The relationship between plasma levels of leptin and androgen in healthy and preeclamptic pregnant women

BACKGROUND: To clarify the role of leptin and androgens in the pathogenesis of preeclampsia, we wanted to assess role of maternal leptin in women with severe and mild preeclampsia and the effects of sex steroid hormones on leptin production. METHODS: The groups consisted of 40 healthy pregnant women (HPW) as well as 55 pregnant women with severe preeclampsia (SPE) and 41 pregnant women with mild preeclampsia (MPE). No significant differences were observed between the three groups regarding age, gestational age and body mass index (BMI). Plasma leptin, total testosterone (T), estradiol (E(2)), dehydroepiandrosterone sulfate (DHEAS) and androstenedione (A) levels were measured. Statistical analysis was achieved with one-way analysis of variance (anova) followed by post hoc multiple comparisons with the Tukey honestly significant difference (HSD) test by using SPSS for Windows statistical computer program, and the Pearson's coefficient of correlation was calculated. RESULTS: The plasma level of leptin was significantly increased in the SPE and MPE groups (p < 0.001), whereas the plasma level of T was significantly increased only in the SPE group (p < 0.001). However, there was no significant difference in plasma levels of DHEAS among the three groups (p < 0.05). The plasma level of A was significantly decreased in the MPE group (p < 0.05). There was no significant difference in the plasma level of E(2) in the MPE and SPE groups (p < 0.05). There was a significant positive correlation between the plasma levels of leptin and E(2) in the MPE group (r = 0.41, p < 0.001). CONCLUSION: We concluded that the elevated plasma levels of leptin and testosterone could contribute to the endothelial dysfunction involved in the pathogenesis of preeclampsia, and that estradiol might lead to an increase in the plasma levels of leptin.     

Granulocyte superoxide anion production and regulation by plasma factors in normal and preeclamptic pregnancy

Data on the respiratory burst activity of granulocytes from healthy and preeclamptic women have remained contradictory. To investigate the role of reactive oxygen species in the etiology of preeclampsia we measured superoxide anion generation by granulocytes from non-pregnant, healthy, and preeclamptic women. We also examined the reciprocal effects of heat-inactivated and non-inactivated plasma on superoxide production. Superoxide generation was measured by ferricytochrome-c reduction. Superoxide production induced by either phorbol-12,13-dibutirate or N-formyl-methionyl-leucyl-phenylalanine was significantly decreased in granulocytes from normal pregnant women compared with non-pregnant and preeclamptic women. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from non-pregnant and preeclamptic women was significantly inhibited by plasma from healthy pregnant women. The N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide production by granulocytes from non-pregnant and preeclamptic women was suppressed only by non-inactivated plasma, not heat-inactivated plasma from healthy pregnant women. Plasma from preeclamptic women did not influence the phorbol-12,13-dibutirate- and N-formyl-methionyl-leucyl-phenylalanine-induced superoxide production by control granulocytes. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from healthy pregnant women was significantly increased by the effect of plasma from non-pregnant and preeclamptic women, but when stimulating with N-formyl-methionyl-leucyl-phenylalanine only non-inactivated plasma caused the same enhancement. These data indicate that reduced superoxide generation in normal pregnancy may be caused by maternal immunosuppressive factors present in plasma. The failure to reduce superoxide production in preeclampsia may be partly responsible for the endothelial dysfunction characteristic of that condition.     

The effect of healthy pregnant plasma and preeclamptic plasma on the phagocytosis index of neutrophil granulocytes and monocytes of nonpregnant women

Objective: Phagocyte function of neutrophil granulocytes and monocytes is decreased in healthy pregnancy and further decreased in preeclampsia. The cause of the declined function is unknown. Decreased phagocyte function can lead to the higher infection rate in healthy pregnancy and may also be responsible for the increased susceptibility to infections and high trophoblast concentration in preeclampsia. The aim of this study is to examine the phagocyte function of neutrophil granulocytes and monocytes. Methods: Monocytes and neutrophil granulocytes were separated from the peripheral circulation of six nonpregnant patients and incubated in plasma samples from six healthy pregnant, six preeclamptic pregnant, and six nonpregnant patients. The cells were marked and evaluated for the phagocytosis index with immunofluorescent microscope after phagocyting the zymosan molecules. Results: Phagocyte function of neutrophils as well as monocytes from nonpregnant patients were decreased significantly when the cells were incubated in plasma samples from healthy pregnant patients, and further decreased when incubated in plasma samples from preeclamptic pregnant women. Conclusion: The decreased phagocyte function of neutrophil granulocytes and that of monocytes in healthy pregnancy and the further decreased phagocyte function in preeclampsia is caused by factor(s) in the maternal circulation.     

