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PubMed1997

Activation of the prostaglandin FP receptor in human granulosa cells.

Prostaglandin F2 alpha (PGF2 alpha) has regulatory (mainly luteolytic) effects in the ovary but the mechanism of action is not completely understood. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to demonstrate the presence of mRNA encoding the PGF2 alpha receptor (FP receptor) in human granulosa-lutein cells. Specific primers for the amplification of cDNA were designed and yielded a single product of 696 bp corresponding to the FP receptor. The identity of this product was verified by sequencing. Fluprostenol, a selective FP receptor agonist, activated phospholipase C (PLC) and increased intracellular free calcium concentration, confirming the functional activation of the receptor. We have demonstrated by Western blotting that granulosa cells express PLC-beta and PLC-gamma isoforms. The cells responded to pervanadate with increased PLC activity and increased tyrosine phosphorylation, demonstrating a functional PLC-gamma tyrosine kinase pathway. However, fluprostenol did not provoke any detectable tyrosine phosphorylation. Moreover, the effect of fluprostenol was inhibited through protein kinase C stimulation by phorbol 12, 13-dibutyrate, and was not affected when cells were treated with phenylarsine oxide, which blocks tyrosine phosphorylation. These results suggest that the FP receptor activates PLC-beta rather than PLC-gamma isoforms. Fluprostenol-induced activation was pertussis toxin resistant. Granulosa cells express G proteins of the Gq family (resistant to pertussis toxin) and mRNA for both G alpha q and G alpha 1 l has been identified by RT-PCR. In conclusion, human granulosa cells have a functional FP receptor the effects of which are mediated through PLC-beta activation probably via Gq/1 l.

Calcium↗
PubMed2002

Analysis of luteal tissue inhibitor of metalloproteinase-1, -2, and -3 during prostaglandin F(2alpha)-induced luteolysis.

Increased matrix metalloproteinase (MMP) expression and activities help to mediate tissue involution through increasing extracellular matrix remodeling and promoting dedifferentiation and, ultimately, apoptosis. Therefore, we hypothesized that prostaglandin (PG) F(2alpha) administration would decrease expression of the tissue inhibitor of metalloproteinase (TIMP)-1, -2, and -3 and effectively increase the MMP:TIMP ratio, leading to glandular involution. In experiment 1, we tested the effects of PGF(2alpha) administration (Day 10 postestrus; Day 0 = estrus) on luteal TIMP-1, -2, and -3 mRNA and protein expression. Corpora lutea were collected at 0, 15, or 30 min or at 1, 2, 4, 6, 12, 24, and 48 h following PGF(2alpha) administration (n = 3-9 animals/time point). Following PGF(2alpha) administration, TIMP-1 mRNA levels decreased (P < 0.05) at 1 and 2 h relative to 0 h (controls), then increased to levels greater than controls at 4 and 6 h. In contrast, TIMP-2 and -3 mRNA levels did not decrease following PGF(2alpha) administration. The TIMP-1, -2, and -3 proteins were localized to large luteal cells (LLCs) within control (untreated) tissues. However, histodepletion of TIMP-1 within LLCs was evident within 30 min (earliest time point collected) following PGF(2alpha) injection and continued through 48 h. Luteal concentration of TIMP-1, as determined by RIA, was decreased (P < 0.05) by 15 min (earliest time point collected) following PGF(2alpha) administration and remained low through 48 h. In contrast, TIMP-2 and -3 immunolocalization was not altered by PGF(2alpha) administration. Experiment 2 was conducted to determine if PGF(2alpha) could initiate the preceding changes in TIMP-1 in early (Day 3) corpora lutea that can bind PGF(2alpha) but are refractory to its luteolytic effects. Serum concentrations of progesterone and luteal concentrations of TIMP-1 mRNA and protein were similar at 0 and 6 h after PGF(2alpha) injection on Day 3 postestrus. These data suggest that an early and sustained effect of PGF(2alpha) is the specific depletion of TIMP-1 within LLCs that are capable of responding to the luteolytic action of PGF(2alpha). This action may increase the MMP:TIMP-1 ratio, creating an environment that favors extracellular matrix degradation and, thereby, facilitates both functional and structural regression.

