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Permanent reduction in heart and kidney organ growth in offspring of undernourished rat dams
SMFM Abstracts S131 452
COMPENSATORY MATERNAL HYPERALDOSTERONISM IN SEVERE TWIN-TO-TWIN TRANSFUSION SYNDROME CORRECTED AFTER LASER COAGULATION OF CHORIONIC PLATE ANASTOMOSES AND AMNIOREDUCTION ILINCA GUSSI1, JACKY NIZARD1, LYDIA MALAGRIDA2, MASSAMI YAMAMOTO1, ROMAINE ROBYR1, YVES VILLE1, 1University of Versailles Saint-Quentin-en-Yvelines, Department of Obstetrics and Gynecology, Poissy, France, 2University of Versailles SaintQuentin-en-Yvelines, Department of Biology, Poissy, France OBJECTIVE: To observe changes in the renin-angiotensin-aldosterone system following the treatment of twin-to-twin transfusion syndrome (TTTS). STUDY DESIGN: Twenty consecutive cases of monochorionic diamniotic pregnancies complicated by severe TTTS at 20–28 weeks of gestation were investigated prospectively. Patients were treated by placental surgery followed by amnioreduction. Tocolysis consisted of one dose of 100 mg intrarectal indomethacin. Maternal venous blood was collected before, 6 and 12-24 hours after surgery. Aldosterone, renin, angiotensine II, ANP and vasopressin were measured by RIA. Simultaneous full blood count and ionograms were performed. Results are expressed as mean G SEM, range intervals as 25 and 75 percentiles. Wilcoxon test was used for statistical analysis. RESULTS: Twenty patients were investigated at 21.5 G 1 weeks with severe TTTS. The mean amniotic fluid volume drained was 1500 G 175 mL. Within 12 hours of treatment, hemoglobin levels decreased by a mean of 1.2 g/dL (0.4–1.6), and this was not explained by perioperative complications. Plasma sodium and potassium levels remained stable and there was maternal hyperaldosteronism, with a mean aldosterone level of 1131.6 G 206 pg/mL (337-1732) for a normal range !355 pg/mL. Aldosterone levels decreased 12 hours after laser and amnioreduction (P = .023). ANP increased as early as 6 hours following amnioreduction (P = .025). Mean renin and angiotensin II levels did not decrease significantly following treatment (P > .05). Vasopressin levels remained within normal ranges (!8 pg/ml) following amnioreduction. CONCLUSION: Marked maternal hyperaldosteronism in TTTS is rapidly corrected following amnioreduction showing that rapid and efficient maternal hormonal adaptive mechanisms succeed in maintaining sodium balance and subsequent volemic homeostasis.
454
LOCALIZATION OF CONTRACTILE PROSTAGLANDIN E2 RECEPTORS IN RAT CERVICAL TISSUE ANDREA HINTON1, PETA GRIGSBY1, BRAD PITZER1, DIANE BROCKMAN1, LESLIE MYATT1, 1University of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio OBJECTIVE: Preterm labor remains a significant problem in obstetrics. Application of progesterone is emerging as a preventative measure for preterm labor, although the mechanism of action remains unclear. Prostaglandin E2 (PGE2) plays a role in cervical ripening and is mediated by changes in the relaxatory and contractile PGE2 receptors. We hypothesize that cervical PGE2 receptors are hormonally regulated by progesterone throughout gestation and labor. The purpose of our study was to investigate the localization of the contractile PGE2 receptors (EP1 and EP3) in the rat cervix during RU486induced labor and progesterone treatment. STUDY DESIGN: Pregnant rats received either RU486 (10 mg/kg, IP; n = 5) or vehicle on day 16 of gestation. Animals were euthanized on day 18 of gestation. A second group received progesterone (2.5 mg/day, IP; n = 18) or vehicle. Animals were sacrificed on days 21, 22, and 23 of gestation (treated; n = 6, vehicle; n = 5, respectively). Cervical tissue was collected and sectioned (8mm) for immunostaining using anti-human EP1 and EP3 polyclonal antibodies. Slides were evaluated for receptor localization and intensity of staining as a reflection of the number of receptors. RESULTS: EP1 receptors were not present in cervical smooth muscle in RU486-treated or control animals, but were localized to the cervical smooth muscle in progesterone-treated and control animals. In contrast, EP3 receptors were localized to the smooth muscle cells in all animal groups. The RU486induced labor increased EP1 and EP3 expression throughout all layers of the cervical epithelium, whereas EP1 and EP3 receptors were present only in the apical layer of the epithelium in both the progesterone-treated and control animals. Progesterone treatment decreased EP1 and EP3 expression when compared to control animals. CONCLUSION: Progesterone appears to differentially regulate expression of contractile EP receptors in the cervix. Understanding the hormonal regulation of the PGE2 receptors in the cervix is important in developing improved management of preterm labor.