Effect of magnesium sulfate on plasma endothelin-1 levels in normal and preeclamptic pregnancies.

OBJECTIVE: We attempted to determine the effects of magnesium sulfate on: (1) endothelin-1 concentration in preeclampsia, preterm labor, and term pregnancy and (2) endothelin-1 release from human umbilical cord endothelial cells. STUDY DESIGN: Plasma samples were prospectively collected from eight women with preeclampsia, six preterm labor patients, and eight term patients undergoing external cephalic version before and 2 hours after magnesium sulfate infusion. Supernatants were collected from human umbilical cord endothelial cells exposed to magnesium sulfate and controls. All samples were assayed with a specific radioimmunoassay for endothelin-1. Paired Student t test and analysis of variance were used for statistical analysis. RESULTS: Magnesium sulfate infusion in preeclampsia lowered endothelin-1 levels compared with preinfusion values (6.6 +/- 3.81 before and 4.75 +/- 2.28 after infusion, p < 0.02). Magnesium sulfate did not have an effect on endothelin-1 concentration in preterm and term pregnancies. Magnesium sulfate did not alter the endothelin-1 release from human umbilical cord endothelial cells. CONCLUSION: A significant reduction of endothelin-1 plasma levels after magnesium sulfate therapy is limited to preeclampsia. In contrast, this lowering effect was not exhibited in women without preeclampsia or in normal endothelial cells.     

L-Arginine erythrocyte transport in normal pregnant and preeclamptic women

OBJECTIVE: Uptake of L-arginine by the cell via amino acid transporter systems is the first step for nitric oxide (NO) production. The current study aimed to assess the total L-arginine uptake in erythrocytes of normal pregnant and preeclamptic women. STUDY DESIGN: Twenty-one normal pregnant and 21 preeclamptic women were studied. To measure total L-arginine uptake in erythrocytes, carbon 14 was used as a marker and Michaelis-Menten kinetic parameters (V(max) and K(m)) were evaluated. RESULTS: In preeclamptic women, there was a significant increase (P<.004) in the mean maximal capacity of transport in erythrocytes (V(max)=982.69 micromol/L cells/h+/-433.51) in comparison with normal pregnant women (V(max)=584.73 micromol/L cells/h+/-422.33). No significant difference was detected in the half-saturation constant (P=0.978). CONCLUSION: The transport kinetics of the NO precursor, L-arginine, is altered in erythrocytes of preeclamptic women. It is possible that abnormal L-arginine uptake may contribute to the pathophysiologic mechanisms of preeclampsia syndrome.     

Progesterone and estradiol production by normal and preeclamptic placentas

Placentas obtained from women with preeclampsia produce more thromboxane, a potent vasoconstrictor, and less prostacyclin, a potent vasodilator, than normal. Although the factors responsible for this are not known, steroids are known to affect eicosanoid production, and the placenta is a rich source of progesterone and estradiol. If placental steroids contribute to the imbalance of increased thromboxane/decreased prostacyclin in preeclamptic placentas, then their placental production might also be abnormal. The following study was performed to see whether the placentas of preeclamptic women produce progesterone or estradiol abnormally. Fresh human term placentas were obtained immediately after delivery from normal and mild preeclamptic pregnancies. Whole placental tissues (350 mg) were incubated for three hours. Samples were collected and analyzed for progesterone and estradiol-17 beta by radioimmunoassay. Progesterone production was significantly higher in preeclamptic than in normal placentas without the addition of a precursor and with the addition of pregnenolone sulfate as a precursor, but not with the addition of pregnenolone alone. Both normal and preeclamptic placentas converted pregnenolone sulfate into progesterone as efficiently as they converted pregnenolone into progesterone. Estradiol production rates were similar in both preeclamptic and normal placentas, regardless of whether dehydroepiandrosterone sulfate was added as a precursor. These data indicate that placentas of women with mild preeclampsia produce more progesterone than normal, probably because they contain more pregnenolone sulfatase and larger stores of endogenous cholesterol. Higher concentrations of progesterone in the preeclamptic placenta could contribute to lower prostacyclin production because progesterone inhibits placental prostacyclin production.     