Animals↗
PubMed2000

Nitric oxide synthase activity and progesterone release by isolated corpora lutea of rabbits in the early and mid-luteal phases of pseudopregnancy are modulated differently by prostaglandin E-2 and prostaglandin F-2alpha via adenylate cyclase and phospholipase C.

By examining in vitro the effects of prostaglandin E-2 (PGE-2) and prostaglandin F-2alpha (PGF-2alpha) induced in the corpora lutea (CL) of pseudopregnant rabbits, we have demonstrated that these prostaglandins modulate luteal nitric oxide synthase (NOS) activity and progesterone production differently, depending on the age of the CL. On CL obtained on day 4 of pseudopregnancy (day-4), PGE-2 was found to depress NOS total activity to 13% of control and to significantly increase basal progesterone secretion by 61%, while PGF-2alpha had no effect. On day-9 CL, PGE-2 was ineffective, but PGF-2alpha caused a 2.5-fold increase of NOS activity and a marked decrease in progesterone production. Using specific inhibitors, we found that the regulatory actions of PGE-2 in vitro are mediated via the adenyl cyclase/protein kinase A (PKA) second messenger system, while the PGF-2alpha-induced luteolytic effects on day-9 CL depend upon activation of the phospholipase C/protein kinase C (PKC) system. The different responsiveness of day-4 and day-9 CL to PGE-2 and PGF-2alpha could depend on receptor availability for these two prostaglandins, even if other cellular mechanisms cannot be excluded. The present study supports a functional role for NOS in regulating the steroidogenic capacity of rabbit CL, and reveals a novel interaction between a stimulatory G-protein-coupled receptor and PKC/PKA-mediated signal transduction modulating NOS activity.

Adenylyl Cyclases↗
PubMed1979

Actions of hormones on the uterus and effect on conceptus development.

The process of reproduction in the mammalian female involves interactions between gonadal and placental steroids and, possibly, protein hormones such as placental lactogen, and the uterine endometrium. These interactions are discussed relative to available data from pigs and with the understanding that the concepts presented may not be directly applicable to other species. Swine embryos enter the uterus for continued development beyond the early blastocyst stage and, within the uterus, the spherical blastocyst, of about 2 mm diameter on day 12, undergoes rapid elongation to an organism of about 1 m in length by day 15 of pregnancy. During this period of elongation, the blastocyst appears to provide the chemical signal, presumably unconjugated estrogens, that allows for corpora lutea (CL) maintenance (luteostatic effect) and, therefore, continued production of progesterone by the CL which is essential for pregnancy. Estrogens from the blastocyst may exert their luteostatic effect on the uterus by causing prostaglandin F2 alpha, the presumed porcine uterine luteolysin, to be secreted in an exocrine (toward the uterine lumen) rather than an endocrine (toward the endometrial stroma and vasculature) direction during pregnancy. Consequently, prostaglandin F2 alpha is sequestered in the uterine lumen and does not become available, via the utero-ovarian vasculature, to exert its luteolytic effect. The potential steroid precursor(s) available to the trophoblast for estrogen synthesis appear to be produced through endometrial conversion of progesterone to unconjugated androgens, e.g., androstenedione and testosterone, and conjugated estrogens, e.g., estrone-sulfate and estradiol-sulfate. The estrogens may, in concert with progesterone and possibly other hormones, placental lactogen for example, act locally, i.e., at the site of placentation to: result in a luteostatic effect; increase uterine blood flow; enhance water, electrolyte and substrate (carbohydrate and amino acid) transport to the site of placentation and across the placenta; affect synthesis and secretion of macro-molecules (histotroph) by the uterine glands that serve as enzymes and (or) carrier molecules and control or modulate physiological and (or) biochemical events essential to placental and fetal development that are not understood.