453
PERMANENT REDUCTION IN HEART AND KIDNEY ORGAN GROWTH IN OFFSPRING OF UNDERNOURISHED RAT DAMS MINA DESAI1, DAVE GAYLE1, JOOBY BABU1, EDITH ORNELAS1, MICHAEL ROSS1, 1Harbor-UCLA Med. Ctr., Dept. of OB/ GYN (LA BioMed), Torrance, California OBJECTIVE: Epidemiological studies have linked fetal growth retardation (IUGR) to increased risk of cardiovascular disease, hypertension and obesity. IUGR effects may result from undernutrition at critical development periods causing reduction in organ growth and permanent changes in their metabolism and/or structure. We investigated the effects of maternal food restriction during pregnancy and/or lactation on adult offspring body and organ growth. STUDY DESIGN: From day 10 to term gestation and through day 21 of lactation, control pregnant Sprague Dawley rats received ad libitum (AdLib; n = 12) food, whereas study rats were 50% food-restricted (FR; n = 12). At birth, litter size was culled to 4 males and 4 females. Half of the control and FR mothers (n = 6) continued to nurse their own pups, whereas the other half (n = 6), were cross-fostered to determine effects of FR during pregnancy or lactation periods. Thus 4 groups were studied: (1) AdLib/AdLib; (2) FR/AdLib; (3) AdLib/FR; (4) FR/FR. At day 21, offspring were weaned to ad libitum feed and body and organ weights (% of body weight) were measured at 9 months of age. RESULTS: FR during pregnancy (FR/AdLib) resulted in markedly heavier offspring (683 G 17 vs 608 G 15 g, P ! .001) with relatively decreased weights of heart (0.24 G 0.01 vs 0.29 G 0.02, P ! .01), kidney (0.63 G 0.01 vs 0.76 G 0.03, P ! .01), lung (0.28 G 0.01 vs 0.36 G 0.02, P ! .01) and brain (0.31 G 0.01 vs 0.35 G 0.01, P ! .01) as compared to controls (AdLib/AdLib). Conversely, FR during lactation (AdLib/FR) or combined periods (FR/FR) resulted in offspring with similar body weights as controls but with relatively decreased growth of heart and kidney. Males in the three study groups exhibited relatively smaller livers, whereas the females showed relatively smaller adrenal glands. CONCLUSION: Sex-dependent, selective and permanent changes in relative organ weight were observed depending upon the period of FR. The impact on heart and kidney growth suggests potential long term risks of adult hypertension and cardiovascular disease among IUGR newborns.
455
LOCALIZATION OF RELAXATORY PROSTAGLANDIN E2 RECEPTORS IN RAT CERVICAL TISSUE ANDREA HINTON1, PETA GRIGSBY1, BRAD PITZER1, DIANE BROCKMAN1, LESLIE MYATT1, 1University of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio OBJECTIVE: Despite advances in obstetric and neonatal care, preterm labor remains a significant problem. Prostaglandins (PG) play a central role in normal and preterm labor, stimulating uterine contractility and ripening the cervix. Cervical dilation, in part, is mediated by changes in the expression of the relaxatory and contractile PGE2 receptors during late gestation and labor. To investigate the regulation of these receptors in the cervix, we determined the localization of the relaxatory PGE2 receptors during RU486-induced labor and progesterone treatment. STUDY DESIGN: Pregnant rats were assigned to receive either RU486 (10 mg/ kg, IP; n = 5) or vehicle (0.3 mL, IP; n = 6) on day 16 of gestation. These animals were euthanized on day 18 of gestation. A second group was assigned to receive progesterone supplementation (2.5 mg/day, IP; n = 18) or vehicle (0.3 mL, IP; n = 15). These animals were sacrificed on day 21, 22, and 23 of gestation (treated: n = 6, vehicle: n = 5, respectively). Cervical tissue was collected and sectioned (8 mm) for immunostaining using anti-human EP2 and EP4 polyclonal antibodies. RESULTS: EP2 and EP4 receptors were localized to cervical smooth muscle and epithelial cells in all animal groups. RU486 treatment induced labor 48h after treatment and increased EP2 and EP4 protein expression in cervical smooth muscle and cervical epithelial cells. In the smooth muscle layer, progesterone treatment increased EP2 protein expression and decreased EP4 expression. In cervical epithelial cells, progesterone treatment enhanced EP4 receptor expression in late gestation when compared to matched controls, but did not increase expression of EP2. CONCLUSION: Progesterone appears to differentially regulate expression of relaxatory EP receptors in the different cell types of the cervix suggesting that these receptors are linked to different signaling pathways. This study may aid in our attempt to further understand the regulation of PGE2 receptors in the cervix, facilitating better approaches for the prevention and treatment of preterm labor.
