Corticotropin-releasing hormone receptor subtype 1 is significantly up-regulated at the time of labor in the human myometrium

Circulating concentrations of CRH rise late in human pregnancy, reaching a peak at labor. The presence of functional CRH receptors, CRH-R1 and CRH-R2, in the human myometrium suggests that CRH may modulate uterine activity. We hypothesized that the number of CRH receptors would be higher in myometrium than fetal membranes (FM) and would change during labor. Myometrial samples were collected from the lower segment (LS) in nonpregnant, preterm (32 +/- 2 weeks), and term (39 +/- 1.6 weeks) pregnant patients before and at labor. Fundus and LS samples were also collected from nonpregnant, pregnant, laboring, and postpartum women. FM were collected at term and at labor. We identified CRH receptors in myometrium and FM by semiquantitative RT-PCR and immunohistochemistry. CRH-R1 messenger ribonucleic acid (mRNA) in the LS was decreased in pregnancy and increased significantly in both preterm and term labor (P < 0.05), but remained unchanged in the fundus. CRH-R2 mRNA was present in 28% of LS myometrium with no change at labor. CRH-R1 and CRH-R2 protein was localized to myometrial smooth muscle in nonpregnant and laboring patients, with lower levels at term. CRH-R1 mRNA was present in chorion and decidua, but CRH-R2 was undetectable in these tissues. We conclude that CRH-R1 is expressed preferentially in myometrium and FM. Changes in CRH receptors during labor are consistent with CRH mediating effects on myometrial activity.     

Conceptus, progesterone, and breed effects on uterine protein secretion in swine

This experiment consisted of the following treatment-breed groups: 1) White crossbred gilts, 2) White crossbred gilts treated with progesterone (200 mg/d in corn oil given on d 2 and 3 after estrus), and 3) Chinese Meishan gilts. Pregnant and nonpregnant gilts (n=3 to 6) from each treatment-breed combination were assigned to be slaughtered on d 10, 11, 12, 13, and 15. At slaughter each uterine horn was flushed with 20 mL of minimal essential medium. Uterine flushings were assayed for total protein, acid phosphatase, uteroferrin, retinol-binding protein, and oxytocin. Uterine flush total protein was increased by progesterone treatment, was unaffected by pregnancy status, and was less in Meishans. Similar patterns were found for retinol binding protein and uteroferrin, except that uteroferrin was greater in pregnant than in nonpregnant gilts. Oxytocin was greater in pregnant than in nonpregnant gilts, was not influenced by progesterone treatment, and was similar in Meishan and in White crossbred gilts. These results indicate that the conceptus does not influence secretion of either total protein or retinol binding protein during pregnancy and that the onset of secretion of these uterine proteins may be controlled by progesterone. The presence of the conceptus is associated with increased uteroferrin and oxytocin production. The decreased secretion of uterine proteins in Meishan gilts may partially explain the slower embryonic development that has been reported for this breed.     

Adrenomedullin, a new vasoactive peptide, is increased in preeclampsia

Adrenomedullin is a novel peptide that elicits a long-lasting vasorelaxant activity. Recently, we found high concentrations of adrenomedullin in maternal and umbilical cord plasma and in amniotic fluid in full-term human pregnancy, indicating a role of this peptide during gestation. To investigate the possibility that adrenomedullin is involved in the pathophysiology of preeclampsia, we measured its concentration in maternal and fetoplacental compartments. We studied 12 normotensive nonpregnant women, 13 hypertensive nonpregnant subjects, 29 patients with preeclampsia, and 30 normotensive pregnant women. In all patients, plasma was collected from the cubital vein, and amniotic fluid samples were obtained by transabdominal amniocentesis or at elective cesarean section. Plasma samples from umbilical vein and placental tissues were collected at delivery. Adrenomedullin was assayed on plasma and amniotic fluid samples using a specific radioimmunoassay, and its localization and distribution on placental sections was determined by immunohistochemistry. Adrenomedullin concentrations were higher in hypertensive than in normotensive nonpregnant patients. Pregnant women had higher adrenomedullin levels than nonpregnant subjects, although maternal plasma adrenomedullin concentrations did not differ between normal pregnant and preeclamptic women. Preeclamptic patients showed higher concentrations (P<0.01) than normotensive pregnant women of adrenomedullin in amniotic fluid (252+/-29 versus 112+/-10 fmol/ micromol creatinine) and umbilical vein plasma (18.1+/-2.1 versus 8. 5+/-1.1 fmol/mL). Increased local production of adrenomedullin is associated with preeclampsia. The fetus seems to be responsible for the higher levels of this hormone. Increased adrenomedullin concentrations may be necessary to maintain placental vascular resistance and/or fetal circulation at a physiological level.     