Animals↗
PubMed1984

Maintenance of the corpus luteum of early pregnancy in the ewe. III. Differences between pregnant and nonpregnant ewes in luteal responsiveness to prostaglandin F2 alpha.

The effects of pregnancy and number of corpora lutea on luteal regression induced with prostaglandin F2 alpha (PGF2 alpha) were examined in 93 ewes. Bred and nonpregnant ewes were assigned randomly to receive a single im injection of PGF2 alpha: 0, 2, 4, 6, 8 or 10 mg/58 kg body weight. Injections were given on d 13 postestrus. The concentration of progesterone in serum 24 h after PGF2 alpha injection was affected by dose (P less than .001). The effect of pregnancy and the interaction of pregnancy with number of corpora lutea on levels of progesterone in serum were significant (P less than .05); therefore, data were partitioned according to pregnancy status and analyzed separately. There was an effect of number of corpora lutea on serum concentration of progesterone in pregnant (P less than .01) but not nonpregnant ewes (P greater than .10). Similar relationships among groups were observed for the concentration of progesterone in luteal tissue. In nonpregnant ewes the minimum dose of PGF2 alpha to produce a significant suppression of progesterone in serum (P less than .05) was 4 mg/58 kg body weight. In pregnant ewes with one or two corpora lutea, the minimum effective doses were 6 and 10 mg/58 kg body weight, respectively. The concentration of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) in serum was related to the dose of PGF2 alpha injected. There were no differences in the concentration of PGFM in serum between pregnant and nonpregnant ewes either before or after injection. Corpora lutea of early pregnancy appear to be resistant to the luteolytic effect of PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Contrasting effects of oestradiol-17 beta and human chorionic gonadotrophin on steroidogenesis in the rabbit corpus luteum.

On Day 10 of pseudopregnancy, rabbits were given an i.v. injection of hCG (10-20 i.u.) that was sufficient to cause new ovulations and the loss of follicular oestradiol secretion. There was an immediate 3-4-fold rise in serum progesterone which returned to near prestimulation values (approximately 27 ng/ml) within 12 h in the presence of an implant containing oestradiol-17 beta. In the absence of oestradiol, serum progesterone continued to decline to reach low values (approximately 4 ng/ml) within 24 h and the original corpora lutea subsequently regressed. The administration of oestradiol 24 h after injection of hCG, when progesterone secretion was low, arrested any further decline in progesterone and then restored serum progesterone to normal values. This steroidogenic effect of oestradiol in vivo was a function of enhanced luteal steroidogenesis; corpora lutea removed and incubated for 12 h produced progesterone at high, linear rates, whereas the corpora lutea from animals that did not receive oestradiol produced low or insignificant quantities of progesterone in vitro. We conclude that hCG at these doses is compatible with continued responsiveness of the corpora lutea to oestrogen and that hCG produces its luteolytic effect primarily by ovulating follicles, thus stopping the secretion of the luteotrophic hormone, oestradiol.

Animals↗
PubMed1999

Luteinizing hormone inhibits conversion of pregnenolone to progesterone in luteal cells from rats on day 19 of pregnancy.

