Profiles of intermediary metabolites in insulin-dependent pregnant diabetic women with or without endogenous insulin production.

The levels of glucose, free fatty acids (FFA), glycerol, 3-hydroxybutyrate (3-HB), cyclic AMP, and C-peptide immunoreactivity (CPR) were determined in venous plasma samples taken every half hour during an 8-h period under standardized conditions in 10 insulin-dependent pregnant women. The metabolic profiles were determined in each trimester of pregnancy. The women were divided into two groups, one with (group I: 3B, 1C, and 1D according to White's classification) and one without (group II: 1B, 3C, and 1D) measurable plasma CPR levels. Plasma glucose values were significantly higher (P less than 0.01) with greater variability in group II than in group I in the first and second trimesters, while no such difference was found in the third trimester of pregnancy. FFA, glycerol, 3-HB, and cyclic AMP levels were not different between the groups in any trimester of pregnancy. Amniotic fluid CPR was higher and skinfold thickness of the newborn greater in group II than in group I. Neonatal complications occurred only in infants of group II mothers. It is concluded that determination of plasma CPR in diabetic women in early pregnancy could give additional prognostic information to that obtained by the White classification.

Plasma endothelin in normal and diabetic pregnancy.

OBJECTIVE: To examine endothelin-1 (ET-1) concentrations longitudinally throughout pregnancy in healthy and insulin-dependent diabetic women and to evaluate the relationship between ET-1 and big ET-1 in normal pregnancy. RESEARCH DESIGN AND METHODS: Venous blood samples were obtained consecutively in gestational weeks 18, 28, and 38 from 40 healthy women with uneventful pregnancies and 24 pregnant women with IDDM. By radioimmunoassay, plasma ET-1 and big ET-1 were analyzed in the healthy women and plasma ET-1 in the diabetic women. RESULTS: In the diabetic pregnant women, plasma ET-1 levels were significantly higher than in healthy pregnant women during the entire observation period (P < 0.001), but did not change with advancing gestational age. Five of the diabetic, but none of the healthy pregnant women, developed preeclampsia. ET-1 levels did not differ between the diabetic women who developed preeclampsia and those who did not. Plasma ET-1 levels in healthy pregnant women were within the range of those in healthy nonpregnant women and did not change during pregnancy. The big ET-1 levels increased and the ET-1/big ET-1 ratio decreased significantly during the observation period. CONCLUSIONS: Plasma ET-1 levels do not change with advancing gestational length. During normal pregnancy, the ET-1/big ET-1 ratio decrease, indicating a suppressed converting enzyme activity or altered clearance of ET-1. Pregnant women with IDDM have markedly elevated ET-1 levels. Although diabetic women with and without preeclampsia did not differ with respect to endothelial dysfunction, as reflected by elevated ET-1 concentration, we cannot exclude that altered endothelial function may be of importance for the increased frequency of preeclampsia in pregnant IDDM patients.

Relation of naproxen kinetics to effect on platelet prostaglandin release in men and dysmenorrheic women.

The purpose of our investigation was to determine kinetics of naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid] relative to its inhibition of PGF 2 alpha release during thrombin-induced platelet aggregation in man after a single oral dose of 250 or 500 mg. Naproxen and its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid were measured by high-performance, reversed-phase liquid chromatography with fluorimetric detection. PGF 2 alpha was measured by radioimmunoassay in platelet-rich plasma (PRP). Our subjects were four healthy adult men and five dysmenorrheic women. Peak concentrations of naproxen varied between 26 and 69 microgram/ml and half-lifes varied between 9.5 and 21.9 hr, mean = 16.4 hr +/- 4.4 (SD). Naproxen plasma protein binding exceeded 99.9%. The concentration of the metabolite was less than 1% of naproxen and followed the same plasma concentration profile as the parent compound. The based concentration of PGF 2 alpha varied between 0.13 and 6.3 ng/ml, mean = 1.5 +/- 1.9 ng/ml. With no exception, there was a marked decrease in the PGF 2 alpha concentration in thrombin-stimulated PRP during therapy, and concentration was inversely correlated to the total plasma naproxen concentration.