Quinine pharmacokinetics in young children with severe malaria

In this study, we determined selenium concentrations in serum samples of healthy women (146 pregnant and 74 nonpregnant) living in the Mediterranean area of the coast of Granada (southeast Spain). The subjects were distributed in two groups: group A (pregnant women), divided into three categories according to the trimester of pregnancy, and group B (nonpregnant women). No significant differences were observed in the selenium levels either among pregnant women according to the trimester of pregnancy or in the group of nonpregnant women. No other significant differences were determined as regards the age of pregnant women (P > 0.05). Serum selenium levels are slightly lower during pregnancy. Considering that serum selenium levels affect the body selenium status, the concentrations determined establish the non-existence of selenium problems in the daily dietary intake with respect to maternal and fetal necessities during pregnancy.     

Fascioloidiasis in game-ranched elk from Montana

The distribution of Fascioloides magna in game-ranched elk and the potential for spread of the parasite through movement of infected animals was examined in Montana (USA). Fecal samples (n = 448) collected from captive elk on 29 game ranches were examined for eggs of F. magna by fecal sedimentation. Eggs were detected in elk on 5 ranches. This suggests that F. magna has been translocated by infected game-ranched elk. The wide distribution of snail intermediate hosts for F. magna in Montana indicates a potential to spread the parasite to other captive cervids domestic livestock or free-ranging wildlife.     

Growth hormone, prolactin and chorionic somatomammotropin in normal and molar pregnancy

Twenty patients with molar pregnancy, ten normal pregnant women and ten healthy non-pregnant women were given 30 g of arginine intravenously. The serum concentration of growth hormone, prolactin and chorionic somatomammotropin (CS) was determined by radioimmunoassay. In addition, serum 17beta-estradiol, estriol and progesterone were also measured. Arginine infusion induced a sharp rise of GH in patients with molar pregnancy and in nonpregnant subjects, but the response in normal pregnancy was blunted. The response of PRL was high in patients with molar pregnancy, blunted in normal pregnancy and very small in nonpregnant subjects. CS did not respond at all to arginine infusion both in normal pregnancy and molar pregnancy. The high response to argine of PRL, normal response of GH and low baseline secretion and no response of CS may be characteristic of molar pregnancy.     

Necrosis of myometrial choriocarcinoma with fulminating sepsis complicating chemotherapy for trophoblastic tumor

OBJECTIVE: In normal pregnancy and pregnancies complicated by preeclampsia it has been demonstrated that there is increased activation of platelets and the clotting and fibrinolytic system. We measured plasma levels of thrombopoietin, a major regulator of platelet production in these conditions. STUDY DESIGN: We compared the thrombopoietin plasma levels of healthy term pregnant patients (n = 21) with those of healthy nonpregnant controls (n = 17), as well as patients with severe preeclampsia (n = 8) and the hemolysis, elevated liver enzymes, low platelets syndrome (n = 6). RESULTS: Thrombopoietin levels in normal pregnant patients and pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome were statistically significantly higher than thrombopoietin levels in nonpregnant controls. Data were analyzed with the Kruskal-Wallis one-way analysis of variance by ranks. CONCLUSIONS: This study is the first to report thrombopoietin levels in pregnancy. Thrombopoietin levels are significantly greater in pregnant patients and in pregnancies complicated by the hemolysis, elevated liver enzymes, low platelets syndrome compared with nonpregnant controls.     

