A randomized study of screening for ovarian cancer: a multicenter study in Japan.

Ovarian cancer is common in women from developed countries. We designed a prospective randomized controlled trial of ovarian cancer screening to establish an improved strategy for the early detection of cancers. Asymptomatic postmenopausal women were randomly assigned between 1985 and 1999 to either an intervention group (n = 41,688) or a control group (n = 40,799) in a ratio of 1:1, with follow-up of mean 9.2 years, in Shizuoka district, Japan. The original intention was to offer women in the intervention group annual screens by gynecological examination (sequential pelvic ultrasound [US] and serum CA125 test). Women with abnormal US findings and/or raised CA125 values were referred for surgical investigation by a gynecological oncologist. In December 2002, the code was broken and the Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry were searched to determine both malignant and nonmalignant diagnoses. Twenty-seven cancers were detected in the 41,688-screened women. Eight more cancers were diagnosed outside the screening program. Detection rates of ovarian cancer were 0.31 per 1000 at the prevalent screen and 0.38-0.74 per 1000 at subsequent screens; they increased with successive screening rounds. Among the 40,779 control women, 32 women developed ovarian cancer. The proportion of stage I ovarian cancer was higher in the screened group (63%) than in the control group (38%), which did not reach statistical significance (P = 0.2285). This is to our knowledge the first prospective randomized report of the ovarian cancer screening. The rise in the detection of early-stage ovarian cancer in asymptomatic postmenopausal women is not significant, but future decisions on screening policy should be informed by further follow-up from this trial.

Activation of mammalian target of rapamycin in postmenopausal ovarian endometriosis.

The purpose of this study was to determine whether Akt and mammalian target of rapamycin (mTOR), downstream targets of phosphatidylinositol 3-kinase, are activated in endometriosis and ovarian cancer specimens. We measured total and phosphorylated levels of Akt and mTOR from 17 frozen ovarian cancers and 15 benign endometriosis specimens (nine from premenopausal women and six from postmenopausal women) by quantitation of signals from western blots using antibodies against these proteins. Elevated phospho-Akt was detected in ovarian cancer versus endometriosis specimens from premenopausal women and endometriosis specimens from postmenopausal women (2.3 +/- 0.45 versus 0.10 +/- 0.06 and 0.17 +/- 0.11; P < 0.05) when the western blot signal of activated kinase was normalized to total kinase levels. Elevated phospho-mTOR was detected in ovarian cancer and postmenopausal endometriosis versus premenopausal endometriosis (0.52 +/- 0.19 and 0.46 +/- 0.29 versus 0.13 +/- 0.08; P < 0.05). Expression of total kinases (normalized to beta-actin) was higher in carcinoma versus endometriosis specimens. Elevation of the active mTOR was specifically detected in postmenopausal endometriosis.

First trimester biological markers for the prediction of pregnancy-induced hypertension.

The purpose of this study is to predict pregnancy-induced hypertension (PIH) by standard methods at the first antenatal visit prior to the 12th gestational week (GW). This is a retrospective study of 1189 primipara and 957 multipara who delivered singleton babies having no major malformations after the 32nd GW. Multiple regression analysis for the development of PIH was performed using the mean arterial blood pressure (MBP), body mass index (BMI), hematocrit count at the first visit prior to the 12th GW, a family history of hypertension number of pregnancies, number of deliveries, past history of hypertension and evidence of threatened abortion as explanatory variables in primipara and multipara, respectively. We obtained a significant regression equation in both primipara and multipara. Multiple correlation coefficient for primipara was 0.40223 (p < 0.01) and for multipara was 0.50764 (p < 0.01). When MBP was over 80 mm Hg, BMI was over 23.6, a family history of hypertension was present, or a past history of hypertension was present, these variables were significantly correlated with the development of PIH both in primipara and multipara. By combining these variables, we obtained 32.7% positive predictive value, 93.5% negative predictive value, 31.7% sensitivity, and 93.7% specificity in primipara and 24.6%, 96.7%, 52.6%, and 89.8% in multipara, respectively. As the incidence of PIH was 8.7% in primipara and 5.9% in multipara, we could predict 3.7 and 4.1 times higher than the true incidence. PIH can therefore be predicted by the simple combination of MBP, BMI, a family history of hypertension, and a past history of hypertension prior to the 12th GW. It can also be predicted by the multiple-regression equation with the use of nine explanatory variables.