We have previously reported that intrabursal ovarian administration of LH at the end of pregnancy in rats induces a decrease in luteal progesterone (P4) synthesis and an increase in P4 metabolism. However, whether this local luteolytic effect of LH is exerted directly on luteal cells or on other structures, such as follicular or stromal cells, to modify luteal function is unknown. The aim of the present study was to determine the effect of LH on isolated luteal cells obtained on Day 19 of pregnancy. Incubation of luteal cells with 1, 10, 100, or 1000 ng/ml of ovine LH (oLH) for 6 h did not modify basal P4 production. The addition to the culture medium of 22(R)-hydroxycholesterol (22R-HC, 10 microgram/ml), a membrane-permeable P4 precursor, or pregnenolone (10(-2) microM) induced a significant increase in P4 accumulation in the medium in relation to the control value. When luteal cells were preincubated for 2 h with oLH, a significant (p < 0.01) reduction in the 22R-HC- or pregnenolone-stimulated P4 accumulation was observed. Incubation of luteal cells with dibutyryl cAMP (1 mM, a cAMP analogue) plus isobutylmethylxanthine (1 mM, a phosphodiesterase inhibitor) also inhibited pregnenolone-stimulated P4 accumulation. Incubation with an inositol triphosphate synthesis inhibitor, neomycin (1 mM), or an inhibitor of intracellular Ca2+ mobilization, (8,9-N, N-diethylamino)octyl-3,4,5-trimethoxybenzoate (1 mM), did not prevent the decrease in pregnenolone-stimulated P4 secretion induced by oLH. It was concluded that the luteolytic action of LH in late pregnancy is due, at least in part, to a direct action on the luteal cells and that an increase in intracellular cAMP level might mediate this effect.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Effects of progesterone antagonist, lilopristone (ZK 98.734), on induction of menstruation, inhibition of nidation, and termination of pregnancy in bonnet monkeys.

The effects of a progesterone antagonist, lilopristone (ZK 98.734), on induction of menstruation, inhibition of implantation or pregnancy, and termination of early and mid-pregnancy were studied in bonnet monkeys. In the regularly menstruating animals, administration of lilopristone (25 mg/day, s.c.) during the mid-luteal phase (Days 20-22 of the menstrual cycle) induced menstruation within 2-4 days after the initiation of treatment. A premature drop in circulating progesterone levels was also observed. The luteolytic effect of lilopristone was prevented by exogenous treatment with hCG; however, the animals showed premature menstruation, in spite of high progesterone levels (above 4 ng/ml). Treatment around the time of implantation (between Days 8 and 12 after the mid-cycle peak in estradiol levels) in mated animals provided 100% pregnancy protection. Treatment of pregnant animals on Days 30-32 of the menstrual cycle, i.e. about Day 20 after the estradiol peak, induced abortion in 8 of 10 animals. A significant (p less than 0.05) decrease in serum progesterone levels was observed on Day 3 after the initiation of treatment. However, the decrease was slower (slope: -0.36, r: 0.96) compared to that observed in nonpregnant animals (slope: -0.72, r: 0.95). In the other two animals, pregnancy was not affected. However, when the treatment was delayed until about Day 50 after the estradiol peak, all four animals aborted. This study suggests that lilopristone is a progesterone antagonist with a potential to induce menstruation, inhibit nidation, and terminate pregnancy. The antifertility effects are mediated through blocking progesterone action at the endometrium as well as decreasing progesterone bioavailability, which appears to be due to its effects on gonadotropin release.

Animals↗
PubMed1990

Effects of oxytocin on in vitro steroid release of midstage small and large porcine luteal cells.

Previously, we have demonstrated an inhibitory effect of oxytocin (OXT) on progesterone (P) and androstenedione (A) release of porcine luteal cell cultures. The present study examines whether OXT modulates P, A, or estradiol (E2) release of so-called small luteal cells (SLC) or of granulosa-derived large luteal cells (LLC). To ensure clean Percoll-gradient separation of the 2 cell types, corpora lutea not older than 6 days were used. SLC, but not LLC, responded to human (h)CG (6 ng/ml) with increased P and A, but not E2, release. When OXT was added to the culture system, both basal as well as hCG-stimulated P release of SLC, but not of LLC, were dose dependently reduced. In contrast, E2 production of SLC and LLC was significantly stimulated by OXT whereas A release of SLC cultures, but not of LLC, was inhibited in response to OXT. In the presence of a specific OXT-antagonist, this inhibitory effect of OXT on P release was abolished, indicating a specific receptor-mediated effect of OXT on porcine luteal cells. When E2 was added to the culture medium, a dose-dependent stimulatory effect on P release of SLC was demonstrated. The presence of the E2 receptor antagonist monohydroxy-tamoxifen in the culture system prevented the E2-induced increase of P release of SLC. E2 was able to counteract dose dependently the OXT-induced inhibition of P release in SLC cultures. These results suggest that OXT may have a dual function in young corpora lutea. The reduction of P and A production can be interpreted as a luteolytic effect of OXT. The simultaneous increase of E2 production, however, may also point to an indirect luteotropic effect since E2 was shown to stimulate luteal P release and to counteract OXT-induced inhibition of P release excessively.

