Proton NMR spectroscopy of the phospholipids in human uterine smooth muscle and placenta.

The parameters regulating the fluidity of myometrial and placental phospholipids include double bonds, fatty acid chain lenght and the cholesterol/phospholipid ratio. The transformation of these parameters was studied during pregnancy and labor. Myometrial and placental tissue samples were collected from 24 patients: 6 were nonpregnant, 6 early-pregnant, 6 late-pregnant not in labor and 6 in labor. After butanol extraction, tissue cholesterol and lipid phosphorus were determined. Proton NMR spectroscopy of the phospholipids was performed at 500 MHz. The myometrial cholesterol/phospholipid ratio was slightly elevated in pregnant patients not in labor. The uterine muscle of the nonpregnant patients contained more CH=CH groups in the phospholipids than that of the late-pregnant patients. There were 29 more double bonds in placental than in uterine tissue per 100 fatty acid molecules. The average fatty acid chain length varied from 14.0 to 18.8. The placenta has longer fatty acid chains than the uterine smooth muscle. The myometrial carbon chain was shortened on the average by 1.4 and the placental by 1.0 carbon atoms, when the patient went into clinical labor. These findings suggest fluidity changes in myometrial and placental phospholipids during human pregnancy and labor.

Tissue phospholipids during human pregnancy by 31P NMR: myometrium, decidua, placenta and fetal membranes.

The biophysical environment formed by phospholipids, rather than the amount of functional proteins, can be rate limiting for factors controlling myometrial contractility and pregnancy maintenance. We therefore studied myometrial, decidual, placental and fetal membrane phospholipids using the 31P NMR spectrum. This enabled us to identify bulk phospholipids over 0.05 mmol/kg. The method was checked for reliability for the reproductive tissues studied. The chemical shift of phospholipid standards was slightly different according to whether a single compound or a mixture was analyzed. The bulk phospholipids found were phosphatidylcholine (PC), phosphatidylethanolamine, sphingomyelin (SM) and phosphatidylinositol. The ratio PC/SM decreased during pregnancy in the decidua, placenta and fetal membranes, but not in the myometrium. Pregnancy did not induce significant changes in the total myometrial phospholipids. Their composition was stable even during clinical labor. The fetal tissues, placenta and fetal membranes contained about twice as much phospholipid as the maternal tissues, myometrium and decidua. There was no sign of lysocompounds, cardiolipin or phosphatidic acid. This supports the view that the extraction and analyzing techniques used earlier probably created artefacts. The increased fluidity of the myometrial and placental phospholipids during pregnancy may depend on factors other than the composition of phospholipids.

Elevated serum group II phospholipase A2 levels are associated with decreased blood flow velocity in the umbilical artery.

Twenty-two hospitalized patients, diagnosed as having hypertensive disorder of pregnancy, were selected from two University Clinics. Maternal serum samples were analyzed for serum group II phospholipase A2 (PLA2-II) by time-resolved fluoroimmunoassay. At the same time, umbilical artery blood flow velocities were measured with color Doppler sonography for orientation and pulsatile Doppler sonography for recording waveforms. Nineteen normotensive third-trimester pregnant patients served as a control group. Maternal serum PLA2-II was elevated in 8 cases with preeclampsia. This elevation was invariably associated with decreased blood flow velocity in the umbilical artery. In 1 case, the clinical condition allowed simultaneous follow-up of serum enzyme and blood flow velocity: a further rise of serum PLA2-II was linked to a further decrease in the blood flow velocity of the umbilical artery. A large spillover of the elevated PLA2-II content from the preeclamptic placenta into the maternal serum is associated with a decrease in blood flow velocity in the umbilical artery. The enzyme might serve as a link between local proximal (placenta) and systemic distal (umbilical arterial blood flow) effectors.

Oviductal function is critical for very early human life.

For normal fertilization, the ovum must be picked up from the ovarian surface or from the abdominal cavity into the ampulla. The rapid transport of gametes includes a complex reorganization of the oviductal smooth muscle electrical activity that precedes the mechanical activity. The 3-day stay at the ampulla-isthmic junction requires both signals from the ovum to the oviduct and vice versa, supporting the ovum and regulating its to-and-fro movements. Oviductal fluid, a principal factor in tubal function, coats the newly fertilized egg, activates transcription and gives a signal for sperm fertility potential. Early blocks to embryo development in in vitro conditions, as compared to in vivo success, means that critical developments during the first cell cycles of embryonic life in the oviduct are actively regulated by oviductal embryotrophic factors. These have been used clinically in co-culture systems. Lytic factors are weak in human and other primates, predisposing to high incidence of tubal pregnancies, with considerable impact on medical practice. Diverse oviductal factors affect the incidence, infection being the most significant. Optimal oviductal function is necessary to provide a proper environment for early human life.