Prevention of pregnancy-induced hypertension by calcium dietary supplement: a preliminary report.

OBJECTIVE: The purpose of this study is to clarify whether the taking of a calcium dietary supplement is able to prevent the development of pregnancy-induced hypertension (PIH) in Japanese people. STUDY DESIGN: Forty-five nulliparous women (Ca-group) with various high-risk factors for PIH started to take a calcium supplement (1 g/day in the form of calcium salts) from the 12th gestational week (GW). Obstetrical outcome of Ca-group was compared to that of the nullipara (n = 453) who did not take a calcium supplement during pregnancy (Non-Ca Group) and that of the nullipara (n = 413) who did not develop PIH among Non-Ca group (normotensive group). RESULTS: The incidence of PIH in the Ca-group was 2.2%, compared to 8.8% of Non-Ca group. The decrease in blood pressure after taking calcium during the first half of the pregnancy was much greater in Ca-group than in the normotensive group. The urinary excretion of sodium and calcium and serum free calcium at the 28th GW were much lower in a woman with PIH, despite of the taking of a calcium supplement, than in the normotensive calcium group. Also, the parathyroid hormone level at the 28th GW was higher in the calcium-taking woman with PIH than in the normotensive calcium group. CONCLUSION: Our preliminary study suggests that among the possible effects of taking a calcium supplement are a decrease in blood pressure and the prevention of PIH in Japanese people, and that calcium metabolism might be related to the development of PIH. However, more study is needed before it will be possible to reach a final conclusion.

Prediction of pregnancy-induced hypertension by isometric exercise.

The purpose of this study is to evaluate an isometric exercise (Hand-Grip test) as a method to predict pregnancy-induced hypertension (PIH). One hundred and twenty-five pregnant women were given the Hand-Grip (HG) test before the 15th gestational week. The Hand-Grip test was rated positive when the systolic blood pressure increased 15 mmHg or more during isometric exercise or decreased 14 mmHg or more immediately after isometric exercise. As a result, the Hand-Grip test had the highest sensitivity (81.8%) and specificity (68.4%) for predicting PIH, compared to other risk factors. The positive predictive value was 20% (second highest among risk factors, the actual incidence of hypertension was 8.8%), and the negative predictive value was 97.5% (highest). In conclusion, by use of a very simple Hand-Grip test early in gestation, we are able to predict PIH with the highest sensitivity.

[Influence of low calcium diet on the vascular response to angiotensin II in pregnant and non-pregnant rabbit vascular endothelium].

This study was conducted in order to evaluate the influence of low calcium intake on the vascular response to angiotensin II (A-II) in pregnant and non-pregnant rabbits. Both were fed on a regular and a low calcium diet, respectively, for a period of at least 25 days. By using the common iliac arterial rings of each of the rabbits, and further classifying the respective arterial rings into those with intact endothelium and those with denuded endothelium, the response to A-II in the rings was compared. A greater degree of refractoriness to A-II was observed in the intact endothelial rings than in the denuded rings regardless of the difference in calcium intake, in both pregnant and non-pregnant rabbits. The refractoriness was however, particularly remarkable in the pregnant arterial rings. Therefore refractoriness to A-II in arterial rings on a low calcium diet is higher than that in the rings on a regular calcium diet regardless of the presence of endothelial cells, in both pregnant and non-pregnant rabbits. It is clear that reduction in the calcium intake results in an increase in the response to A-II, which is caused by increased reactivity of the vascular smooth muscle layer.

[Changes in blood pressure in two types (absolute and relative) of pregnancy induced hypertension (hypertensive type of toxemia)].