Androstenedione↗
PubMed1987

Effects of hachimijiogan, tokishakuyakusan and keishibukuryogan on the corpus luteum function and weights of various organs in vivo.

27-day-old female rats received 20 IU PMS and 56 hours later, 40 IU hCG and were orally given with 20 or 200 micrograms of Hachimijiogan (TJ-7), Tokishakuyakusan (TJ-23) or Keishibukuryogan (TJ-25) daily for 3 or 5 days before sacrifice. Seven days after hCG treatment, the serum and ovarian tissue were assayed for progestins. 200 micrograms/day of TJ-23 significantly (p less than 0.05) decreased the progesterone and 17 alpha-hydroxyprogesterone levels, whereas it significantly (p less than 0.01) increased 20 alpha-hydroxyprogesterone. TJ-7 and TJ-25 showed a tendency to decrease these progestins. These results suggest that TJ-23 has a luteolytic effect on the corpus luteum in vivo.

Animals↗
PubMed1985

The effect of prostaglandin F2 alpha analog on the plasma concentration of progesterone in the bandicoot, Isoodon macrourus (Marsupialia:Peramelidae), during lactation.

Prostaglandin F2 alpha (PGF) analog was administered to bandicoots during lactation to determine whether PGF2 alpha is involved in the regression of the marsupial corpus luteum. The concentration of progesterone in the plasma, and the morphology of the corpus luteum were monitored following PGF analog treatment. When the drug was administered early in lactation, there was no apparent change in luteal function. However, when PGF analog was administered on Days 30 and 31 of lactation an immediate decrease in plasma progesterone concentration to 0.1 ng/ml was observed and regression of the corpora lutea was observed by Day 36. The corpus luteum of numerous eutherian species is resistant to the luteolytic effects of prostaglandin F2 alpha in the early luteal phase. The corpus luteum of the bandicoot appears to be resistant in a similar manner during early lactation.

Animals↗
PubMed1982

Sensitivity of pituitary and corpus luteum responses to single intranasal administration of (D-ser[TBU]6-des-gly-NH2(10)) luteinizing hormone-releasing hormone ethylamide (Buserelin) in normal women.

We have previously shown that intranasal administration of Buserelin (Hoechst AG, Frankfurt, Germany) at mid-luteal phase inhibits progesterone secretion and shortens the luteal phase. In order to determine the best possible use of this medication, we studied the effect of increasing doses (50 to 1500 microgram) of the luteinizing hormone-releasing hormone (LH-RH) agonist administered between days 6 and 12 after the luteinizing hormone (LH) peak on the pituitary response and corpus luteum function. A near-maximal gonadotropin response was obtained at a dose of 200 microgram. Maximal LH stimulation was observed at 4 hours, and serum levels of the hormone remained elevated for at least 14 hours at the two highest doses. Maximal serum follicle-stimulating hormone (FSH) levels were usually observed 2 hours later than for LH, and the response was longer lasting. A 2- to 2.5-fold stimulating of serum progesterone levels was observed at 8 hours for all doses studied. There was a tendency for a dose effect on serum estradiol levels, a 2-fold stimulation being obtained at 14 hours at the highest dose of LH-RH analog. Up to 200 microgram, there was no apparent change in the luteal phase. At the 500-microgram dose, there was a clear tendency for decreased estradiol and progesterone concentrations during the treatment cycle, while at 1000 and 1500-microgram doses steroid levels were clearly inhibited and the luteal phase was shortened by 2.5 days. Posttreatment cycles were normal. Thus the corpus luteum is sensitive to a single high intranasal dose of Buserelin, the luteolytic effect being related to the prolonged gonadotropin response.

