Is prostaglandin F2α involved in the increased myometrial contractility of primary dysmenorrhoea?

The concentrations of prostaglandin F₂α (PGF₂α) and E₂ (PGE₂) in menstrual fluid collected daily from 13 women with primary dysmenorrhoea and 11 matched controls, were compared with the pattern of uterine contractility during the hour following the menstrual fluid collection. The intra-uterine pressure (IUP) was measured using a micro-transducer catheter and the tracings analysed.On Day 2 the concentration of PGF₂α correlated with the peak area, but not with amplitude, duration or rate of contraction. These findings add additional support to the hypothesis that increased production of PGF₂α could contribute to the increased uterine contractility in primary dysmenorrhoea.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

Luteolytic action of 15-keto prostaglandin F2α in the rhesus monkey

The naturally-occurring metabolite of prostaglandin F_2α, 15-keto prostaglandin F_2α (15-keto PGF_2α), elicited rapid and sustained declines in serum progesterone concentrations when administered to rhesus monkeys beginning on day 22 of normal menstrual cycles. Evidence for luteolysis of a more convincing nature was obtained in studies where a single dose of 15-keto PGF_2α was given on day 20 of ovulatory menstrual cycles in which intramuscular injections of hCG were also given on days 18–20; serum progesterone concentrations fell precipitously in monkeys within 24 hours following intramuscular administration of 15-keto PGF_2α. However, corpus luteum function was impaired in only 4 of 11 early pregnant monkeys when 15-keto PGF_2α was administered on days 30 and 31 from the last menses, a time when the ovary is essential for the maintenance of pregnancy. Gestation failed in 2 additional monkeys 32 and 60 days after treatment with 15-keto PGF_2α, but progressed in an apparently normal manner in the remaining 5 animals. Two pregnant monkeys treated with 15-keto PGF_2α on day 42 from the last menstrual period, a time when the ovary is no longer required for gestation, continued their pregnancies uneventfully. Corpus luteum function was not impaired in 9 control monkeys which received injections of vehicle or hCG at appropriate times during the menstrual cycle or pregnancy.     

Effects of PGF2α and PGF2α, 1–15 lactone on the corpus luteum and on early pregnancy in the rhesus monkey

The effects of prostaglandin (PG)F_2α and PGF_2α, 1–15 lactone were compared in luteal phase, non-pregnant and in early pregnant rhesus monkeys. Animals treated with either PG after pretreatment with human chorionic gonadotropin (hCG) had peripheral plasma progesterone concentrations that were not statistically different from those in animals treated with hCG and vehicle. However, menstrual cycle lengths in monkeys treated with PGF_2α, 1–15 lactone were significantly (P <0.02) shorter than those in vehicle treated animals. In the absence of hCG pretreatment, plasma progesterone concentrations were significantly (P <0.008) lower by the second day after the initial treatment with either PGF_2α or PGF_2α, 1–15 lactone than in vehicle treated monkeys. Menstrual cycle lengths in monkeys treated with either PG were significantly (P <0.04) shorter than those in animals treated with vehicle. There were no changes in plasma progesterone concentrations in early pregnant monkeys treated with PGF_2α, and pregnancy was not interrupted. In contrast, plasma progesterone declined and pregnancy was terminated in 5 of 6 early pregnant monkeys treated with PGF_2α, 1–15 lactone. These data indicate that PGF_2α, 1–15 lactone decreases menstrual cycle lengths in non-pregnant rhesus monkeys. More importantly, PGF_2α, 1–15 lactone terminates early pregnancy in the monkey at a dose which is less than an ineffective dose of PGF_2α.     