The total peroxyl radical-trapping ability of plasma and cerebrospinal fluid in normal and preeclamptic parturients

Plasma and cerebrospinal fluid total peroxyl radical-trapping antioxidative parameter (TRAP) and the main antioxidant components of TRAP (vitamin E, ascorbic acid, uric acid, protein sulfhydryl groups, and the unidentified antioxidant proportion) were analyzed in 11 preeclamptic parturients, 9 healthy parturients with an uncomplicated pregnancy, and 10 healthy nonpregnant women. In addition, the possible effects of ongoing labor were studied in 10 healthy parturients. The samples of plasma and cerebrospinal fluid (CSF) were collected at cesarean section (pregnant women) or minor surgical procedure (nonpregnant women). Normal pregnancy or ongoing labor induced no significant changes in total TRAP, as compared with nonpregnant women, but significant changes in the percentage contributions of individual antioxidants were noted in plasma and CSF. In preeclampsia, a significant increase in TRAP was noted in both plasma and CSF. This increase was mainly due to an increased proportion of uric acid and unidentified antioxidants in plasma samples, and an increased proportion of unidentified antioxidants in CSF. The concentration of CSF ascorbic acid was decreased in preeclampsia, and a negative correlation between CSF ascorbic acid and blood pressure was observed.     

Volume of luteal tissue and concentration of serum progesterone in cows bearing homogeneous corpus luteum or corpus luteum with cavity

Ultrasonographical examinations of ovarian structures were performed in 27 inseminated cows at estrus days and on days 4, 9, 20, 25, 30, and 40 after ovulation. Three cows were used twice. Corpora lutea (CLs) with a cavity were compared with homogeneous CLs. in pregnant and nonpregnant cows. Diameters and volumes of CLs and cavities, as well as volumes of luteal tissue and concentrations of serum progesterone were determined. The volumes of the structures were calculated using a mathematical formula for a rotary ellipsoid. Homogeneous CLs and CLs with a cavity and their luteal tissue reached a maximum volume in nonpregnant and pregnant cows on day 9 after ovulation. At this time, CLs volumes were 7.52 +/- 3.14 (homogeneous CLs, n = 4) and 4.54 cm3 (CLs with a cavity, n = 1) in nonpregnant cows, and 6.05 +/- 1.71 (homogeneous CLs, n = 10) and 9.54 +/- 2.67 cm3 (CLs with a cavity, n = 15) in pregnant cows. The volumes of luteal tissue were 7.52 +/- 3.14 and 4.33 cm in nonpregnant cows and 6.05 +/- 1.71 and 8.62 +/- 3.46 cm3 in pregnant cows. Concentrations of progesterone in peripheral blood in pregnant cows bearing a homogeneous CLs or CLs with a cavity on day 9 were 3.15 +/- 0.69 ng ml-1 and 4.12 +/- 1.28 ng ml-1, respectively. The concentrations of progesterone were higher in pregnant cows in comparison with nonpregnant cows. CLs with a cavity in pregnant cows contained a higher volume of luteal tissue and higher secretory activity compared to homogeneous.     

Effect of reperfusion modality on outcome in nonsmokers and smokers with acute myocardial infarction (a Primary Angioplasty in Myocardial Infarction [PAMI] substudy). PAMI Investigators

BACKGROUND: We present our experience with laparoscopic cholecystectomy in pregnant patients, with consideration of the physiological changes of pregnancy affecting anesthetic and surgical management. METHODS: We reviewed the medical records of all pregnant patients undergoing laparoscopic surgery at Brigham and Women's Hospital between January 1, 1991 and April 30, 1995. RESULTS: Laparoscopic cholecystectomy was performed without complication in ten patients (gestational age 9-30 weeks). Details of anesthetic and surgical management are described. The anesthetic and surgical implications of pregnancy-associated physiological changes in the gastrointestinal, respiratory, cardiovascular, and central nervous system are reviewed. CONCLUSIONS: With appropriate attention to the altered physiology of pregnancy, laparoscopic cholecystectomy can be performed safely and effectively during pregnancy.     

Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with small-bore catheter drainage

OBJECTIVES: The study's aims were to investigate the levels of gravidin, an endogenous phospholipase A2 inhibitor, in pregnancy and pre-eclampsia and to establish its effects on neutrophil function. STUDY DESIGN: Serum samples were collected from 9 nonpregnant, 15 preeclamptic, and 10 healthy pregnant women and assayed for free gravidin by enzyme-linked immunosorbent assay. Neutrophil phospholipase A2 and respiratory burst activities were determined in the presence of isolated free gravidin by cellular arachidonic acid release and superoxide anion production. RESULTS: Levels of free gravidin were higher in the healthy pregnant (36.1 +/- 5.5 ng/mL) and preeclamptic (17.8 +/- 2.8 ng/mL) groups than in the nonpregnant control group (3.9 +/- 0.5 ng/mL) and were significantly different between pregnancy groups (P <.01, Mann-Whitney U test). Free gravidin caused a concentration dependent decrease in N-formyl-methionyl-leucyl-phenylalanine-stimulated neutrophil arachidonic acid release (inhibitory concentration of 50% 25 nmol/L) and superoxide anion generation (inhibitory concentration of 50% 32 nmol/L). CONCLUSIONS: Circulating levels of free gravidin are reduced in pre-eclampsia compared with normal pregnancy. This may encourage an increase in the respiratory burst of neutrophils in pre-eclampsia and could contribute to the oxidative stress and vascular damage that characterize this disease.     

Corticotropin-releasing hormone and proopiomelanocortin-derived peptides are present in human myometrium

CRH and POMC-derived peptides are produced at a number of intrauterine sites in both the nonpregnant and pregnant states. It is hypothesized that CRH and POMC-derived peptides may be produced locally by the uterus to modulate myometrial contractility. This study has examined the distribution of these peptides in human uterine tissue during the ovulatory cycle and pregnancy. The immunoperoxidase staining method was used to localize CRH and POMC-derived peptides: ACTH, beta-endorphin, and alphaMSH. Immunoreactive (IR-) CRH and IR-POMC-derived peptides, beta-endorphin and alphaMSH, were observed in the myometrial smooth muscle, vascular smooth muscle, endometrial glandular epithelium, and luminal epithelium of the nonpregnant uterus (n = 17). Staining for IR-CRH did not change during the cycle from the proliferative (n = 8) to the secretory phases (n = 9). Conversely, staining for IR-beta-endorphin and IR-alphaMSH was only observed during the secretory phase of the cycle (n = 9). In uterine tissue obtained from pregnant women (n = 20) IR-CRH was present in the myometrial smooth muscle, vascular smooth muscle, decidua, and glandular epithelium. IR-POMC-derived peptides were not detectable at any uterine site during pregnancy (n = 20). IR-CRH was measurable in myometrial extracts collected from pregnant women undergoing cesarean section (20.9+/-3.8 ng/g wet wt; n = 7) and from nonpregnant premenopausal women undergoing hysterectomy (7.7+/-2.1 ng/g wet wt; n = 6). IR-CRH concentrations significantly increased with pregnancy. Levels of messenger ribonucleic acid encoding for CRH were examined in nonpregnant (n = 4) and pregnant (n = 10) myometrial smooth muscle and were also significantly increased with pregnancy. This study has demonstrated that levels of CRH and POMC peptide in human uterine tissue change with pregnancy and that CRH is produced locally by myometrial smooth muscle cells. These studies are consistent with the possibility that the CRH peptide has an autocrine/paracrine activity during pregnancy and labor that may be related to the modulation of myometrial contractility.     