Cholesterol in serum and vaginal content in healthy, non-pregnant women

We examined 97 healthy and non-pregnant women aged between 17 and 58 years, who especially did not show any symptoms of vulvitis or colpitis, for the contents of cholesterol in serum and vaginal smear. In the vaginal smear we found significantly lower concentrations of total cholesterol as in serum, whereas the part of free cholesterol on total cholesterol in vaginal smear was triple than in serum and its absolutely concentration was double than that in serum. Possible reasons are discussed.     

Angiotensin II sensitivity in nonpregnant formerly preeclamptic women and healthy parous controls

BACKGROUND: In women prone to develop hypertensive complications, vascular reactivity fails to decrease in early pregnancy. Since hypertensive syndromes of pregnancy seem to be superimposed on a preexisting disorder, we tested the hypothesis that in formerly preeclamptic women, as compared to healthy parous controls, circulatory reactivity to angiotensin II is enhanced in the follicular phase of the menstrual cycle. METHODS: Sixty formerly preeclamptic women were subdivided into a hypertensive (HYPERT, n = 14), a normotensive thrombophilic (THROMB, n = 26), and a normotensive nonthrombophilic (ASYMPT, n = 20) subgroup. In these women and in 11 healthy parous controls we assessed at least 5 months postpartum at day 5 (+/-2) of the menstrual cycle the following variables: body weight, height, plasma volume, reactivity to infused angiotensin II of arterial blood pressure, heart rate, glomerular filtration rate (GFR), effective renal blood flow, and the hormones of the renin-angiotensin-aldosterone (RAAS) axis. RESULTS: At baseline, THROMB did not differ from controls. In contrast, ASYMPT exhibited slight overweight, reduced plasma volume, and reduced renal blood flow. HYPERT much resembled ASYMPT except for the overweight, renal perfusion, and GFR. Infusion of angiotensin II led to comparable decreases in renal perfusion and filtration, and to increases in blood pressure. However, sensitivity to this substance correlated inversely with relative and absolute sizes of the plasma volume compartment. CONCLUSION: Circulatory sensitivity to infused angiotensin II is comparable between nonpregnant formerly preeclamptic women and healthy parous controls. However, responsiveness to this agent is enhanced among women with a contracted plasma volume compartment, a condition commonly observed among formerly preeclamptic women.     

Plasma adiponectin concentrations in non-pregnant, normal and overweight pregnant women

AIMS: Adiponectin is an adipokine that has anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic properties. This hormone has been implicated in both the physiological adaptation to normal pregnancy and in obstetrical complications. The aims of this study were to determine normal maternal plasma concentrations of adiponectin throughout gestation and to explore the relationships between plasma adiponectin concentration, pregnancy, and maternal overweight. METHODS: A cross-sectional study was designed to include normal pregnant (normal weight and overweight; 11-42 weeks of gestation), and non-pregnant women. Plasma adiponectin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. RESULTS: (1) Adiponectin was detectable in the plasma of all patients; (2) there was no significant differences in the median adiponectin concentration between pregnant and non-pregnant women; (3) plasma adiponectin concentrations were negatively correlated with gestational age only among normal weight pregnant women; and (4) overweight patients had significantly lower plasma adiponectin concentrations than normal weight women. CONCLUSIONS: Consistent with the increased insulin resistance and weight gain that occur in pregnancy, adiponectin concentrations were negatively correlated with gestational age. The results of this study and the nomogram herein presented, can serve as the basis to explore the relationship between adiponectin and pregnancy complications and facilitate the clinical use of this important adipokine.     