The criteria for pregnancy induced hypertension (PIH: hypertensive type of toxemia) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute PIH (A-PIH)" diagnosed by (1) systolic blood pressure (SBP) greater than or equal to 140 mmHg and less than 160 mmHg or (2) diastolic blood pressure (DBP) greater than or equal to 90 mmHg and less than 110 mmHg. The other one is "relative-PIH (R-PIH)" diagnosed by (3) an increase in SBP greater than or equal to 30 mmHg compared to the usual SBP or (4) an increase in DBP greater than or equal to 15 mmHg compared to the usual DBP (In this paper, blood pressure prior to the 12th gestational week is considered as "usual" blood pressure). However, there has been no report in which two types of PIH are assessed. Our hypothesis is that the pathophysiology of the two types of PIH is different. We have already reported the clinical background of two types of PIH. The purpose of this study is to clarify the pathophysiological difference by evaluating the blood pressure change during pregnancy. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before the 32nd gestational week were excluded). Among the nullipara, 765 women (79.4%) were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. Among the multipara, the N-group consisted of 632 women (84.6%), the A-PIH: 4.6% and R-PIH: 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fetal growth in two types (absolute and relative) of pregnancy induced hypertension (hypertensive type of toxemia)].

The criteria for pregnancy induced hypertension ("PIH" which is a hypertensive type of toxemia) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute PIH (A-PIH)" diagnosed by (1) systolic blood pressure (SBP) greater than or equal to 140 mmHg and less than 160 mmHg or (2) diastolic blood pressure (DBP) greater than or equal to 90 mmHg and less than 110 mmHg. The other one is "relative-PIH (R-PIH)" diagnosed by (3) an increase in SBP greater than or equal to 30 mmHg compared to usual SBP or (4) an increase in DBP greater than or equal to 15 mmHg compared to usual DBP (In this paper, blood pressure prior to the 12th gestational week is considered as "usual" blood pressure). We have already investigated the pathophysiological difference through the background and the change in blood pressure throughout pregnancy and puerperium in these two types of PIH. The purpose of this study is to clarify the pathophysiological difference by evaluating the influence of hypertension on fetal growth. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before the 32nd gestational week were excluded). Among nullipara, 765 women (79.4%) were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. Among multipara, the N-group consisted of 632 women (84.6%), A-PIH: 4.6% and R-PIH: 10.3%. There is no difference among the three groups in gestational days but the body weight, the chest circumference, and the abdominal girth at birth of A-PIH show a significant difference from those of the R-PIH and N-groups in both nullipara and multipara.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical backgrounds in two kinds (absolute and relative) of mild pregnancy induced hypertension].

The criteria for pregnancy induced hypertension (PIH) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute-PIH (A-PIH)" diagnosed by 1) systolic blood pressure (SBP) greater than = 140mmHg and less than 160mmHg or 2) diastolic blood pressure (DBP) greater than = 90mmHg and less than 110mmg. Another one is "Relative-PIH (R-PIH)" diagnosed by 3) an increase in SBP greater than = 30mmHg compared to normal SBP or 4) an increase in DBP greater than = 15mmHg compared to normal DBP. However, there has been no report in which two types of PIH are assessed. Our hypothesis is that the pathophysiology of two types of PIH is different. The purpose of this study is to clarify the pathophysiological difference by evaluating the clinical backgrounds. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before 32 gestational weeks were excluded). Among 765 nullipara women, 79.4% were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. In the multipara N-group, the figures were 632 women (84.6%), A-PIH, 4.6% and R-PIH, 10.3%. Clinical backgrounds showed that the incidence of hypertensive family history, high hematocrit (greater than = 39.0) before the 12th gestational week or obesity (Kaup index greater than = 24 before pregnancy) was significantly higher in A-PIH than in the N-group of nullipara and higher in the A-PIH than in the R-PIH and N-groups of multipara.(ABSTRACT TRUNCATED AT 250 WORDS)

[Influence of estrogen and progesterone on the vascular response to angiotensin-II in non-pregnant rabbit vessels--intact or denuded endothelium].

