilical arteries (mean 9.8 ng/ml) were significantly (p < 0.01) lower than those in umbilical veins (mean 12.9 ng/ml). Leptin levels in neonatal veins on the fifth day (mean 3.0 ng/ml) were markedly (p < 0.001) lower than those in umbilical arteries of the same neonates (mean 10.9 ng/ml). CONCLUSION The higher leptin levels in umbilical veins than in umbilical arteries and the marked decrease during the neonatal period suggest that the placenta is one of the major sources of leptin in the fetal circulation.

Clinical value of FDG-PET in the follow up of post-operative patients with endometrial cancer

Objective: The clinical usefulness of FDG-PET in the follow up of post-operative patients with endometrial cancer was retrospectively evaluated.Methods: Twenty-one post-operative patients with endometrial cancer received 30 FDG-PET examinations to evaluate recurrence or response to treatment. The findings of FDG-PET were compared with their serum levels of tumor markers, CT and/or MRI findings, and the final outcome. Results of FDG-PET were also correlated with the clinical course of each patient.Results: In detecting recurrent lesions and evaluating treatment responses, FDG-PET, with the help in anatomic information by CT/MRI, showed better diagnostic ability (sensitivity 100.0%, specificity 88.2%, accuracy 93.3%) compared with combined conventional imaging (sensitivity 84.6%, specificity 85.7%, accuracy 85.0%) and tumor markers (sensitivity 100.0%, specificity 70.6%, accuracy 83.3%). FDG-PET had no false-negative results, suggesting the possibility of its use as the first-line examination in a patient’s follow-up. FDG-PET could detect unknown lesions in 4 cases, and, as reported for other malignancies, FDG-PET affected the patient management in one-third of the cases. Furthermore, the results of FDG-PET correlated well with the clinical outcome of the patients, with patients with negative PET results tending to show disease-free courses.Conclusions: These results suggest that, despite the limited number of patients studied, FDG-PET was accurate in detecting recurrence and evaluating therapeutic response, and could afford important information in the management of post-operative patients with endometrial cancer. FDG-PET also appeared to have a possibility to predict the outcome of each patient.

Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors

Neurotrophin (NT) is important in the survival, maintenance and differentiation of neuronal tissue, and functions in follicle maturation, tumor growth, angiogenesis and immunomodulation; however, the expression of NT and its receptors (NTR) in human placenta and their influence on fetal growth are unclear. Here we investigated the correlation of NT and NTR in human placenta with uterine environment and fetal growth. TrkB, a NTR, mRNA was expressed on decidual and villous tissue and increased with gestational age, localizing in the trophoblast layer and endothelium by immunohistochemistry. Villous TrkB mRNA was significantly increased in preeclampsia (PE) than in controls and was higher in the normotensive small for gestational age (SGA) placenta, although it was not significant. It was also significantly increased in the small twin of discordant twin pregnancies. Brain-derived neurotrophic factor (BDNF), the main ligand of TrkB, was expressed in membranous chorion and villous tissue and was significantly higher in maternal plasma in normotensive SGA and PE than in controls. TrkB mRNA expression was up-regulated on cultured villous tissue explants and on JEG-3, a choriocarcinoma cell line, by H(2)O(2) treatment. BDNF decreased apoptotic cells in H(2)O(2)-treated JEG-3, indicating that BDNF/TrkB signaling had anti-apoptotic effects against oxidative stress in JEG-3, suggesting a protective role of BDNF/TrkB in human villous tissue under unfavorable conditions in utero.

Neonatal Exposure to Leptin Augments Diet‐induced Obesity in Leptin‐deficient Ob/Ob Mice

Objective: Epidemiological evidence has revealed that undernutrition in utero is closely associated with obesity and related detrimental metabolic sequelae in adulthood. Recently, using a wild‐type (wt) mouse model in which offspring were exposed to intrauterine undernutrition (UN offspring), we reported that the premature leptin surge during neonatal growth promotes lifelong changes in energy regulating circuitry in the hypothalamus, thus playing an important role in the development of pronounced obesity on a high‐fat diet (HFD) in adulthood. Here, we further evaluate the essential involvement of leptin in the developmental origins of obesity using leptin‐deficient ob/ob mice.