Effects of suprofen and other prostaglandin synthstase inhibitors in a new animal model for myometrial hyperactivity

An model for studying factors related to dysmenorrhea and for evaluating drugs for their inhibitory effects on uterine contractility induced by arachidonic acid and prostaglandins has been developed. Intravenous administration of arachidonic acid and PGF₂α to guinea pigs during the late stage of the estrous cycle, induced dose related uterine contractions and an elevation in uterine basal pressure similar that seen in patients with dysmenorrhea. Pretreatment with prostaglandin synthetase inhibitors inhibited the response to arachidonic acid. The order of relative potency was suprofen (1) > indomethacin (0.65) > naproxen (0.52) > ibuprofen (0.43) > aspirin (0.31). The effectiveness of maximal response for suprofen was significantly greater than that of the other compounds tested. Simultaneous administration of suprofen with PGF₂α also blocked induction of uterine contractions, suggesting the possibility that suprofen also antagonizes PGF₂α receptor binding. Bradykinin also induced uterine constractions, an effect blocked by pretretment with suprofen. Finally, histochemical studies demonstrated stimulation of uterine catecholamine levels (norepinephrine) by arachidonic acid, PGF₂α and bradykinin. These effects were blocked by suprofen.These data suggest that suprofen, an analgesic prostaglandin synthetase inhibitor, may be of use in the clinical tretment of the uterine contractions associated with primary dysmenorrhea.     

Different responses to prostaglandin F2α and E2 in human extra- and intramyometrial arteries

Tubal segments of the ascending uterine arteries and of intramyometrial arteries were obtained from 18 women who underwent hysterectomy at various phases of the menstrual cycle. Ring preparations of the vessels were mounted in organ baths and isometric tension was recorded. In extramyometrial arteries (outer diameter 2–3 mm) prostaglandin (PG) F_2α most potently, but also PGE₂ caused concentration-related contractions. In contrast, the contractant effects of both PGs on intramyometrial arteries (outer diameter 0.5–0.6 mm) were negligible. Both extra- and intramyometrial vessels were relaxed to a moderate degree (10–25%) by low concentrations of PGF_2α and PGE₂. No significant differences between the responses to vasopressin and noradrenaline were found between the vessel preparations. Thus human uterine arteries seem to change their responses to PGF_2α and PGE₂ as they enter the myometrium and decrease in diameter, and the results raise doubt about the view that direct vasoconstrictor effects of these PGs contribute to the regulation of myometrial blood flow. Such effects of vasopressin and noradrenaline cannot be excluded.     

Effect of prostaglandin F2α on the hCG-stimulated progesterone production by human corpora lutea

The effect of prostaglandin PGF_2α on the hCG stimulated and basal progesterone production by human corpora lutea was examined . hCG (40 i.u./ml) stimulated progesterone formation in corpora lutea of early (days 16–19 of a normal 28 day cycle), mid (days 20–22) and late (days 23–27) luteal phases. This stimulation was inhibited by PGF_2α (10 μg/ml) in corpora lutea of mid and late luteal phases. PGF_2α alone did not show a consistent effect on basal progesterone production. The inhibition of hCG stimulated progesterone production by PGF_2α at times corresponding to luteolysis indicates a role for that prostaglandin in the process of luteolysis in the human corpus luteum.     

Evaluation of the role of the F prostaglandins in canine bile flow

Prostaglandin F_2α (PGF_2α) has been shown to be an effective stimulant of hepatic bile flow producing a specific chloride rich bile. Subsequent evaluation by radioimmunoassay has shown that prostaglandin F compounds are present in relatively large amounts in canine hepatic bile. This study evaluates the effect of PGF_2α administration and of prostaglandin synthetase inhibition by aspirin and indomethacin on bile flow and radioimmunoassayable prostaglandin F (iPGF) secretion. Chronic, canine bile fistula preparations were utilized and the enterohepatic circulation was maintained by intravenous bile salts. Bile volume and composition were evaluated by standard techniques as well as bile PGF concentration by radioimmunoassay during bile salt infusion and during bile salt and PGF_2α, aspirin and indomethacin infusion in varying doses. Both aspirin and PGF_2α were potent stimulatns of hepatic bile flow with aspirin producing a chloride rich bile similar to that produced by PGF_2α. PGF_2α produced dose related increases in bile iPGF concentration and output indicating that as the systemic concentration increases during infusion of PGF_2α the lipid appears in bile. Aspirin in the highest dose administered, decreased iPGF concentration in bile while output was unchanged. Indomethacin was ineffectual in consistently altering bile flow or iPGF secretion. This study demonstrates that iPGF is present in canine bile, that its concentration can be altered by prostaglandin infusion while prostaglandin synthetase inhibition has minimal effects on bile iPGF secretion.     