The prostaglandin E2 and F2 alpha receptor genes are expressed in human myometrium and are down-regulated during pregnancy

Prostaglandin (PG) E2 and PGF2 alpha are believed to play important roles in the myometrial contraction and the initiation of labor. Myometrial contraction by these prostanoids is mediated mainly through EP3 and FP, which are specific receptors to PGE2 and PGF2 alpha, respectively. During normal pregnancy, uterine myometrium are relaxed until term. To explore the involvement of EP3 and FP in the myometrial relaxation during pregnancy, we examined the EP3 and FP gene expressions in nonpregnant and pregnant myometrium obtained by hysterectomy for gynecological diseases. In all samples examined, expressions of EP3 and FP genes were detected. During pregnancy, the expression of EP3 gene in human myometrium was significantly reduced, to 60% of that in nonpregnant myometrium. The expression of FP gene in human myometrium also decreased during pregnancy to 55% of that in nonpregnant myometrium. In the myometrium from the nonpregnant women taking combined oral contraceptives, the gene expressions of EP3 and FP were not significantly changed as compared to those in nonpregnant controls. The down-regulation of EP3 and FP during pregnancy may play a role in the relaxation of myometrium and thus in the maintenance of normal pregnancy in humans.     

Cytomegalovirus infections and hematopoietic disorders

OBJECTIVE: In a seroepidemiologic study the effects of pregnancy and other factors on humoral response to human papillomavirus type 16 infection were examined. STUDY DESIGN: Multiple serum samples were taken at 3-month intervals for 15 months from 77 pregnant and 85 nonpregnant women. Serologic response to human papillomavirus type 16 proteins was analyzed with a peptide-based enzyme-linked immunosorbent assay. RESULTS: Seroreactivity was higher in nonpregnant women than in pregnant women, suggesting a reduced humoral immune response against human papillomavirus infections during pregnancy. Among the pregnant women a twofold to threefold decrease in mean reactivity in the E4 protein-based assay was detected between early gestation and delivery. The presence of human papillomavirus type 16 or 18 deoxyribonucleic acid was significantly associated with reactivity to the E6 protein (p = 0.0005) and the E4 protein (p = 0.06). Reactivity to the E4 protein also correlated with an abnormal Papanicolaou smear. CONCLUSIONS: The observation of changes in humoral response to genital human papillomavirus infections during pregnancy warrants further investigation with highly seroreactive assays.     

Identification and expression of G-proteins in human myometrium: up-regulation of G alpha s in pregnancy

We report that human myometrium contains G alpha i1, G alpha i3, and G alpha q, and G alpha 11, which are expressed at similar levels in tissues from pregnant and nonpregnant women. G alpha i2 is also expressed, but at a slightly reduced level, in tissue taken from pregnant compared to nonpregnant donors. The major finding of this investigation is the substantial increase in G alpha s expression in pregnant myometrium. The increase in G alpha s levels may play a crucial role in maintaining relaxation of the uterus by favoring cAMP formation during pregnancy.     

Measurement of gestagen concentration in feces using a bovine milk progesterone quantitative test EIA kit and its application to early pregnancy diagnosis in the sow

We attempted to measure the gestagen concentration in the feces of pigs by using a commercial bovine milk progesterone quantitative test EIA kit, and investigated the possibility of applying of this method of gestagen concentration measurement to early pregnancy diagnosis in the sow. Feces were collected from the rectum of the pig, and 0.5 g of the feces was placed in 20 ml of distilled water, stirred, and centrifuged. The supernatant was used as the fecal solution for measurement of gestagen. The procedure used for measuring gestagen in feces was the same as that for the measurement of progesterone in milk, except that a standard fecal gestagen solution (0.5-30.0 ng/ml) was prepared by the authors in the laboratory. The sensitivity of measurement using this method was 0.80 ng/ml, or 32.0 ng/g of fecal weight. The recovery was 105.2-105.6%. Intra-assay coeffecients of variation (CVs) were 2.8-8.5%. The interassay CVs were 7.4-10.2%. Gestagen concentrations in feces measured by the present method and progesterone concentrations in peripheral plasma, collected at the same time as the feces were highly correlated (r = 0.98, p < 0.001). The criteria for diagnosis of pregnancy based on the fecal gestagen level was positive for a gestagen level of > or = 200 ng/g and negative for a gestagen level of < 200 ng/g. When fecal gestagen measurements were applied to early pregnancy diagnosis in 149 sows, the accuracy of diagnosis from day 21 to day 25 after the last mating was 96.2% for positive cases (102/106) and 95.3% for negative cases (41/43). Thus, the results of this study show the quantitative measurement of the fecal gestagen concentration in the sow using a bovine milk quantitative test EIA kit is a practical method for early pregnancy diagnosis.     