During pregnancy, vascular sensitivity to A-II is reduced and it was clarified that this refractoriness to A-II is due to a change in EDRF output in pregnant rabbits. The present study aimed at elucidating whether estrogen or progesterone is responsible for the augmentation of EDRF output. 17-OH-estradiol was administered (200 micrograms/kg/day) for 7 days to 8 non-pregnant rabbits, while progesterone was similarly administered (2,000 micrograms/kg/day) to 8 other non-pregnant rabbits. Twenty-four nonpregnant rabbits were employed as the controls. Common iliac arterial rings prepared from each group were compared for the isometric response to A-II. The arterial rings with intact endothelium prepared from the progesterone-treated group were found to have a smaller pD2 value and a smaller maximum response to A-II than the estrogen-treated group. On the other hand, no differences between the progesterone group and estradiol group were observed in these values for the endothelium-denuded arterial rings. These findings indicated that the augmentation of EDRF output during pregnancy is brought about by progesterone.

[Role of endothelial cells on refractoriness to angiotensin-II in pregnant and non-pregnant rabbits].

Vascular refractoriness to angiotensin-II (A-II) during pregnancy is well recognized. The present study was designed to evaluate how the response of endothelial cells of arterial rings to A-II changes in pregnant rabbits (n = 24) when compared with non-pregnant rabbits (n = 24). The response of the arterial rings with intact endothelium to A-II was markedly decreased in the pregnant rabbit group in comparison with the non-pregnant rabbit group. In contrast, in the case of the arterial rings whose endothelium had been removed, there was no difference between the two rabbit groups in the response to A-II. However, the maximum response of arterial rings to A-II was significantly lower in the pregnant group than the non-pregnant group under the presence of the endothelium. This study revealed that the arterial rings with intact endothelium prepared from the pregnant group shows markedly increased refractoriness to A-II, while no such difference is seen with rings from which the endothelium had been removed. That is, this study indicated that an endothelium-derived relaxing factor (EDRF) is deeply involved in refractoriness to A-II in pregnant rabbits.

Uterine resting tonus and maternal hypertension during late pregnancy--existence of intrauterine capacity.

The uterine resting tonus was measured with an open-end catheter beginning from the 24th gestational week through the onset of labor in order to investigate changes in the intrauterine environment from the physical aspect. The measurements were performed in 183 primiparas for a total of 272 times and 102 multiparas for a total of 120 times. The uterine resting tonus was almost constant from the 2nd trimester through the 3rd trimester, but it tended to increase gradually beginning 2-3 weeks prior to the onset of delivery. This tendency was more pronounced in primiparas, and their mean tonus was about 5mmHg higher than that of multiparas throughout the pregnancy. In 55 subjects in whom both the resting tonus and blood pressure were simultaneously measured at least twice during pregnancy, the mean maternal blood pressure increased as the resting tonus increased. The above findings revealed a positive correlation between the resting tonus and the maternal blood pressure and suggested the presence of a critical point in terms of the intrauterine capacity, which derives from the properties of the uterine muscle and the intrauterine contents, consisting mainly of the fetus. The increase in the resting tonus is surmised to be related to this critical point.

Maternal responses to long-term hypoxemia in sheep.