Inhibition of uterine prostaglandin-F2α production by bovine conceptus secretory proteins

The effect of bovine conceptus secretory proteins (CSP) on uterine prostaglandin (PG)-F_2α production was evaluated in dairy cattle following injection of estradiol-17β. Intrauterine injections of dialyzed serum proteins (Control, n=5) or CSP (n=5) were administered from days 15 through 18 post-estrus. Following intrauterine treatments on day 18, all cows were injected with E₂ (3 mg) to stimulate uterine PGF_2α production. Plasma concentrations of progesterone (P₄) and 15-keto-13,14-dihydro-PGF_2α (PGFM) were determined by RIA. The PGFM responses following E₂ challenge were decreased (p<0.01) for cows receiving CSP versus serum proteins into the uterine lumen. Individual PGFM, P₄ and cycle length responses are discussed. Data suggest that proteins secreted by the bovine conceptus suppress uterine PGF_2α production during pregnancy recognition in the cow.     

The effect of intrauterine administration of prostacyclin on the contractility of the non-pregnant uterus in vivo

Prostacyclin was infused into the uterus of non-pregnant women either during early menstruation or in the secretory phase of the cycle. A dose of 5 μ/min produced little systemic effect and caused a significant decrease in uterine activity on Days 1 and 2 of the menses whereas 0.5 μg/min did not. However, when dysmenorrhoeic pain and increased uterine activity were produced by infusion of PGF_2α during the secretory phase, PGI₂ neither decreased the activity nor the pain. This indicates that PGI₂ does not cause uterine relaxation by blocking the action of PGF_2α.     

Fetal-maternal secretion of prostaglandins in the cow

A study was conducted to measure the blood plasma concentrations of prostaglandin F₂α (PGF₂α), 13,14-dihydro-15-keto-prostaglandin F (PGFM), 6-keto-prostaglandin F₁α (6-keto), prostaglandin E₂ (PGE₂), and thromboxane B₂ (TBX₂) in the ovarian vein, uterine artery, uterine vein, umbilical artery and umbilical vein in 24 cows from days 80 to 260 of pregnancy. Blood was collected during surgery and all prostaglandins were measured using specific radioimmunoassay procedures. Results indicate that PGF₂α blood levels are higher in the umbilical vessels and uterine vein than in the ovarian vein and uterine artery. PGFM and PGE₂ showed a trend towards higher values in the umbilical than in the maternal vessels, but the levels of 6-keto and TBX₂ were not different among the vessels studied. No differences across time couls be observed in any of the prostaglandins measured, partly due to the great variability in blood levels among animals during the same stage of pregnancy.     

Corpus luteum function in the ewe: Effect of PGF2α and prostaglandin synthetase inhibitors

A series of experiments were conducted to evaluate the effects of mode and frequency of administration and estrous cycle stage on the response of the cycling ewe to PGF_2α. The effects of dexamethasone, arachadonic acid and prostaglandin synthetase inhibitors on estrous cycle length and plasma progesterone levels were also determined.Intramuscular administration of 5 or 10 mg of PGF_2α, on days 8 and 9 after estrus (5 ewes/group), significantly (p<.01) shortened the mean length of the estrous cycle and the interval from the end of treatment to estrus. Mean plasma progesterone levels, 24 hours after initial injection, were significantly (p<.01) lowered. When administered on day 8 only, these doses were considerably less effective in shortening estrous cycle length or lowering plasma progesterone levels. Intravaginal administration of PGF_2α, by polyurethane tampon, was also largely ineffective.Treatment of ewes with 10 mg of PGF_2α i.m., on days 3 and 4 of the estrous cycle, resulted in a return to estrus in 2 days in 25% of the treated animals. Plasma progesterone levels of PGF_2α-treated ewes were significantly lower than controls on the second, third and fourth days after the start of dosing. It would appear that PGF_2α exerts a retarding effect on developing CL functionality.The prostaglandin synthetase inhibitors, aspirin, flufenamic acid and 1-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetic acid, were administered orally or parenterally for 16 days beginning on day 8 of the estrous cycle. These compounds failed to prolong estrous cycle length. Parenteral administration of dexamethasone did not result in PGF_2α release in the cycling ewe, at least not in quantities sufficient to induce luteolysis. The prostaglandin precursor, arachadonic acid, also was not luteolytic when given parenterally to cycling ewes.     