Natural oestrogen in the female climacteric--influence on blood coagulation and fibrinolysis.

The aim of the present study was to investigate the effect on blood coagulation and fibrinolysis of a natural oestrogen preparation, piperazine oestrone sulphate, prospectively in menopausal women. Scopolamine was given to the control group. The women were investigated before and during treatment with regard to factors VIII, VII, X, V, fibrinopeptide A, antithrombin III, plasminogen, rapid antiplasmin and alpha 1-antitrypsin. There was no significant change towards hypercoagulability or decreased fibrinolysis in any group. In the oestrogen group, however, a tendency towards an increased level of plasminogen and a decreased level of antiplasmin was demonstrated. In the scopolamine group there was an unexpected fall in factors X and V and also in plasminogen and alpha 1-antitrypsin. A low level of some blood coagulation factors in some of the women before treatment is somewhat astonishing; none of them had any history of excessive bleeding.

Effects of isradipine on endothelin-induced constriction of myometrial arteries in normotensive pregnant women.

The results of our previous studies suggested that endothelin-1 (ET-1) might be contributory to the impaired uteroplacental blood flow seen in preeclampsia. The aim of this study was to investigate the in vitro influence of isradipine on ET-1-induced contraction of myometrial resistance arteries from pregnant women, as these vessels are partly responsible for the regulation of uteroplacental blood flow in preeclampsia. Small myometrial arteries were dissected from myometrium obtained from 20 normotensive term pregnant women undergoing elective cesarean section and mounted in a tissue chamber. Tension was recorded isometrically. When ET-1 (10(-8) mol/L)-contracted vessels were exposed to increasing concentrations (10(-6), 10(-5), and 10(-4) mol/L) of isradipine, the myometrial arteries demonstrated essentially no relaxation. A significant mean relaxation of 31% was seen only with the highest isradipine concentration of 10(-3) mol/L. Pretreatment with isradipine attenuated ET-1-induced contraction by 26% at 3 x 10(-4) mol/L and by up to 80% at 10(-3) mol/L. Preincubation with lower concentrations of isradipine did not significantly reduce subsequent ET-1 contraction. The present study has thus shown that isradipine at high concentrations counteracts ET-1-induced constriction of myometrial arteries in term pregnant women. Pretreatment with isradipine at high concentrations attenuates the ET-1 contraction.

Transplacental passage of isradipine in the treatment of pregnancy-induced hypertension.

The aim of this study was to assess the concentration of isradipine in maternal and fetal plasma, and in amniotic fluid under steady-state conditions. Eight women were treated with 5-mg isradipine tablets twice daily and eight women were given slow-release isradipine capsules (SRO) twice daily for hypertension in pregnancy. Blood and amniotic fluid sampling for analysis of drug concentration was performed at delivery. In the isradipine tablet group, maternal and fetal plasma levels were 788 +/- 701 pg/mL (mean +/- SD) and 270 +/- 90 pg/mL, respectively. The corresponding levels in the SRO-treated group were 463 +/- 217 pg/mL and 185 +/- 95 pg/mL, respectively. In the amniotic fluid, the concentration was 74 +/- 42 pg/mL in the tablet group and 45 +/- 14 pg/mL in the SRO group. Therefore, isradipine passes the placental barrier, but its concentration is considerably lower in the fetal compartments.

Maternal hemodynamics and impaired fetal growth in pregnancy-induced hypertension.

Twenty-one subjects with pregnancy-induced hypertension were investigated with regard to the relationship between maternal hemodynamics and fetal growth. Five of the infants were small for gestational age (SGA) (less than tenth percentile) and 16 were appropriate for gestational age (AGA) (greater than tenth percentile). Mean arterial blood pressure, cardiac output, and stroke volume were significantly lower in the group of mothers with SGA infants than in the group with AGA infants (102 +/- 3 versus 115 +/- 3 mmHg, 5.8 +/- 0.2 versus 8.2 +/- 0.3 L/minute, and 76 +/- 7 versus 100 +/- 5 mL, respectively). The results of this investigation suggest that the hemodynamic background to the blood pressure increase in pregnancy-induced hypertension ranges from a low cardiac output, high vascular resistance condition to a high-output, low-normal resistance variant. The former subtype is often associated with the birth of an SGA infant.