To determine the maternal cardiovascular responses to long-term hypoxemia, we studied three groups of animals: 1) pregnant ewes (n = 20) at 110-115 days gestation subjected to hypoxia for up to 28 days; 2) pregnant ewes (n = 4) that served as normoxic controls; and 3) nonpregnant ewes (n = 6) subjected to hypoxemia for up to 28 days. We measured mean arterial pressure, heart rate, uterine blood flow, and uterine vascular resistance continuously for 1 h/day while the ewe was exposed to an inspired O2 fraction of 12-13% for at least 17 days. Arterial PO2, O2 saturation, hemoglobin, arteriovenous O2 difference, and uterine O2 uptake were measured daily while blood volume and erythropoietin concentration were measured weekly. In the pregnant hypoxic group arterial PO2 decreased from a control value of 101.5 +/- 5.1 to 59.2 +/- 5.1 Torr within a few minutes, where it remained throughout the study. The hemoglobin concentration increased from 8.9 +/- 0.5 to 10.0 +/- 0.5 g/dl within 24 h where it remained, whereas erythropoietin concentration increased from 16.6 +/- 2.1 to 39.1 +/- 7.8 mU/ml at 24 h but then returned to near-control levels. Arterial glucose concentration, mean arterial pressure, and cardiac output decreased slightly but insignificantly. In contrast, body weight, heart rate, blood volume, uterine blood flow, uterine O2 flow, uteroplacental O2 uptake, and the concentrations of catecholamines and cortisol remained relatively constant. Thus both pregnant and nonpregnant sheep experience relatively minor cardiovascular and hematologic responses in response to long-term hypoxemia of moderate severity.

Fetal responses to long-term hypoxemia in sheep.

The effect of acute or short-term hypoxia on fetal cardiovascular hemodynamics has been well known; however, little is known about the effect of long-term hypoxemia. To determine the fetal hemodynamic responses to this stress we studied two groups of animals: 1) pregnant ewes (n = 20) at 110-115 days of gestation subjected to hypoxia for up to 28 days and 2) pregnant ewes (n = 4) that served as normoxic controls. We chronically catheterized the fetal brachiocephalic artery and vein. Five to 6 days after surgery, control measurements were made of mean arterial blood pressure, heart rate, arterial PO2, O2 saturation, hemoglobin, hematocrit, blood volume, and the concentrations of erythropoietin, cortisol, epinephrine, and norepinephrine. The next day the ewes were placed in a chamber with an inspired O2 fraction of 12-13%. Within a few minutes fetal arterial PO2 decreased from control value of 29.7 +/- 2.1 to 19.1 +/- 2.1 Torr, where it remained. Hemoglobin increased from 10.0 +/- 1.0 to 12.9 +/- 1.9 g/dl by day 7, where it remained. This was associated with an increase of erythropoietin from 22.8 +/- 2.2 to 144 +/- 37 mU/ml within 24 h, but by day 7 it had returned to levels slightly above normal. Epinephrine also increased moderately and remained elevated throughout the study. However, values of mean arterial pressure and heart rate did not differ from controls. Perhaps surprisingly, these fetuses were able to compensate so that at term their body weights were normal, 3.77 +/- 0.2 kg.

[The influence of increased uterine resting tonus on renal sympathetic nerve activity in pregnant rabbit].

We have shown that an increase in uterine resting tonus causes an increase in maternal blood pressure and a decrease in renal blood flow, and a neural factor may control this phenomenon through a Utero-Renal Reflex in pregnant rabbits. To explore this possible neural factor, we examined the changes in renal sympathetic nerve activity (R-SNA) in late pregnant rabbits under urethane anesthesia. SNA was measured with a bipolar electrode and renal cortical blood flow (RBF) was measured by a thermocouple method. An increase in uterine resting tonus was made by inserting a small balloon into the uterine cavity on the ovarian or cervical side. An increase in resting tonus on the ovarian side caused an increase in maternal blood pressure, increases in R-SNA and renal vascular resistance (RVR), and a decrease in RBF. However, an increase in resting tonus on the cervical side resulted in an increase in maternal blood pressure, slight increases in R-SNA and RVR, and an increase in RBF. These data indicate that an increase in uterine resting tonus can stimulate R-SNA, which in turn causes the deterioration of renal circulation.

[Studies on renal sympathetic nerve activity related to the existence of a utero-renal reflex in pregnant rabbit].