COMPENSATORY MATERNAL HYPERALDOSTERONISM IN SEVERE TWIN-TO-TWIN TRANSFUSION SYNDROME CORRECTED AFTER LASER COAGULATION OF CHORIONIC PLATE ANASTOMOSES AND AMNIOREDUCTION ILINCA GUSSI1, JACKY NIZARD1, LYDIA MALAGRIDA2, MASSAMI YAMAMOTO1, ROMAINE ROBYR1, YVES VILLE1, 1University of Versailles Saint-Quentin-en-Yvelines, Department of Obstetrics and Gynecology, Poissy, France, 2University of Versailles SaintQuentin-en-Yvelines, Department of Biology, Poissy, France OBJECTIVE: To observe changes in the renin-angiotensin-aldosterone system following the treatment of twin-to-twin transfusion syndrome (TTTS). STUDY DESIGN: Twenty consecutive cases of monochorionic diamniotic pregnancies complicated by severe TTTS at 20–28 weeks of gestation were investigated prospectively. Patients were treated by placental surgery followed by amnioreduction. Tocolysis consisted of one dose of 100 mg intrarectal indomethacin. Maternal venous blood was collected before, 6 and 12-24 hours after surgery. Aldosterone, renin, angiotensine II, ANP and vasopressin were measured by RIA. Simultaneous full blood count and ionograms were performed. Results are expressed as mean G SEM, range intervals as 25 and 75 percentiles. Wilcoxon test was used for statistical analysis. RESULTS: Twenty patients were investigated at 21.5 G 1 weeks with severe TTTS. The mean amniotic fluid volume drained was 1500 G 175 mL. Within 12 hours of treatment, hemoglobin levels decreased by a mean of 1.2 g/dL (0.4–1.6), and this was not explained by perioperative complications. Plasma sodium and potassium levels remained stable and there was maternal hyperaldosteronism, with a mean aldosterone level of 1131.6 G 206 pg/mL (337-1732) for a normal range !355 pg/mL. Aldosterone levels decreased 12 hours after laser and amnioreduction (P = .023). ANP increased as early as 6 hours following amnioreduction (P = .025). Mean renin and angiotensin II levels did not decrease significantly following treatment (P > .05). Vasopressin levels remained within normal ranges (!8 pg/ml) following amnioreduction. CONCLUSION: Marked maternal hyperaldosteronism in TTTS is rapidly corrected following amnioreduction showing that rapid and efficient maternal hormonal adaptive mechanisms succeed in maintaining sodium balance and subsequent volemic homeostasis.
454
LOCALIZATION OF CONTRACTILE PROSTAGLANDIN E2 RECEPTORS IN RAT CERVICAL TISSUE ANDREA HINTON1, PETA GRIGSBY1, BRAD PITZER1, DIANE BROCKMAN1, LESLIE MYATT1, 1University of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio OBJECTIVE: Preterm labor remains a significant problem in obstetrics. Application of progesterone is emerging as a preventative measure for preterm labor, although the mechanism of action remains unclear. Prostaglandin E2 (PGE2) plays a role in cervical ripening and is mediated by changes in the relaxatory and contractile PGE2 receptors. We hypothesize that cervical PGE2 receptors are hormonally regulated by progesterone throughout gestation and labor. The purpose of our study was to investigate the localization of the contractile PGE2 receptors (EP1 and EP3) in the rat cervix during RU486induced labor and progesterone treatment. STUDY DESIGN: Pregnant rats received either RU486 (10 mg/kg, IP; n = 5) or vehicle on day 16 of gestation. Animals were euthanized on day 18 of gestation. A second group received progesterone (2.5 mg/day, IP; n = 18) or vehicle. Animals were sacrificed on days 21, 22, and 23 of gestation (treated; n = 6, vehicle; n = 5, respectively). Cervical tissue was collected and sectioned (8mm) for immunostaining using anti-human EP1 and EP3 polyclonal antibodies. Slides were evaluated for receptor localization and intensity of staining as a reflection of the number of receptors. RESULTS: EP1 receptors were not present in cervical smooth muscle in RU486-treated or control animals, but were localized to the cervical smooth muscle in progesterone-treated and control animals. In contrast, EP3 receptors were localized to the smooth muscle cells in all animal groups. The RU486induced labor increased EP1 and EP3 expression throughout all layers of the cervical epithelium, whereas EP1 and EP3 receptors were present only in the apical layer of the epithelium in both the progesterone-treated and control animals. Progesterone treatment decreased EP1 and EP3 expression when compared to control animals. CONCLUSION: Progesterone appears to differentially regulate expression of contractile EP receptors in the cervix. Understanding the hormonal regulation of the PGE2 receptors in the cervix is important in developing improved management of preterm labor.