Objective assessment of obstructive sleep apnea in normal pregnant and preeclamptic women

Objective: Obstructive sleep apnea (OSA) is a risk factor for adverse pregnancy outcomes. The aim of this study was to evaluate the association between OSA and preeclampsia. Methods: Between 30 and 39 weeks gestation, objective sleep apnea were evaluated in 38 normal pregnant and 40 preeclamptic women. Preeclampsia was defined by having a blood pressure (BP) > 140/90 mmHg on two occasions after the 20th week of pregnancy with excess protein in the urine (> 300 mg in 24 h) or 30 mg persistent proteinuria (+ 1 in dipsticks) in random samples. Objective sleep apnea was evaluated using an overnight in-hospital sleep evaluation using the SOMNOwatch plus Respiratory Screener. OSA was defined as an apnea–hypopnea index (AHI) ≥ 5, and further grouped into severity categories: mild (5–14.9), moderate (15–29.9), and severe (≥ 30). Results: Mean AHI was 33.3 ± 12.1 in preeclamptic women and was 23.8 ± 15.8 in normal pregnant women (p = 0.008). There was significant difference in prevalence of OSA severity (none, mild, moderate, or severe) between groups. Out of 33 preeclamptic women, 11 women had moderate and 22 women had severe OSA. Whereas, among 33 normal pregnant women, 8, 13, and10 women had mild, moderate, and severe OSA, respectively. Two normal pregnant women had no OSA (AHI< 5). Conclusion: Our study suggests women are susceptible to developing OSA during pregnancy that is associated with an increased risk of preeclampsia.     

An imbalance in the production of proinflammatory and anti-inflammatory cytokines is observed in whole blood cultures of preeclamptic women in comparison with healthy pregnant women

Objective: To compare the production of pro- and anti-inflammatory cytokines by whole blood samples stimulated with lipopolysaccharide from normotensive and preeclamptic women. Methods: The synthesis of tumor necrosis factor-α, interleukyn-1β, interleukin-6 and interleukin-10 were assayed by immunosorbent assays in 56 and 50 preeclamptic and normotensive women, respectively. Results: Preeclamptic women showed a higher synthesis (p?p?Conclusion: Preeclamptic women showed an imbalance in the production of pro and anti-inflammatory cytokines in comparison with normotensive women.     

Pulsatile secretion of pregnancy-associated plasma protein-A (PAPP-A) in non-pregnant women

No changes in PAPP-A levels could be detected when plasma samples were obtained every second day throughout the entire menstrual cycle in three healthy women. But when measured every 30 min throughout 12 consecutive hours, in four healthy women, PAPP-A followed a pulsatile pattern which may originate in the endometrium since no PAPP-A pulses were detected in a long-term hysterectomized woman, or in two men. The pulses were not related to levels of oestradiol, progesterone, FSH or LH.     

Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women

OBJECTIVE: B-type natriuretic peptide (BNP) is synthesized in cardiac ventricles in response to volume expansion. This study evaluated BNP levels to determine trends during pregnancy, and to assess BNP as a diagnostic tool in preeclampsia. STUDY DESIGN: We studied 163 BNP levels in 118 pregnant women, ranging from first trimester to term. An additional 34 patients with preeclampsia were studied and compared to 25 normal control patients at term. Plasma BNP values were determined using a standard assay. RESULTS: The median BNP levels during the 1st, 2nd, 3rd trimester, and at term were equivalent (18.4, 17.9, 15.5, and 17.8 pg/mL, respectively, P = .796). The median BNP levels in normal patients, mild preeclamptics, and severe preeclamptics were 17.8, 21.1, and 101 pg/mL, respectively, with the severe group being significantly higher than the mild group (P = .003) and any phase of normal pregnancy (P < .001 in each case). A BNP cut-off of <40.6 pg/mL had a negative predictive value of 92% in excluding preeclampsia. CONCLUSION: In normal pregnancies, median BNP values are <20 pg/mL, and stable throughout gestation. In severe preeclampsia BNP levels are elevated. This may reflect ventricular stress and/or subclinical cardiac dysfunction associated with preeclampsia.     

Pulsatile secretion of pregnancy-associated plasma protein-A (PAPP-A) in non-pregnant women

Summary. No changes in PAPP-A levels could be detected when plasma samples were obtained every second day throughout the entire menstrual cycle in three healthy women. But when measured every 30 min throughout 12 consecutive hours, in four healthy women, PAPP-A followed a pulsatile pattern which may originate in the endometrium since no PAPP-A pulses were detected in a long-term hysterectomized woman, or in two men. The pulses were not related to levels of oestradiol, progesterone, FSH or LH.     