Cardiovascular responses to isometric handgrip exercise: an invasive study in pregnancy-induced hypertension.

Nine patients with pregnancy-induced hypertension and nine healthy pregnant controls were compared in the last trimester with regard to cardiovascular and sympathoadrenal reactivity during a standardized isometric handgrip exercise test. At rest, the blood pressure elevation with pregnancy-induced hypertension resulted from increased systemic vascular resistance. The test increased the blood pressure, heart rate, cardiac output, stroke volume, and epinephrine and norepinephrine concentrations in arterial plasma, but did not change the calf or systemic vascular resistance. The responses of the two groups did not differ significantly with regard to any of the above variables. Thus, pregnancy-induced hypertension does not seem to be associated with exaggerated cardiovascular or sympathoadrenal reactivity to isometric exercise when compared with normal pregnancy. The mechanism underlying the blood pressure response appears to be similar in the two groups, ie, an increase in cardiac output.

Sympathoadrenal and cardiovascular responses to mental stress in pregnancy-induced hypertension.

Nine patients with pregnancy-induced hypertension and nine healthy pregnant controls with similar gestational lengths were compared with regard to cardiovascular and sympathoadrenal reactivity during a standardized mental stress procedure (Stroop color word conflict test). The test induced increases in blood pressure, heart rate, cardiac output, arterial plasma epinephrine and norepinephrine concentrations, and a decrease in calf vascular resistance, but no changes in stroke volume or systemic vascular resistance. The responses of the two groups did not differ significantly with regard to any of the mentioned variables. Pregnancy-induced hypertension does not seem to be associated with an exaggerated cardiovascular or sympathoadrenal reactivity to mental stress when compared to normal pregnancy.

Effects of nitroglycerin on the uterine and umbilical circulation in severe preeclampsia.

OBJECTIVE: To determine the effects of nitroglycerin on placental circulation in severe preeclampsia. METHODS: Twelve women with severe preeclampsia were examined. Uterine and umbilical artery pulsatility indices (PI) were assessed by pulsed Doppler ultrasound before and after infusion of nitroglycerin, starting at 0.25 micrograms/kg per minute with stepwise dosage increases until a diastolic blood pressure (BP) of 100 mmHg was achieved. Blood pressure and heart rate were recorded every 5 minutes. Blood was sampled for analysis of the second messenger of nitric oxide, cyclic guanosine monophosphate (cGMP), before and at the end of the infusion. RESULTS: During the infusion, the mean systolic BP decreased from 161 (95% confidence interval [CI] 154-169) to 138 mmHg (95% CI 131-146), and the diastolic pressure decreased from 116 (95% CI 111-122) to 103 (95% CI 96-110) mmHg (P < .01). The PI of the uterine artery did not change significantly (1.23 [95% CI 1.01-1.61]) versus 1.30 [95% CI 1.01-1.88]), whereas umbilical artery PI decreased significantly (P < .01), from 1.35 (95% CI 1.09-1.73) to 1.20 (95% CI 1.05-1.40), with a more pronounced decrease in patients with high basal values. Cyclic GMP remained essentially unchanged (6.4 [95% CI 5.4-7.7] versus 5.5 [4.7-6.6] nmol/L). CONCLUSION: The reduction in the PI of the umbilical artery during nitroglycerin-induced BP reduction implies vasodilation in the umbilical circulation. The absence of an increase in cGMP does not support the view that the nitroglycerin effect is reflected by the plasma concentration of cGMP.

Endothelin-1 and big endothelin-1 levels in normal term pregnancy and in preeclampsia.