Mastitis today: incidence, prevention and treatment.

The study concerned 664 women of South-West Finland, and they were studied 5-12 weeks after delivery. The total frequency of mastitis in this population was much higher than generally reported in literature, 24% as opposed to 3%. The frequency of mastitis was similar among nulli- and multiparous women. The diagnosis was based on the judgement of midwives of physicians. If a multiparous woman has had mastitis during a previous puerperium, the probability of mastitis during a subsequent puerperium is threefold. The type of skin, its reaction of the sun, allergies, rashes, getting cold and oxytocin medication during delivery did nto affect the incidence of mastitis. Mothers under 21 and over 35 years of age had a decreased incidence (P = 0.034) of mastitis. If the women had sore nipples, the frequency increased (P = 0.003). Prophylaxis, by means of physical training, neither decreased nor increased the frequency of puerperal mastitis. The treatment advised by midwives and physicians was primarily conservative, but 38% received antibiotics; some of the antibiotics were not effective against staphylococcal infection.

Vaginal progesterone after tubal pregnancy.

We studied the effect of vaginal progesterone (P) treatment during the luteal phase of patients who had had a tubal pregnancy (TP) and were planning another, in a prospective, randomized, double-blind trial. The outpatient clinics of two University hospitals and three central hospitals had 135 patients treated for tubal pregnancy: 100 with grossly normal fallopian tubes (supposing an accidentally abnormal luteal phase as a possible etiology of their first TP) and 35 with signs of earlier pelvic inflammatory disease (PID etiology). They were treated with vaginal P (25 mg b.i.d.) or placebo during cycle days 16-24, for 10 months. Serum P levels after a single vaginal or oral dose were compared. The rates of conception, delivery, spontaneous abortion and recurrent TP were recorded, and fetal and placental weight measured. Both vaginal and oral formulas of P provoked a physiological (24-43 nmol/l) rise in serum concentrations. P and placebo-treated cycles resulted in a nearly equal number of pregnancies (33/37 resp.). Of the 55 infants born 53 were to mothers without signs of earlier PID (53/100); only 2 (2/35) to mothers in whom signs had been present. Recurrent TP occurred in 9% of all pregnancies. Four out of six recurrent TPs were patients with signs of PID (4/35), but two were without such signs (2/100): one occurred during placebo and one during P-treated cycle. Prophylactic P treatment of patients at risk of recurrent TP does not improve fertility or prevent recurrent TP. This indicates, that the functional etiology of recurrent TP, as compared to infection, is not important.

Group I and group II phospholipase A2 in serum during normal and pathological pregnancy.

Phospholipase A2 groups I (pancreatic) and II (synovial) could be a link between local and systemic changes in pregnancy, reflected in catalytic activity. We studied whether normal pregnancy, preeclampsia, preterm labor and four other diseases have processes involving serum phospholipase A2s. Pancreatic and synovial-type phospholipase A2 were measured in the serum of 59 normal pregnant women and 89 patients with pathological pregnancy by newly developed time-resolved fluoroimmunoassays, and the catalytic activity by a radiochemical method using micellar phosphatidylcholine as substrate. During pregnancy weeks 6-14, synovial-type phospholipase A2 and catalytic activity were elevated 2- to 4-fold, but at 37 weeks values were normal. Pregnancy-induced hypertensive diseases increased by 4- to 10-fold the concentration of synovial-type phospholipase A2, reflected in catalytic activity. In 8 out of 14 cases, the enzyme was increased if the fetus was to be delivered prematurely. The enzymes studied remained within the reference interval in cases of hepatogestosis, fetal asphyxia, diabetes and twin pregnancy. Newly developed specific immunoassays for measuring different types of phospholipase A2 in serum can provide insights for clinical follow-up.

Distribution of oral nimesulide in female genital tissues.

Nimesulide is a non-steroidal anti-inflammatory agent which has proved to be effective in reducing menstrual discomfort in dysmenorrhoeaic women. To determine the concentrations of this drug in the uterus (fundus, cervix), oviduct, and ovaries and to correlate these findings with plasma concentrations, a single oral dose of 100 mg nimesulide was administered 1 to 6 h before surgery to 12 women undergoing hysterectomy and salpingo-oophorectomy, mainly for fibroids. Tissue samples were taken, concentration of nimesulide measured by HPLC, and findings compared with plasma concentrations. One patient not undergoing treatment served as control. Nimesulide concentration in the tissues studied was highest 3 h after administration, as expected from the drug's pharmacokinetic profile. The highest tissue/plasma ratio (0.5) was also found at that time. Average tissue concentrations at 1, 2, 3, and 6 h after drug intake ranged from 0.3 to 1.8 micrograms g-1, and plasma concentrations from 2.6 to 4.1 micrograms ml-1. Nimesulide was evenly distributed in the tissues studied.