We have shown that the changes in renal blood flow (RBF) and renal sympathetic nerve activity (R-SNA) in metreurysis are different on the ovarian side from those on the cervical side. We examined their dissimilar mechanisms, and the changes in noradrenaline in the renal vein under metreurysis as an indicator of SNA and we also explored the pathway of Utero-Renal Reflex. In pregnant rabbits, SNA was measured by using bipolar electrode and renal cortical blood flow was measured by the thermocouple method. Noradrenaline was measured by HPLC. A small balloon was inserted into the uterine cavity on the ovarian or cervical side to increase the uterine resting tonus (URT). Noradrenaline increased under metreurysis with the increase in R-SNA. After protecting the abdominal large vessels an increase in URT in the cervical side caused the elevation of mean blood pressure, an increase in R-SNA and a decrease in RBF. After blocking the nerve around the suspensory ligaments an increase in URT in ovarian side did not cause an increase in R-SNA or a decrease in RBF. These data indicate that an increase in URT can stimulate R-SNA through the Utero-Renal Reflex, which in turn causes the deterioration of renal circulation.

Fetal breathing adaptation to prolonged hypoxaemia in sheep.

Prolonged (6 days) fetal hypoxaemia was produced by placing pregnant ewes in an environmental chamber. A constant flow of N2 into the chamber reduced the fraction of inspired oxygen (Fi02) to 0.139 +/- 0.001, simulating an altitude of 4270 m. This reduced maternal PaO2 by about 39 mmHg and PaCO2 by nearly 5 mmHg, which produced a hypocapnic (delta PaCO2 = -5 mmHg) hypoxaemia (delta PaO2 = -8 mmHg) in the fetus. An analysis of the first 4 h of breathing recorded each day (1800-2200 h; start of hypoxaemia: 1200 h) showed that the incidence (12 +/- 2.0 min/day) during the first day of hypoxaemia was significantly less (P less than 0.05) than that (24 +/- 3.1 min/h) during the same time of the control day. By the second day, breathing had returned to normal. Further analysis indicated that a normal incidence of breathing may have occurred as early as 14 h after starting hypoxaemia. These results suggest that fetal breathing movements adapt rather quickly to this degree of hypocapnic hypoxaemia.

Influence of maternal hyperoxia or hypercarbia on the hemodynamics of the placenta and fetal brain.

Pregnant rabbits were subjected to inhalation of different gases, and the changes in placental blood flow (PBF), fetal heart rate (HR), and fetal cerebral blood flow (CBF) associated with the changes in maternal blood gas levels were studied. The results are given below. In maternal hyperoxia, maternal blood pressure (BP) was not much influenced and PBF remained unchanged or was slightly decreased when the PCO2 level was not varied or when it was lowered. In contrast, not only maternal BP but also PBF was increased when the PCO2 level was elevated. In the absence of a conspicuous increase in PCO2, neither fetal HR nor CBF varied, regardless of PBF. Both maternal BP and PBF were increased in mild to moderate maternal hypoxia (PO2 greater than 40 mmHg) and decreased in severe hypoxia (PO2 less than 30 mmHg). The decreasing trend of fetal HR or CBF was strengthened as maternal hypoxia was intensified. An obvious decrease in either parameter was observed in severe maternal hypoxia (PO2 less than 30 mmHg). Fetal HR and CBF were well maintained. in hypoxic dams with increased PBF as compared with those with unchanged or decreased PBF. The higher the PCO2 level or the lower the pH value, the more was fetal bradycardia that was apt to occur, even in a mildly hypoxic state.

Experimental study on the hemodynamics of the neonatal brain.

The effects of inhalation of different gases were studied in neonatal rabbits with the following results: In neonates with normal heart rate (HR), hyperoxia induced by O2 inhalation did not appreciably affect HR, but it increased cerebral tissue PO2, while decreasing cerebral blood flow (CBF). In many of those which fell into a state of marked bradycardia, not only HR and CBF but also cerebral tissue PO2 levels were recovered as a result of O2 inhalation. CBF was increased even when HR was hardly changed (at least when the HR decrease was 10% or less) by hypercarbia due to inhalation of CO2 mixed air. Severe hyperoxia induced by N2O inhalation caused bradycardia and reduced CBF.