Metabolism of prostaglandins within the pregnant uterus.

The metabolism of E and F prostaglandins has been studied in both fetal and maternal tissues obtained from the pregnant human uterus. Both 15-hydroxyprostaglandin dehydrogenase and 13,14-prostaglandin reductase are shown to be widely distributed in these tissues. Comparison of the levels of enzyme activity in different tissues demonstrates that the greatest metabolism of prostaglandins takes place in the membranes and placenta and that there is much less in the myometrium and the decidua. The lowest enzyme activity was found in the umbilical cord, and no metabolism could be demonstrated in amniotic fluid or in umbilical venous blood. The significance of these findings is discussed.     

The contractile response of the human uterus, fallopian tubes, and ovary to prostaglandins in vivo

In vivo studies were carried out in 8 women to ascertain the effects of prostaglandins (PGs) E2 and F2alpha on the human fallopian tubes and ovaries. Recording devices were surgically implanted into the tubal lumen through catheters. 100 mcg. of either PGE2 or PGF2alpha or a mixture of equal amounts of the 2 totaling 100 mcg. were administered intravenously and the effects recorded. Graphs of the effects are presented. The 2 pure substances and the mixture all had a stimulatory effect on the uterus at all phases of the menstrual cycle. There were, however, qualitative and potency differences between PGE2 and PGF2alpha. On a weight basis, PGE2 had more powerful effects on the myometrium. The 2 PGs had opposing effects on the fallopian tubes, with PGF2alpha stimulating while PGE2 inhibited tubal motility. A contractile response of the ovary following intravenous administration of PGF2alpha was noted; no change in intraovarian pressure was recorded following injection of up to 100 mcg. PGE2. The compound was mildly stimulatory. The ability of PGE2 to induce relaxation of the tubes while stimulating uterine activity provides a clue as to why it is more effective in inducing abortion than PGF2alpha. It is suggested that relaxation of the tubal isthmus induced by seminal PGE2 facilitates sperm penetration into the tube.     

The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin

In order to develop inhibitors of vasopressin (VP) and oxytocin (OXY) action on uterine activity, 1-deaminated vasotocin derivatives with modifications at positions 2, 4 and 8 were developed. Two of the most effective analogues in the rat, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-vasotocin (dE-VVT) and 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT) were now tested on human nonpregnant myometrium obtained at hysterectomy in fertile age and on pregnant myometrial tissue obtained at elective cesarean section. The effect was compared with that of a previously synthesized analogue 1-deamino-Tyr(OEt)-oxytocin (dE-OXY) which has already been tested in nonpregnant and pregnant women in vivo. Both of the new analogues competitively inhibited the action of the posterior pituitary hormones. On the nonpregnant uterus dE-VVT was about five times and dE-TVT almost twenty-five times more potent than dE-OXY in inhibiting the effects of VP. On pregnant myometrium, dE-TVT inhibited oxytocin action about as effectively as a five-fold stronger concentration of dE-OXY, and dE-VVT slightly less. A moderate agonistic effect of dE-OXY on pregnant myometrium was found, whereas it was minimal with dE-VVT and not detectable at all with dE-TVT. It appears that these two analogues, particularly dE-TVT, would be interesting for clinical testing both in dysmenorrhea, where increased VP secretion could be of etiological importance, and in premature labor where an increased myometrial concentration of OXY receptors has been demonstrated.     

Management of acute puerperal inversion of the uterus with beta-mimetic drugs and prostaglandins

The sequential administration of a β₂-mimetic and a prostaglandin were found to be a most useful approach to the first-aid management of acute inversion of the puerperal uterus.     

Transplantation of the human uterus.

Human uterine transplantation was performed on 6 April 2000 on a 26-year-old female who lost her uterus 6 years earlier due to post-partum hemorrhage. The donor, a 46-year-old patient with multiloculated ovarian cysts, underwent a hysterectomy modified to preserve tissue and vascular integrity. The donor uterus was connected in the orthotopic position to the recipient's vaginal vault and additional fixation was achieved by shortening the uterosacral ligament. The uterine arteries and veins were extended using reversed segments of the great saphenous vein, then connected to the external iliac arteries and veins, respectively. Immunosuppression was maintained by oral cyclosporine A (4 mg/kg/body wt.), azathioprine (1 mg/kg/body wt.) and prednisolone (0.2 mg/kg/body wt.). Allograft rejection was monitored by Echo-Doppler studies, magnetic resonance imaging (MRI), and measurement of the CD4/CD8 ratio in peripheral blood by fluorescence activated cell sorter (FACS scan). An episode of acute rejection was treated and controlled on the ninth day with anti-thymocytic globulin (ATG). The transplanted uterus responded well to combined estrogen--progesterone therapy, with endometrial proliferation up to 18 mm. The patient had two episodes of withdrawal bleeding upon cessation of the hormonal therapy. Unfortunately, she developed acute vascular thrombosis 99 days after transplantation, and hysterectomy was necessary. Macro- and microscopic histopathological examination revealed acute thrombosis in the vessels of the uterine body, with resulting infarction. Both fallopian tubes remained viable, however, with no evidence of rejection. The acute vascular occlusion appeared to be caused by inadequate uterine structure support, which led to probable tension, torsion, or kinking of the connected vascular uterine grafts.     

Extracorporeal perfusion of the human uterus

Uterine specimens specially prepared for extracorporeal perfusions (arterial and venous stumps available for catheterization) were perfused with oxygenated Krebs-Ringer bicarbonate-glucose buffer for periods of up to 12 hours to investigate the feasibility of obtaining constant flow, stability of biochemical parameters, and adequate distribution of the perfusion fluid. Flow rates of 10 to 30 ml/min per artery could be maintained at pressures ranging from 80 to 120 mm Hg. Arteriovenous gradients of oxygen and carbon dioxide tensions were relatively stable and levels of lactate, lactic dehydrogenase, and creatine kinase released to the medium, indicators of tissue hypoxia or cell lysis, declined after 30 minutes of perfusion, remaining low and stable up to 12 hours. Distribution of methylene blue and radiopaque solutes was practically complete throughout the fundus and upper two thirds of the uterus. A mixture of tritium-labeled estrone sulfate and carbon 14-labeled estrone was injected as a bolus through an arterial catheter during perfusion. Perfusate samples were collected for 30 minutes, and tissue samples were taken at the end of this period. Tritium/carbon 14 ratios in myometrium and perfusate indicated preferential uptake of the unconjugated estrogen. Tritium/carbon 14 ratios were higher in endometrium than in myometrium, which suggests an enhanced permeability of endometrial capillaries to estrone sulfate.     

Regulation of prostaglandin synthesis in the human uterus

Prostaglandins are important regulators of many aspects of reproductive processes from ovulation, fertilization and pregnancy recognition to labor and parturition. These biologically potent compounds are members of the large family of eicosanoids, derived from polyunsaturated fatty acids, principally arachidonic acid, found in the membrane phospholipids of virtually every cell of the human body, accounting for the ubiquity of prostaglandins, which act in a paracrine or autocrine fashion via discrete receptors. The availability of specific prostaglandins in various cells and tissues depends on the presence and activity of specific enzymes that convert a common precursor to the end product, as well as on the rate of enzymatic or spontaneous inactivation of the bioactive compounds. Here we offer a brief review of the regulation of prostaglandin generation in human uterine tissues, focusing on their role in labor and parturition at term and preterm.