Androgen synthesis in human fetal testis exposed in utero to a combination of norethindrone acetate and ethinyl estradiol.

The effect of norethindrone acetate (NET-Ac) and ethinyl estradiol (EE2) on the 3 beta-hydroxysteroid dehydrogenase (HSD)-delta5-isomerase complex of the human fetal testis was studied by administration of 20 mg NET-Ac and 0.04 mg EE2 p.o on a single day to 4 women, pregnant 10-16 weeks, before abortion was induced, the other 4 patients serving as controls. Testosterone and androstenedione formation from radioactive dehydroepiandrosterone was measured in 8 fetuses by incubation of testicular tissue in vitro. The presence of normal feta Leydig cells was confirmed by electron microscopy. There was no difference between the enzyme activities of testicles in the experimental and control groups. The findins give values of 3 beta-HSD-isomerase activity in human fetal testis and suggest that the steroidogenic function of the fetal testis exposed for a short time to normally used contraceptive steroids remains at the same magnitude.

Pancreatic and catalytic phospholipase A2 in relation to pregnancy, labor and fetal outcome.

The serum pancreatic and catalytic phospholipase A2 level (PLA2) in human pregnancy is normal, and the increase of pancreatic enzyme before delivery is small. In patients with pruritus associated with obstetric hepatosis maternal serum had a slightly lower pancreatic PLA2 level if the cholic acid level was higher. Umbilical cord blood has twice as much pancreatic PLA2 as maternal blood. If the enzyme concentration was very high, pregnancies were postterm and the newborns had low Apgar scores. Amniotic fluid contains these enzymes, but there is no change in the enzymes during the course of pregnancy. The amount of pancreatic enzyme was not reflected in catalytic activity. A very high PLA2 activity was observed in 1 patient with suspected amniotic fluid embolism and in the meconium, but low in the first urine of neonates.

Low serum progesterone levels and tubal dysfunction--a possible cause of ectopic pregnancy.

We analyzed 22 human oviducts by the suction electrode method for electrical activity (preceding and reflecting the mechanical activity), as related to serum progesterone levels. Eleven patients had high progesterone levels (greater than or equal to 20 nmol/L), but the other 11 patients had low levels. When the serum progesterone level was low, the oviductal electrophysiologic characteristics were those associated with poor ovum transfer: low probability of prouterine propagation of the activity at the fimbrial end of the tube: high-frequency but low number of electrical bursts, reflecting possible weak propulsive force; and a high occurrence rate of sine-wave-like activity and inactive areas where ovum retention can occur. These phenomena could be related to the higher incidence of ectopic pregnancies in patients with luteal phase defect.

Acute and chronic effects of oral enprostil, a synthetic dehydroprostaglandin E2, on uterine contractility.

In acute experiments eleven nonpregnant women received a single oral dose of enprostil (prostaglandin E2 analogue) 35-140 mcg. Uterine activity was measured by a microtransducer-tipped Millar catheter. A single, oral dose of enprostil caused a long-lasting contracture response of the uterus. 3 h after enprostil, uterine resting pressure (RP) was still high. In chronic experiments, eleven women with regular menstrual cycles received 35 mcg or 70 mcg BID enprostil and placebo in a crossover, double-blind fashion from cycle day 10 +/- 3 for four weeks, then had a washout period of four weeks followed by another four-week treatment period. An increase of uterine RP after enprostil was dose-dependent. After two weeks of twice-daily administration of enprostil, the baseline RP was lower than after placebo (p less than 0.01) and the increase in RP after the morning enprostil less than that seen on the first day. In eight patients studied, the mean values of plasma progesterone were normal, both during placebo--and enprostil--treated cycles.

A study of the effect of mifepristone (antiprogesterone) followed by prostaglandin on uterine activity and fetal heart rate in patients having a termination of pregnancy.

In the 72 h after a single oral dose of 400 mg of the antiprogesterone mifepristone, 12 out of 14 first and one second trimester fetuses had a slight increase in heart rate; 2 fetuses died and one aborted. During the same 72 h, uterine activity increased moderately, and was physiological with no increase in resting pressure. The treatment sensitized the uterus to prostaglandin (PG) about ten-fold. A low, 0.05 mg IM, dose of sulprostone caused the demise of 5 more fetuses and caused the onset of clinical abortion in less than 2 h. After a relatively short hypertonic phase uterine resting pressure fell to normal levels and active contractions occurred leading to expulsion of uterine contents. The plasma level of progesterone (P) remained unaltered after mifepristone treatment, but the levels of estradiol 17b (E2) and cortisol increased. The plasma level of mifepristone was 1640 +/- 424 ng. ml -1 at 72 h, and the substance was still detectable after one week.