To study the concentrations of endothelin-1 (ET-1) and its precursor, big ET-1, in samples of amniotic fluid, fetal urine, umbilical arterial and venous blood, retroplacental blood and maternal uterine and brachial venous blood obtained from normal and preeclamptic women. Samples were collected from 31 healthy pregnant women (16 in labor and 15 undergoing elective cesarean section) and 35 preeclamptic women (9 in labor and 26 undergoing cesarean section). Big ET-1 and ET-1 were measured by radioimmunoassay and the ET-1 to big ET-1 ratios were calculated. In preeclamptic women there was a significant elevation of ET-1 in the maternal brachial and uterine veins and of big-ET-1 in the brachial vein. The ET-1 concentrations and the ET-1/big ET ratios were significantly higher on the fetal side (i.e., in the umbilical vein and amniotic fluid) than in maternal blood, but in these sampling locations there was no difference between the normal pregnancy and preeclampsia group. A significant negative correlation (r = -0.67, P < 0.01) was found between plasma ET-1 in the umbilical vein and birth weight in the preeclamptic group. ET-1 was significantly higher in amniotic fluid than in the first neonatal urine of corresponding pregnancies (15.0 +/- 2.0 vs. 3.0 +/- 2.9 pmol/l, P < 0.05). The ET-1 and big ET-1 concentrations are significantly higher in fetal plasma and amniotic fluid than in maternal plasma, indicating increased endothelin converting enzyme activity and increased ET-1 production in utero. The elevated ET-1 concentration in maternal blood in preeclamptic compared with normal pregnant women and the negative correlation between ET-1 in the umbilical vein and birth weight suggest that ET-1 plays a pathophysiological role in preeclampsia and other conditions with intrauterine growth restriction.

Neurochemical differentiation of human bulbospinal monoaminergic neurons during the first trimester.

The neurochemical differentiation of bulbospinal noradrenergic and serotonergic neurons has been followed in first trimester human fetuses. Analysis of microdissected CNS regions revealed detectable levels of noradrenaline (NA) and serotonin (5-HT) in pons, medulla oblongata and throughout the spinal cord from 5-6 weeks of gestation. In all regions there was a pronounced increase in tissue levels of the monoamines, especially from 8-9 weeks on. 5-HT levels were lower than NA levels except for pons, where the opposite was true. With increasing fetal age, the results seemed less consistent because of considerable interindividual variations. Using immunohistochemical localization of tyrosine hydroxylase (TH), a marker for noradrenergic neurons, immature cell bodies were seen in the brain stem at the earliest stage studied, that is at 4 weeks of gestation. Several TH and 5-HT-immunoreactive (IR) cell groups were found in pons and medulla oblongata at 5 weeks. Significant structural differentiation of TH- and 5-HT-IR cell bodies was seen during the first trimester. Immunoreactive fibers began to appear at 5 weeks in the cervical spinal cord. At 6 weeks both types of fibers could be found in the white matter throughout the entire spinal cord while fibers in gray matter appeared at 9 weeks. The number of TH-IR fibers was considerably larger than the number of 5-HT-IR fibers. This is the first time the biochemical development of human bulbospinal monoaminergic neurons during the first trimester has been described. Continued investigations of the ontogenetic growth and differentiation of these human bulbospinal monoaminergic neurons will gain necessary insight into the genetically determined capacity for plasticity, potentially possible to activate later in life in response to spinal cord injury. Further, intraspinal transplantation of CNS tissue relevant to the severed spinal cord would by necessity entail selection of embryonic cell populations. Using such therapeutic strategies, detailed knowledge of the inherent capacities of the donor tissues will be crucial.

Nerve conduction in diabetic pregnancy. A prospective study.

Repeated neurographic examinations were performed during and after the pregnancies of 32 diabetic women who had no signs of neuropathy before pregnancy or at the initial examination during the first trimester. The motor conduction velocity, the sensory conduction velocity and the peak amplitude of the compound action potential of the investigated peripheral nerves were not affected by pregnancy. It is concluded that pregnancy does not impair nerve conduction or induce neuropathy in most diabetic women.

Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17 beta-oestradiol and progesterone in the pre- and post-menopause.

