Norimasa Sagawa

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.

Mechanism and clinical significance of elevated CA 125 levels in the sera of pregnant women

To clarify the mechanism of CA 125 elevation in maternal sera, serum levels of CA 125 and CA 19-9 were measured in 122 apparently healthy pregnant women (fifth to fortieth week of gestation) and 50 postpartum women (26 term deliveries and 24 second-trimester induced abortions). Serum levels of CA 125 showed an initial increase by the tenth week and then decreased to less than 35 U/ml, remaining below this level until delivery. However, within 1 hour after term delivery or second-trimester induced abortion, the CA 125 levels showed a second increase and decreased rapidly thereafter. In contrast, serum levels of CA 19-9 did not change significantly during these periods. Combined with our previous finding that the decidua contains abundant CA 125 but little CA 19-9, these results indicate that the elevated CA 125 levels in maternal sera originate from the decidual cells affected by chorionic invasion or the placental separation.

Umbilical vein-artery differences of plasma amino acids in the last trimester of human pregnancy.

The plasma levels of 20 free amino acids in the umbilical veins and umbilical arteries of 8 premature (29--36 weeks gestation) and 16 mature (38--42 weeks gestation) newborn infants were measured at delivery. In premature newborn infants, most of the 20 amino acids were significantly higher in the umbilical vein than in the umbilical artery. Only glutamic acid was significantly lower in the umbilical vein than in the umbilical artery. In mature newborn infants, 7 (Ala, Lys, Leu, Val, Ile, Phe and His) of the 20 plasma amino acids were significantly higher and 4 (Glu, Gly, Ser and Orn) were significantly lower in the umbilical vein than in the umbilical artery. These results indicate that the relative contribution of individual amino acids to the placental supply of nitrogen to the human fetus discernibly changes with increasing fetal age during the last trimester of gestation.

Changes in the Serum Levels of Human Chorionic Gonadotropin and the Pulsatility Index of Uterine Arteries during Conservative Management of Retained Adherent Placenta

Objective: Our purpose was to assess the natural course of retained adherent placenta at term.

Immunohistochemical localization and tissue levels of tumor-associated glycoproteins CA 125 and CA 19-9 in the decidua and fetal membranes at various gestational ages.

To investigate the sources and biologic significance of CA 125 and CA 19-9 in amniotic fluid, immunohistochemical and biochemical localization of these tumor-associated glycoproteins in the decidua and fetal membranes was studied. Immunohistochemically, CA 125 and CA 19-9 were localized in the cytoplasm of decidua cells and amnion epithelial cells but not in the chorion and placental tissue. Biochemically, the 12,000 X g supernatant fractions of decidua and amnion tissues contained relatively large amounts of CA 125 and CA 19-9, 73% to 96% of which was present in the cytosolic fractions of these tissues. The CA 125 levels in the amniotic fluid decreased, whereas those of CA 19-9 increased with gestation, which correlated well with the respective levels in amnion tissues. These findings suggest that amnion cells produce and secrete these glycoproteins into the amniotic cavity. However, it is possible that the decidua also secretes CA 125 into the amniotic cavity through the chorion and amnion such as in the case of prolactin.

Analysis of the levels of CA125, carcinoembryonic antigen, and CA19-9 in the cervical mucus for a detection of cervical adenocarcinoma

To verify whether analysis of the levels of CA125, carcinoembryonic antigen (CEA), and CA19‐9 in the cervical mucus is effective for a detection of cervical adenocarcinomas or not, simultaneous measurement of these three tumor markers in the cervical mucus samples from women without gynecologic disorders, with leiomyoma, with cervical squamous cell carcinomas, and with cervical adenocarcinomas was performed. Extremely high levels of CA125 with low levels of both CEA and CA19‐9 were demonstrated in the cervical mucus samples from women without gynecologic disorders and with leiomyoma. The cervical mucus samples from cervical adenocarcinomas showed low CA125 levels with extremely high CEA and/or CA19‐9 levels. Therefore, analysis of the levels of these three tumor markers in the cervical mucus possibly helps in the diagnosis of cervical adenocarcinomas if CEA and/or CA19‐9 show extremely high levels. When a ratio of (CEA + CA19–9)/CA125 was calculated, all women without gynecologic disorders and with leiomyoma showed a ratio <0.5, whereas ten of 11 cases of cervical adenocarcinomas had a ratio ≥0.5. Only one case of microinvasive adenocarcinoma showed a ratio <0.5. Accordingly, the ratio ≥0.5 strongly suggested an existence of cervical adenocarcinoma, although it included some cases of squamous cell carcinomas (four of 17 cases).

Severe congenital cytomegalovirus infection with fetal hydrops in a cytomegalovirus-seropositive healthy woman

We report the case of a woman whose two consecutive pregnancies resulted in intrauterine fetal death due to severe congenital cytomegalovirus infection. In both pregnancies, congenital cytomegalovirus infection was prenatally diagnosed on the basis of detection of cytomegalovirus DNA and specific IgM in cord blood. This case suggests that severe congenital cytomegalovirus infection can occur even in seropositive healthy women.

Role of sex steroid hormones in relative refractoriness to angiotensin II during pregnancy

Normal human pregnancy is associated with significant vascular refractoriness to the pressor effects of infused angiotensin II, and in women destined to develop pregnancy-induced hypertension, this refractoriness is lost several weeks before the onset of hypertension. The plasma concentrations of sex steroid hormones gradually increase throughout pregnancy. In the present study, the effect of infusion of 17 beta-estradiol (E2), progesterone, or 5 alpha-dihydroprogesterone on the pressor response to infused angiotensin II (0.002 to 0.1 micrograms X min-1 X kg-1) was evaluated in eight unanesthetized and chronically instrumented nonpregnant ewes. Pressor response to infused angiotensin II (0.02 to 0.1 micrograms X min-1 X kg-1) was significantly suppressed by a 60-minute infusion of E2 (0.8 micrograms X kg-1), whereas infusion of progesterone (4 micrograms X min-1 X kg-1) or 5 alpha-dihydroprogesterone (0.8 micrograms X min-1 X kg-1) did not affect the pressor response. Neither the acid-base status, plasma renin activity, nor serum electrolytes were altered by the administration of E2 or progesterone. These results indicate that E2 may play an important role in the refractoriness to infused angiotensin II during pregnancy, and that this refractoriness by E2 is not mediated by changes in chemoreceptor reflex, renin-angiotensin system, or serum electrolytes, but more likely by the changes in the characteristics of the vascular wall.

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.