Oral administration of the prostaglandin enisoprost induces uterine activity and softens the cervix during first trimester pregnancy.

48 patients in the first trimester of pregnancy received a single oral dose of placebo or enisoprost (prostaglandin E1 analogue): 10, 25, 50, 100, 200 or 400 micrograms. Uterine activity was recorded for 1 h before and for 4 h after administration of the study drug with a Millar microtransducer. There was a dose-related increase in mean resting and active pressure, but not in frequency of pressure cycles. At the highest dose used, namely 400 micrograms, all 6 subjects bled. Enisoprost dilated the cervix and any further dilatation required was easy to accomplish.

Alterations in intrauterine pressure, menstrual fluid prostaglandin F levels, and pain in dysmenorrheic women treated with nimesulide.

A double-blind crossover study was carried out to evaluate the therapeutic efficacy of nimesulide and its effects on uterine activity, menstrual fluid prostaglandin F, and pain in women suffering from primary dysmenorrhea. Twenty-three women entered the clinical pharmacologic study. Intrauterine pressure was monitored with a microballoon-tipped catheter on the first day of menstruation. During the maximal pain period (based on monitoring in six patients), nimesulide significantly decreased intrauterine pressure; the measure of pain relief was consistent with decrease of uterine activity. In another six patients, the registration of intrauterine pressure during the submaximal pain period demonstrated that both in the nimesulide- and placebo-treated cycles, the uterine activity was at a lower mean level than that registered during maximal pain. Furthermore, when two 100-mg oral doses of nimesulide were administered to 11 dysmenorrheic women, in double-blind, crossover conditions with placebo as a blank reference, it brought about a reduction of menstrual fluid prostaglandin F2 levels from 382 to 94 ng/mL, (P less than .001). Fourteen women entered a four-cycle, double-blind, crossover therapeutic trial. Each patient was randomly assigned to one of two treatment sequences with nimesulide 200 mg/d PO or placebo. The therapy was judged very effective or good in 22 of 28 cycles treated with nimesulide compared with nine of 27 cycles treated with placebo (P less than .01). The amount of bleeding during the treated cycles did not change, and there were no complaints of untoward signs or symptoms related to the therapies.

Pancreatic phospholipase A2 (PPLA2) during human pregnancy.

Pancreatic phospholipase A2 in human serum during pregnancy is within the normal range. In the amniotic fluid, the amount of immunoreactive pancreatic phospholipase A2 increases from 1.3 microgram/l at 16 weeks to 2.9 micrograms/l near term, but does not correlate with PLA2-activity. Meconium-stained amniotic fluid had highly elevated pancreatic, but not kinetic, PLA2. The fetal pancreas and its high PLA2-content may contribute to the progressive increase in uterine activity during human pregnancy.

Constriction of the fetal ductus arteriosus by progesterone.

Progesterone substitution in the rat during pregnancy days 17-21 or administration 6 h before spontaneous delivery constricted the fetal ductus arteriosus. The rapid whole-body freezing technique was used. Indomethacin-induced constriction of the fetal ductus arteriosus was not affected by progesterone treatment.

Acute urinary bladder tamponade with hypovolemic shock due to placenta percreta with bladder invasion. Case report.

A rare case with residual tissue of placenta previa invading posterior parts of the bladder as placenta percreta complicated by massive late hematuria with hypovolemic shock two months after gynecologic-obstetric operation is presented. The patient was finally treated by emergency bladder resection. If a grand multipara with a history of hysterotomies, such as cesarean sections, presents lower abdominal pain involving hematuria during pregnancy, placental invasion of the bladder may be suspected. The primary treatment by hysterectomy should be complemented by bladder resection. This placental type may have high steroidogenesis.

Induction of human labor at term: uterine activity, inducibility, duration and neonatal jaundice.

A total of 821 patients, 39-40 weeks pregnant, was obstetrically normal at admission. In 212 of them intra-uterine pressure (IUP) was monitored before and during inducing labor by oxytocin, in 212 patients delivery was also induced by oxytocin but not monitored, in 197 by combining oxytocin and amniotomy, and 200 had spontaneous delivery. Inducibility could be predicted by uterine baseline activity and a 50 mu i.v. shot of oxytocin, together with determination of cervical status and placental location. The duration of labour induction was affected by parity, placental location and cervical status, but was predicted only to a minor degree by baseline activity and uterine oxytocin sensitivity. Amniotomy did not affect caesarean, section rate. The newborn child benefited from IUP monitoring: fewer transfers to pediatrics were necessary, there was less neonatal jaundice and fewer blood exchanges. It is assumed that if labor is not monitored through IUP, oxytocin may cause neonatal hyperbilirubinaemia through episodes of increased uterine resting pressure.