Serum concentrations of 17 beta-oestradiol (E2), unconjugated oestrone (E1), total oestrone (tE1), progesterone (P), follicle-stimulating hormone (FSH) and sex-hormone-binding globulin (SHBG) were measured before and after daily intravaginal administration of 250 micrograms micronized E2 and 10 mg micronized P for 14 days to 12 post-menopausal and for 1 day only (during cycle days 5-8) to 11 pre-menopausal women. In the post-menopausal women the levels of all steroids increased to maximum values on day 1, 8-10 h after administration and fell thereafter. In the pre-menopausal women the steroid concentrations rose slowly to a plateau level 10-15 h after administration. Significantly higher absorption of E2 and E1 (area under the curve increments) was noted in the post-menopausal than in the pre-menopausal women. In the post-menopausal women the steroid levels measured on days 7 and 14 corresponded to those observed in the very early or late luteal phase. Area under the curve increments were usually smaller on days 7 and 14 than on day 1 and the absorption kinetics altered to a 'pre-menopausal' pattern. FSH levels were significantly reduced as from 12 h after administration on day 1 and onwards. A slight (10%) but significant increase in SHBG levels was noted on day 14. It was concluded that the combined E2 and P treatment used in this investigation brings about a physiological response with only minimal side effects on the liver as judged from changes in SHBG concentrations.

Adrenal steroids in post-menopausal women: relation to obesity and to bone mineral content.

Basal levels and ACTH-induced increments of serum 17 alpha-hydroxyprogesterone (170HP), cortisol, 4-androstene-3,17-dione (A-4), dehydroepiandrosterone (DHA), and dehydroepiandrosterone sulphate (DHAS) were related to the degree of obesity and to trabecular bone mineral density in 29 postmenopausal women. The ACTH-induced increment of 170HP (delta 170HP) was negatively correlated to basal DHA and delta DHA. Positive correlations were found between obesity, expressed as Broca's index, and delta DHA and the delta DHA/delta 170HP ratio. Bone mineral density was positively correlated to basal DHAS, delta DHA, delta DHAS and the delta DHA/delta 170HP ratio, and negatively correlated to delta 170HP. DHA and 170HP represent a crossroad in adrenocortical steroid biosynthesis, leading to delta 5-androgens and glucocorticoids as main products. Besides age, obesity may also influence the intra-adrenal distribution between these two main steroidogenic pathways. The results suggest that differences at a very early stage of the adrenal steroidogenesis may influence calcium homeostasis in the post-menopausal woman.

Adrenocortical steroids, bone mineral content and endometrial condition in post-menopausal women.

In 23 post-menopausal women, serum levels of cortisol, unconjugated dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), testosterone, unconjugated and total oestrone and prolactin were measured before and during an ACTH test. Significant positive correlations were found between basal levels of DHA and DHAS; DHA and unconjugated oestrone; DHA and total oestrone; testosterone and total oestrone and between unconjugated and total oestrone. ACTH significantly raised the levels of the steroids but not of prolactin. Significant positive correlations were found between basal levels and ACTH induced increments in DHA; between basal DHAS and increments in DHA and between increments in DHA and DHAS. A significant negative correlation was found between basal levels and increments in cortisol. No significant correlations were found between other combinations of hormone basal levels and/or increments. Significant positive correlations were found between basal levels of DHAS and the DHA response to ACTH respectively, and trabecular bone mineral content of the distal forearm. A significant correlation was also found between bone mineral content and pre-cancerous/cancerous state of the uterine epithelium. The results are a further support to the concept of a link between adrenal androgens and bone mineral density, and do also indicate a relation to endometrial pathology. The lack of correlation between cortisol and other steroids indicate different regulatory mechanisms. Prolactin does not seem to be involved in the regulation of the adrenal androgen synthesis.

Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: differences related to age and sex.

Serum concentrations of dehydroepiandrosterone sulphate (DHAS) were determined in 590 healthy women aged 20-87 yr. Simultaneous assays of dehydroepiandrosterone (DHA) were performed in 417 of the women. DHA and DHAS levels correlated negatively with age while the DHA/DHAS ratio proved to be unrelated to age. When values for 60 healthy men in the age range 20-84 yr were compared with those obtained in 60 randomly-selected healthy women who were exactly age-matched, the DHAS levels were found to be significantly lower and the DHA/DHAS ratios significantly higher in the women. These results might be of use in establishing normal clinical ranges for serum DHA, DHAS and the DHA/DHAS ratio in women.