Reduction by human chorionic gonadotropin of the luteolytic effect of prostaglandin F2 in ewes

The ability of human chorionic gonadotropin (HCG) to reduce the luteolytic effect of prostaglandin (PGF_2^α) was demonstrated in cycling ewes. As expected, treatment with 10 mg of PGF_2^α alone on Day 10 of the estrous cycle exerted a potent negative effect on the function and structure of corpus luteum (CL) as indicated by reduced plasma progesterone, CL progesterone, and CL weight. However, the identical PGF_2^α treatment failed to significantly reduce either luteal function or luteal weight when administered to ewes that were also treated with HCG on Days 9 and 10 of the estrous cycle. Treatment with HCG alone had a positive effect on CL as indicated by increased plasma progesterone, CL progesterone, and CL weight. Treatment with HCG did not render the CL totally insensitive to the negative effects of PGF_2^α because plasma progesterone was reduced when the dose of PGF_2^α was doubled. Whether CL regressed or continued to function after treatment with both HCG and PGF_2^α appeared to depend upon a balance between the positive and negative effects of the two hormones.     

Biological activities of 17-phenyl-18,19,20-trinorprostaglandins

In a number of assay ssytems, some 17-phenyl-trinor prostaglandins were similar in activity and potency to the corresponding parent prostaglandin. In others, the 17-phenyl analogs appeared several times more potent. In the hamster antifertility assay, which is considered to measure luteolytic activity, 17-phenyl-18,19,20-trinor prostaglandin F_2α was about 90-times PGF_2α in potency.Rat blood pressure responses to 17-phenyl analogs were significant. The 17-phenyl-trinor PGF_2α pressor potency was 5 times that of PGF_2α. The 17-phenyl-trinor PGE₂ blood pressure response was atypical since a pressor rebound phenomenon followed the expected depressor response. Lastly, 17-phenyl-trinor PGF_2α was more potent than PGF_2α in synchronizing the estrous cycle in beef cows.     

In vivo inhibition of the human non-pregnant uterus by prostaglandin E2

The discrepancy between the effect of PGE₂ on the non-pregnant myometrium (relaxation) as compared to (stimulation) has not yet been solved. Nine women in the early post-menopause volunteered for the investigation. Prostaglandin (PG) F_2α or E₂ was administered either by single intravenous (i.v.) injection or by intra-uterine instillation and the uterine contractility was recorded by the microballoon technique. The response of the menopausal uterus to i.v. injections of PGF_2α or PGE₂ was characterized by rapid stimulation while intra-uterine instillation of PGF_2α induced gradual but sustained elevation of uterine tonus. However, the intra-uterine injection of PGE₂ caused inhibition of different components of uterine contractility. The fact that PGE₂ can also inhibit the motility of the menopausal non-pregnant uterus coincides with earlier results i.e. the discrepancy may not exist. Moreover, in one cycling patient (13–18th days of the menstrual cycle) similar results were also obtained. Two theories were offered to explain why PGE₂ stimulated the uterus when given as a single i.v. injection but inhibited the same organ when instilled locally into the uterine cavity.     