453
PERMANENT REDUCTION IN HEART AND KIDNEY ORGAN GROWTH IN OFFSPRING OF UNDERNOURISHED RAT DAMS MINA DESAI1, DAVE GAYLE1, JOOBY BABU1, EDITH ORNELAS1, MICHAEL ROSS1, 1Harbor-UCLA Med. Ctr., Dept. of OB/ GYN (LA BioMed), Torrance, California OBJECTIVE: Epidemiological studies have linked fetal growth retardation (IUGR) to increased risk of cardiovascular disease, hypertension and obesity. IUGR effects may result from undernutrition at critical development periods causing reduction in organ growth and permanent changes in their metabolism and/or structure. We investigated the effects of maternal food restriction during pregnancy and/or lactation on adult offspring body and organ growth. STUDY DESIGN: From day 10 to term gestation and through day 21 of lactation, control pregnant Sprague Dawley rats received ad libitum (AdLib; n = 12) food, whereas study rats were 50% food-restricted (FR; n = 12). At birth, litter size was culled to 4 males and 4 females. Half of the control and FR mothers (n = 6) continued to nurse their own pups, whereas the other half (n = 6), were cross-fostered to determine effects of FR during pregnancy or lactation periods. Thus 4 groups were studied: (1) AdLib/AdLib; (2) FR/AdLib; (3) AdLib/FR; (4) FR/FR. At day 21, offspring were weaned to ad libitum feed and body and organ weights (% of body weight) were measured at 9 months of age. RESULTS: FR during pregnancy (FR/AdLib) resulted in markedly heavier offspring (683 G 17 vs 608 G 15 g, P ! .001) with relatively decreased weights of heart (0.24 G 0.01 vs 0.29 G 0.02, P ! .01), kidney (0.63 G 0.01 vs 0.76 G 0.03, P ! .01), lung (0.28 G 0.01 vs 0.36 G 0.02, P ! .01) and brain (0.31 G 0.01 vs 0.35 G 0.01, P ! .01) as compared to controls (AdLib/AdLib). Conversely, FR during lactation (AdLib/FR) or combined periods (FR/FR) resulted in offspring with similar body weights as controls but with relatively decreased growth of heart and kidney. Males in the three study groups exhibited relatively smaller livers, whereas the females showed relatively smaller adrenal glands. CONCLUSION: Sex-dependent, selective and permanent changes in relative organ weight were observed depending upon the period of FR. The impact on heart and kidney growth suggests potential long term risks of adult hypertension and cardiovascular disease among IUGR newborns.
455
LOCALIZATION OF RELAXATORY PROSTAGLANDIN E2 RECEPTORS IN RAT CERVICAL TISSUE ANDREA HINTON1, PETA GRIGSBY1, BRAD PITZER1, DIANE BROCKMAN1, LESLIE MYATT1, 1University of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio OBJECTIVE: Despite advances in obstetric and neonatal care, preterm labor remains a significant problem. Prostaglandins (PG) play a central role in normal and preterm labor, stimulating uterine contractility and ripening the cervix. Cervical dilation, in part, is mediated by changes in the expression of the relaxatory and contractile PGE2 receptors during late gestation and labor. To investigate the regulation of these receptors in the cervix, we determined the localization of the relaxatory PGE2 receptors during RU486-induced labor and progesterone treatment. STUDY DESIGN: Pregnant rats were assigned to receive either RU486 (10 mg/ kg, IP; n = 5) or vehicle (0.3 mL, IP; n = 6) on day 16 of gestation. These animals were euthanized on day 18 of gestation. A second group was assigned to receive progesterone supplementation (2.5 mg/day, IP; n = 18) or vehicle (0.3 mL, IP; n = 15). These animals were sacrificed on day 21, 22, and 23 of gestation (treated: n = 6, vehicle: n = 5, respectively). Cervical tissue was collected and sectioned (8 mm) for immunostaining using anti-human EP2 and EP4 polyclonal antibodies. RESULTS: EP2 and EP4 receptors were localized to cervical smooth muscle and epithelial cells in all animal groups. RU486 treatment induced labor 48h after treatment and increased EP2 and EP4 protein expression in cervical smooth muscle and cervical epithelial cells. In the smooth muscle layer, progesterone treatment increased EP2 protein expression and decreased EP4 expression. In cervical epithelial cells, progesterone treatment enhanced EP4 receptor expression in late gestation when compared to matched controls, but did not increase expression of EP2. CONCLUSION: Progesterone appears to differentially regulate expression of relaxatory EP receptors in the different cell types of the cervix suggesting that these receptors are linked to different signaling pathways. This study may aid in our attempt to further understand the regulation of PGE2 receptors in the cervix, facilitating better approaches for the prevention and treatment of preterm labor.