Site-Specific Augmentation of Amnion Cyclooxygenase-2 and Decidua Vera Phospholipase-A2 Expression in Labor: Possible Contribution of Mechanical Stretch and Interleukin-1 to Amnion Prostaglandin Synthesis

Objective: To investigate a possible site-specific augmentation of prostaglandin (PG) synthesis in the fetal membranes during labor. Methods: We used reverse transcriptase-polymerase chain reaction or Western blot analysis to evaluate the expression of cytosolic phopholipase A2 (cPLA2) and cyclooxygenase-1, -2 (COX-1, -2), in both the upper and lower parts of the amnion, chorion laeve, and decidua vera tissues from term pregnant women before (n = 8) and after labor (n = 24). Prostaglandin E2 (PGE2) secretion from amnion-derived WISH cells was assessed using enzyme-linked immunosorbent assay after stimulation by cyclic mechanical stretching and interleukin-1 (IL-1). Results: The expression of cPLA2 and COX-1 and COX-2 mRNAs was detected in all samples examined. Western blot analysis revealed that COX-2 expression in the upper part of the amnion, chorion laeve, and decidua vera tissues after labor was 4.7-, 4.9-, and 3.7-fold higher than that before labor, respectively (P < .05 for all). The cPLA2 protein expression in the upper part of the amnion and chorion laeve tissues after labor was 14.0- and 8.8-fold higher than that before labor, respectively (P < .05 for both). Moreover, in specimens obtained after labor, the amnion COX-2 expression and the decidua vera cPLA2 expression in the lower part of the fetal membrane was 1.9- and 2.6-fold higher than the respective levels in the upper part (P < .05 for both). In an in vitor study, cyclic mechanical stretching significantly enhanced IL-1-augmented PGE2 secretion from WISH cells. Conclusion: In the lower part of the amnion and decidua vera tissues, adjacent to the dilating cervical canal, PG synthesis was upregulated site specifically after labor. Such enhancement of amnion PG synthesis might be regulated at least partly by IL-1 and cyclic distension.

T1 Signal Intensity and Height of the Anterior Pituitary in Neonates: Correlation with Postnatal Time

BACKGROUND AND PURPOSE: The anterior pituitary of a term neonate is usually hyperintense on T1-weighted MR images, which may represent histologic changes of the gland due to the effect of high estrogen levels during the fetal period; however, MR findings of a preterm neonate have not been fully evaluated. The purpose of this study was to investigate whether intensity and size of the neonatal anterior pituitary on MR images obtained near term of corrected age correlates with the gestational age at birth or postnatal time. MATERIALS AND METHODS: Data of 88 consecutive neonates (gestational age, 24–41 weeks; mean, 31.5 weeks) were analyzed. All of the neonates underwent MR imaging at a corrected age of 0 months ± 4 weeks. Relative signal intensity of the anterior pituitary compared with that of the pons on T1-weighted sagittal images was calculated. Height of the pituitary was also measured. Stepwise regression analysis was performed to evaluate the effects of gestational age at birth and postnatal time on the relative signal intensity and on the pituitary height. RESULTS: The relative signal intensity significantly negatively correlated with postnatal time (P = .001) but not with gestational age at birth (P = .42). Pituitary height significantly negatively correlated with postnatal time (P = .049) but not with gestational age at birth (P = .071). CONCLUSION: A significant negative correlation exists between postnatal time and signal intensity on T1-weighted MR images of the anterior pituitary obtained near term. A nonhyperintense anterior pituitary is a normal MR finding of preterm neonates when imaged near term.

17β-Estradiol Up-Regulates Prostacyclin Production in Cultured Human Uterine Myometrial Cells Via Augmentation of Both Cyclooxygenase-1 and Prostacyclin Synthase Expression

Objective: To investigate whether 17β-estradiol elevates prostacyclin (PGI2) production in human myometrial cells in the middle of gestation. Methods: The concentration of 6-keto-PGF1α, a stable metabolite of PGI2, in the culture medium was assessed using enzyme-linked immunosorbent assay (ELISA). Western blot analysis and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) using TaqMan (Applied Biosystems, Foster City, CA) technology were performed to evaluate the expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-1 (COX-1), COX-2, and prostacyclin synthase (PGIS) in cultured human myometrial cells prepared from second trimester pregnant women (n = 3) after stimulation with 17β-estradiol. Results: Treatment with 17β-estradiol (4-400 nM) dose-dependently elevated PGI2 secretion from cultured human myometrial cells. Western blot analysis detected cPLA2 and COX-1 and PGIS protein expression in the cultured human myometrial cells; however, COX-2 protein expression was below the detection sensitivity. Stimulation with 40-nM 17β-estradiol significantly up-regulated protein and mRNA expression of both COX-1 and PGIS. Conclusion: 17βEstradiol from placenta may contribute to the augmentation of PGI2 production in the human myometrium in the middle of gestation via up-regulation of both COX-1 and PGIS expression.

A case of successful management of maternal septic shock with multiple organ failure following amniocentesis at midgestation

Maternal sepsis is an unusual but catastrophic complication of amniocentesis. We report a case of successful treatment of maternal septic shock and multiple organ failure following amniocentesis at midgestation, possibly due to needle puncture of the sigmoid colon, which was tightly adherent to the anterior surface of the pregnant uterus.

Neonatal exposure to leptin reduces glucose tolerance in adult mice.

Aim:  The aim of this study was to evaluate the effect of leptin treatment in mouse neonates on glucose metabolism in adulthood.