Administration, Intranasal↗
PubMed1997

[The effects of gossypol on rat luteal cells, human decidual cells and cytotrophoblasts].

The direct effects of gossypol on the serum-free primary cultures of rat luteal cells and cytotrophoblasts were observed. The results indicate that: (1) Gossypol affected the viability of the cultured rat luteal cells, LD50: 1.6 (0.4-2.9) micrograms.ml-1. (2) The basal secretions of progesterone were significantly inhibited at low and high concentrations. The activities of 3 beta-HSD, adenyl cyclase and hCG-stimulated progesterone production were inhibited by higher concentrations of gossypol. (3) Gossypol damaged cultured human decidual cells and cytotrophoblasts, the LD50 were 3.5(0.4-6.6) micrograms.ml-1 and 4.1(0.6-7.6) micrograms.ml-1, respectively. These results suggest that the luteolytic effect is the main mechanism of action for the termination of early pregnancy by gossypol, while the direct damaging effects on decidual cells and cytotrophoblasts may also play a role in the termination of early pregnancy.

Animals↗
PubMed1979

Effect of D-Trp6-LH-RH on the pituitary-gonadal axis during the luteal phase in the baboon.

An effect of E-Trp6-LH-RH (superactive LH-RH agonist) in the pituitary and ovarian function was examined. Four regularly cycling baboons were used for this study. After determination of control values of plasma levels of LH, oestrogen and progesterone during the entire menstural cycle, D-Trp6-LH-RH was infused subcutaneously for 7 days during the early luteal phase in these four baboons. An infusion of D-Trp6-LH-RH increased plasma LH and oestrogen, but it failed to alter the plasma level of progesterone. From these results, it seems unlikely that 1) D-Trp6-LH-RH has a luteolytic effect, and 2) an increased ovarian oestrogen causes luteolysis in the baboon.

Animals↗
PubMed2001

Overview of current research in parturition.

The mechanism of human parturition is not understood and further research into this important physiological process is needed. Preterm labour remains a major cause of perinatal mortality and morbidity and there is controversy about the effectiveness of current tocolytic agents. In some species, notably the sheep, parturition is preceded by an activation of the fetal hypothalamic-pituitary-adrenal axis. However, in primates this axis has a supportive, rather than essential, role. A fall in maternal progesterone levels is a prerequisite for parturition in most mammals and this takes place either through increased conversion of progesterone to oestrogens in the placenta, or through the demise of the corpus luteum of pregnancy, depending on the species. In primates and guinea-pigs parturition occurs without an apparent fall in maternal progesterone levels. Gene targeting experiments in mice have demonstrated the critical role of prostaglandin FP receptors, necessary to mediate the luteolytic effect of PGF(2alpha) before parturition. Prostaglandin synthesis is required for the onset and progress of labour as demonstrated by experiments with cPLA(2)- and PGHS-1-deficient mice. The importance of local tissue conversion of progesterone to reduced androgens in the regulation of cervical ripening has been demonstrated in 5alpha-reductase-deficient mice. The chronic and ubiquitous gene inactivation obtained with conventional methods has disadvantages, in that it may allow the activation of compensating pathways, making the interpretation of results difficult. This problem may be overcome by using pulsed and tissue-selective gene knockout strategies. The study of human parturition is complicated by the lack of access to direct experimentation, whereas the endocrine differences between species make it difficult to extrapolate animal data to humans. However, the development of genomic/proteomic technologies that allow the simultaneous screening of thousands of genes and gene products in small samples of tissue, and new methods to study the biochemistry of receptors and proteins involved in smooth muscle physiology promise new insights into the control of human labour. Nevertheless, the integration of rapidly expanding knowledge into a complete understanding of the roles of the mother and the fetus in the initiation of parturition, and the development of selective medication for the effective management of preterm labour remain an arduous challenge for the next decade. Experimental Physiology (2001) 86.2, 213-222.