Hydroxyprogesterone caproate and progesterone increase tumor necrosis factor-alpha production in lipopolysaccharide stimulated whole blood from non-pregnant women

OBJECTIVE: Hydroxyprogesterone caproate (17-P) and progesterone have been shown to decrease the rate of preterm birth in high-risk pregnant women, but the mechanism of action is unknown. We hypothesized that 17-P or progesterone would reduce production of the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), after lipopolysaccharide (LPS) stimulation of whole blood. STUDY DESIGN: Whole blood collected from 10 non-pregnant women in the follicular phase was treated with LPS (1000 ng/mL) alone or with either 17-P or progesterone (125 ng/mL and 1250 ng/mL) and LPS. Supernatant collected after 24 h was tested for TNF-alpha by enzyme immunoassay. Results were compared using the Wilcoxon rank sum test. RESULTS: Whole blood treated with 17-P or progesterone in addition to LPS produced significantly higher TNF-alpha concentrations than blood treated with LPS alone. CONCLUSION: 17-P and progesterone appear to have a pro-inflammatory effect during LPS stimulation of blood from non-pregnant women in vitro. Our data suggest that the reduction in pre-term birth in women treated with progesterone is not mediated through an anti-inflammatory effect on peripheral blood cells.     

Comparison of plasma prostaglandins in the non-pregnant and pregnant women: a longitudinal study

Plasma levels of PGE2 and PGF2 alpha were determined in women from 24 to 40 weeks of pregnancy with non-pregnant women as controls. The plasma levels of PGE2 showed no significant changes as gestation advanced except for late pregnancy only. Furthermore, there were no significant differences observed between the control and pregnant subjects except late in pregnancy. On the other hand, the concentrations of PGF2 alpha in the pregnant subjects revealed a significant increase (p less than 0.005) compared with those of the controls, though no significant changes were observed with the advance of gestation except for late pregnancy. The PGF2 alpha/PGE2 ratio showed a six to ten times rise during pregnancy (p less than 0.005) compared with that of the controls. Therefore, the results obtained in the present study may explain the effectiveness of prostaglandin synthetase inhibitors in suppressing preterm uterine contraction and they also indicate the involvement of some factors in the initiation and inhibition of the myometrium contraction.     

The effect of 17beta-estradiol on isolated omental arteries from preeclamptic women

OBJECTIVE: To study the effect of 17beta-estradiol on isolated omental arteries from preeclamptic women. STUDY DESIGN: Rings of omental artery with intact endothelium were mounted in organ chambers for isometric tension recording. We studied the effect of pharmacological concentrations of 17beta-estradiol on potassium chloride-induced tension and the concentration-contraction relationships for norepinephrine and calcium. RESULTS: Cumulative application of 17beta-estradiol, in a concentration-dependent manner, relaxed potassium chloride contracted rings. Sixty minutes of incubation with 17beta-estradiol (10(-5)mol/l) attenuated the tension developed in response to potassium chloride, norepinephrine and calcium. Tamoxifen (10(-6)mol/l) did not antagonize the inhibitory actions of 17beta-estradiol. CONCLUSIONS: Pharmacological concentrations of 17beta-estradiol retain the capability for relaxing omental artery rings from preeclamptic women. The loss of refractoriness to norepinephrine, increased responsiveness to calcium ions and decreased ability of 17beta-estradiol to inhibit calcium-induced tension may be responsible for increased vascular reactivity in preeclampsia.     

Effect of a combination of norethynodrel and mestranol on plasma luteinizing hormone in normal women

Plasma luteinizing hormone (LH) levels were measured by radioimmunoassay in 6 normal nulliparous women (ages 21-25) during 2 consecutive menstrual cycles. Cycle 1 served as the control, while a combination of 5 mg norethynodrel and .075 mg mestranol (Enovid) was administered daily during the second cycle. Midcycle LH peaks observed in all subjects during the control cycle were completely suppressed in the treated cycle. Basal LH levels during the treated cycle were significantly lower than during the follicular phase of control cycles. Mechanisms by which Enovid could affect plasma LH include decreased synthesis or release of LH and different sites of drug action with different dosages.