Anandamide-derived Prostamide F2α Negatively Regulates Adipogenesis

Lipid mediators variedly affect adipocyte differentiation. Anandamide stimulates adipogenesis via CB₁ receptors and peroxisome proliferator-activated receptor γ. Anandamide may be converted by PTGS2 (COX2) and prostaglandin F synthases, such as prostamide/prostaglandin F synthase, to prostaglandin F_2α ethanolamide (PGF_2αEA), of which bimatoprost is a potent synthetic analog. PGF_2αEA/bimatoprost act via prostaglandin F_2αFP receptor/FP alt4 splicing variant heterodimers. We investigated whether prostamide signaling occurs in preadipocytes and controls adipogenesis. Exposure of mouse 3T3-L1 or human preadipocytes to PGF_2αEA/bimatoprost during early differentiation inhibits adipogenesis. PGF_2αEA is produced from anandamide in preadipocytes and much less so in differentiating adipocytes, which express much less PTGS2, FP, and its alt4 splicing variant. Selective antagonism of PGF_2αEA receptors counteracts prostamide effects on adipogenesis, as does inhibition of ERK1/2 phosphorylation. Selective inhibition of PGF_2αEA versus prostaglandin F_2α biosynthesis accelerates adipogenesis. PGF_2αEA levels are reduced in the white adipose tissue of high fat diet-fed mice where there is a high requirement for new adipocytes. Prostamides also inhibit zebrafish larval adipogenesis in vivo. We propose that prostamide signaling in preadipocytes is a novel anandamide-derived antiadipogenic mechanism.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

Discriminating analysis of “in vitro” prostaglandin release by myometrial and luminal sides of the ewe endometrium

An original perifusion device which allows a discrimination between the 30 mn releases of prostaglandins F₂α and E₂ by the luminal and the myometrial faces of sheep endometrium is described. Tissue was sampled on day 4, 14, 16 or 17 of the cycle and on day 14 or 17 of pregnancy. Total prostaglandin (PG) release measured with this device was in good agreement with PG's concentrations in media of in vitro endometrium incubations already described.Discrimination analysis of the PGs release by each side of the endometrial tissue during the 30 mn perifusion time releaved that PGF₂α concentrations of the perifusion medium issued from the lumen compartment were higher than those of the myometrial compartment in all physiological status where corpus luteum is active (including early pregnancy). Therefore in the ewe, it seems that luteal structure maintenance during early pregnancy is not due, as in the giltm to a shift in PGF₂α secretion towards the uterine lumen.     

Prostacyclin induces a surprising long-lasting motility in quiescent uterine strips (indomethacin-treated) isolated from ovariectomized rats

Dose-response curves for several prostaglandins (PGI₂; PGD₂; PGF₂ and PGE₂); BaCl₂ or prostaglandin metabolites (15-keto-PGF_2α; 13, 14-diOH-15-keto-PGF_2α; 6-keto-PGF_1α and 6-keto-PGE₁ in quiescent (indomethacin-treated) uterine strips from ovariectomized rats, were constructed. All PGs tested as well as BaCl₂, triggered at different concentrations, evident phasic contractions. Within the range of concentrations tested the portion of the curves for the metabolites of PGF_2α was shifted to the right of that for PGF_2α itself; the curve for 6-keto-PGF_1α was displaced to the right of the curve for PGI₂ and that for 6-keto-PGE₁ to the left.It was also demonstrated that the uterine motility elicited by 10⁻⁵ M PGF_2α and its metabolites was long lasting (more than 3 hours) and so it was the activity evoked by PGI₂; 6-keto-PGF_1α and BaCl₂, but not the contractions following 6-keto-PGE₁, which disappeared much earlier. The contractile tension after PGF_2α; 15-keto-PGF_2α; 13, 14-diOH-15-keto-PGF_2α and PGI₂, increased as time progressed whilst that evoked by 6-keto-PGF_2α or BaCl₂ fluctuated during the same period around more constant levels.The surprising sustained and gradually increasing contractile activity after a single dose of an unstable prostaglandin such as PGI₂, on the isolated rat uterus rendered quiescent by indomethacin, is discussed in terms of an effect associated to its transformation into more stable metabolites (6-keto-PGF_1α, or another not tested) or as a consequence of a factor which might protects prostacyclin from inactivation.