Female↗
PubMed1997

Effects of low doses of prostaglandin F2 alpha during the early luteal phase before and after implantation in beagle bitches.

Three groups of five beagle bitches were treated three times a day with natural prostaglandin F2 alpha (PGF2 alpha) at a dosage of either 20 micrograms kg-1 bodyweight (days 5-8 of metoestrus), 50 micrograms kg-1 bodyweight (days 5-11 of metoestrus) or 20 micrograms kg-1 bodyweight after detection of pregnancy (days 20-21 after ovulation) for 7 days. A dose of 20 micrograms PGF2 alpha kg-1 bodyweight administered during the early luteal stage could not induce a reliable decrease of progesterone concentrations, while injections of 50 micrograms PGF2 alpha kg-1 bodyweight beginning before implantation resulted in arrest of luteal progesterone production and prevention of nidation in all five bitches. The application of 20 micrograms PGF2 alpha kg-1 bodyweight shortly after implantation induced functional arrest of corpora lutea and led to embryonic or fetal resorption in all cases. In general, the luteolytic effect of low PGF2 alpha doses was insufficient because of the recovery of the corpora lutea seen in nearly all bitches and the prolonged process of embryonic or fetal resorption that increase the risk of uterine disease.

Abortion, Induced↗
PubMed2004

Role of the endothelin-1 system in the luteolytic process of pseudopregnant rabbits.

The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process of controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 microg iv) administration at d 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both d 4 and 6. Pretreatments with Bosentan, a dual ET(A)/ET(B) receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1 but not that induced by prostaglandin F2alpha (PGF2alpha). In CL cultured in vitro, ET-1 increased (P </= 0.01) both PGF(2alpha) production and luteal nitric oxide synthase activity but decreased (P < or = 0.01) progesterone release. Addition of ET(A) receptor antagonist BQ123 or COX inhibitor blocked the ET-1 luteolytic effects. Positive staining for ET-1 receptors was localized in ovarian blood vessels, granulosa cells of large follicles, and luteal cells. Immunoblot analysis of ET-1 receptor protein revealed a strong band of approximately 48 kDa in d-9 CL. Up to d 6 of pseudopregnancy, ET-1 mRNA abundance in CL was poorly expressed but then increased (P < or = 0.01) at d 9 and 13. ET(A)-receptor transcript increased (P < or = 0.01) at d 6, remained at the same level up to d 13, and then declined to the lowest (P < or = 0.01) levels at d 22. ET(B)-receptor mRNA increased (P < or = 0.01) throughout the late-luteal stage from d 13 up to d 18. Our data suggest that the luteolytic action of ET-1 may be a result of PGF2alpha synthesis from both luteal and accessory cells, via the COX pathways.

Animals↗
PubMed1977

Effect of 15(s)15-methyl-PGF2alpha-methyl ester vaginal suppositories on circulating hormone levels in early pregnancy.

Intravaginal administration of 15-methyl-PGF2alpha-methyl ester in the form of suppositories terminated pregnancy in 70 percent of the cases whose last menstrual periods ranged from 35 to 56 days. The use of these suppositories in 49 patients, between 57 to 80 days of gestation, dilated the cervix by 10 mm or more, in one hundred percent of the cases. A decrease in circulating levels of estradiol-17beta and progesterone was observed following 15-methyl-PGF2alpha administration. The mean estradiol-17beta levels declined by about 55.9 percent at 9 hours whereas, the corresponding fall in progesterone was 32.7 percent. This was indicative of a direct action of 15-methyl-PGF2alpha on the corpus luteum. The vaginal use of 15-methyl-PGF2-alpha-methyl ester suppositories thus appears to be a promising method for the termination of early pregnancy and for pre-operative cervical dilatation. The termination of early pregnancy appears to be partly due to the luteolytic effect of 15-methyl-PGF2alpha besides stimulating uterine contractions.

Abortion, Induced↗