Colorectal cancer complicating pregnancy

Colorectal carcinoma complicating pregnancy is rare but associated with a high maternal mortality rate. Stage for stage the survival data are the same for pregnant patients and nonpregnant controls, however diagnosis is often delayed due to pregnancy-associated gastrointestinal symptoms masking cancer symptoms. A high degree of suspicion, especially in high-risk patients, is the key to early detection and improved prognosis. Digital rectal exams, occult fecal blood tests, and flexible sigmoidoscopy or colonoscopy are performed as indicated. Treatment primarily consists of en-bloc resection of the malignancy and regional lymph nodes; timing of colorectal surgery and delivery are based upon clinical presentation, fetal age, and maternal desires.     

Nitric oxide synthase activities in human myometrium and villous trophoblast throughout pregnancy

OBJECTIVE: To study the changes in nitric oxide synthase activities in human myometrium and trophoblast throughout pregnancy and around delivery. METHODS: Samples of villous trophoblast were collected from women undergoing elective cesarean delivery at term (n = 12) or voluntary termination of pregnancy in the first (n = 27) or second (n = 11) trimesters of pregnancy. Myometrial samples were obtained from nonpregnant women undergoing hysterectomy (n = 5) and pregnant women both before (n = 7) and after (n = 7) the onset of spontaneous labor at term. Nitric oxide synthase activity was quantified for homogenized samples using the L-citrulline assay in the presence and absence of calcium. RESULTS: The highest levels of nitric oxide synthase activity were found in first-trimester villi (range 2-29 nmol L-citrulline/minute/g protein), with a significant fall in activity in the third trimester (range 2-10 nmol L-citrulline/minute/g protein; P < .001 for both calcium-dependent and calcium-independent activity). Myometrial activities were relatively low compared with those in the trophoblast (0-2 nmol L-citrulline/minute/g protein), with no significant differences in calcium-dependent activities between subgroups. Myometrial calcium-independent activities were lower in pregnant than in nonpregnant women (P = .007), with those in labor having levels higher than those not in labor (P = .048). CONCLUSION: Levels of nitric oxide synthase activity are relatively high in villous trophoblast, particularly during the first trimester. Although the contribution to total nitric oxide production in the uterus by myometrial nitric oxide synthase appears to be relatively small, nitric oxide produced by the trophoblast may play a role in maintaining uterine quiescence by a paracrine effect. Further work is needed to test this hypothesis and explore other possible roles for trophoblast-derived nitric oxide in early pregnancy.     

Effects of corticosteroid hormone on the epiphyseal growth center of immature pregnant mice

Immature pregnant mice treated with glucocorticoid hormone (triamcinolone hexacetonide) were killed 1 week following delivery. The epiphyseal growth plates of the humerus and their cellular constituents were analyzed quantitatively. It became evident that pregnancy per se evokes a marked suppressive effect upon young cartilage cells, thus interfering with the normal process of endochondral bone formation. Pregnant mice treated with glucocorticoid hormone experienced an even higher degree of chondrocytic derangement, however, to a lesser extent than chondroxytes of nonpregnant mice treated with the hormone. It therefore appears that pregnancy-induced elevation of systemic estrogens and progesterone provides some kind of a protection against the antianabolic activity of glucocorticoids upon chondrocytes.