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.     

Plasma 13, 14-dihydro-15-keto-PGF2 (PGFM) in pregnant and nonpregnant heifers prior to and during surgery and following intrauterine injection of PGF2

On day 17 postestrus or postmating, heifers were given intrauterine injections of saline (2 pregnant, 2 non-pregnant) or 200 μg PGF₂α (7 pregnant, 6 nonpregnant) through cannulae installed surgically into the uterine horn ipsilateral to the corpus luteum bearing ovary. Jugular blood samples were collected prior to the laparotomy at which the cannulae were installed during surgery, and for 90 min following the intrauterine injection. Plasma was assayed for progesterone and 13,14-dihyro-15-keto-PGF₂α )PGFM). Laparotomies were reopened to confirm proper cannula placement and to determine if blastocysts were present in mated heifers. Concentrations of PGFM were higher in pregnant compared to nonpregnant heifers during the presurgery (68 26 24 26 pg/ml; P < 0.25) and surgery (186 47 65 17 pg/ml; P < .05) periods. Pregnancy status did not alter the mean concentrations of PGFM (pregnant, 554 70 pg/ml; nonpregnant, 422 81 pg/ml) or the half-life of its decline in concentration (18 min) following intrauterine injection of PGF₂α. Pregnancy at 17 days in cattle does not appear to influence PGF₂α transport from the uterine lumen or its metabolism in the uterus or elsewhere in response to an acute intrauterine injection.     

Induction of 20α-hydroxysteroid dehydrogenase in rat corpora lutea of pregnancy by prostaglandin F2α

20α-OH-SDH is a marker of luteolysis in rat corpora lutea and appearance of this enzyme is inhibited by prolactin but stimulated by LH or hCG. PGF₂α induced 20 α-OH-SDH activity in corpora lutea of pregnant rats and a significant fall in peripheral plasma progesterone concentrations when administered i.m. for two consecutive days. Rats treated with PGF₂ α on days 8 and 9 of pregnancy were resorbing implants by day 10. Exogenous progesterone, but not estrogen, prevented implant resorption, yet 20 α-OH-SDH appeared in the corpora marking luteolysis. HCG, LH and prolactin, but not FSH, prevented pregnancy termination and inhibited induction of 20 α-OH-SDH in rats treated with PGF₂ α in early pregnancy. PGF₂α also induced 20α-OH-SDH in luteal tissue of intact and hypophysectomized rats treated on days 14 and 15 of pregnancy, but neither exogenous steroids or gonadotrophins blocked the induction of the enzyme in rats treated at this time. The increase in lutein 20α-OH-SDH activity during the peripartal period was partially blocked by administration of the prostaglandin biosynthesis inhibitor, indomethacin, suggesting a role for endogenous prostaglandins in the induction of 20α-OH-SDH at term. It appears that PGF₂α acts directly on the ovary to induce 20α-OH-SDH activity by preventing the luteotrophic action of prolactin. Other luteal NADPH-dependent dehydrogenase activities are not markedly stimulated following PGF₂α administration.     

Dose and time dependent luteotropic and luteolytic action of prostaglandin F2α in the luteinized rabbit ovary

The mechanism of stimulatory and inhibitory action of PGF_2α on ovarian steroidogenesis both under and conditions has been studied in the pseudo-pregnant rabbits. Short term incubation of the ovaries with PGF_2α (2.82 × 10⁻⁵M) resulted in an increased synthesis of progesterone and 20α-OH P. The addition of PGF_2α in the medium and further incubation of the ovaries obtained from rabbits that had been constantly infused with PGF_2α (0.5 μg/min.) for two hours resulted in increased synthesis of these progestins. The ratio of progesterone to 20α -OH P was also enhanced under these conditions and thus supported the luteotropic action of small doses of PGF_2α under short term incubations. However, as the amount of PGF_2α infused was increased to 5 μg/min., the addition of PGF_2α under conditions strikingly decreased the production of these progestins. The ratio of progesterone to 20α -OH P was also decreased and thus was indicative of luteolytic action of higher doses of PGF_2α. High doses of PGF_2α (5.64 × 10⁻⁴M) failed to I cause any significant change in the progestin synthesis under short term incubation. These results thus suggest that the luteotropic and luteolytic action of PGF_2α in the luteinized rabbit ovary is dose and time dependent.     

Effect of prostaglandin F2α on uterine or ovarian secretion of prostaglandins E and F2α in vivo in 90–100 day hysterectomized, intact or ovariectomized pregnant ewes

Vehicle or 8 or 16 mg of PGF_2α per 58 kg body weight was given intramuscularly to intact, hysterectomized or ovariectomized 90–100 day pregnant ewes in three separate experiments. Both doses of PGF_2α increased PGF_2α in ovarian venous plasma compared with controls at 72 hr post treatment in intact (P≤0.05) but did not in hysterectomized (P≥0.05) 90–100 day pregnant ewes. Concentrations of PGE in ovarian venous blood of intact ewes did not differ (P≥0.05) between treatment groups and were equivalent to concentrations of PGE determined in uterine venous plasma. PGE was decreased in ovarian venous plasma by PGF_2α in hysterectomized ewes (P≤0.07). PGE in uterine venous plasma averaged 6 ng/ml over the 72-hr treatment period in intact and ovariectomized 90–100 day pregnant ewes and was 12 fold greater (P≤0.05) than PGF_2α which averaged 500 pg/ml in uterine venous plasma. Both PGF_2α and PGE increased (P≤0.05) by 64 hr in uterine venous plasma of the 8 mg PGF_2α — treated intact pregnant ewes. A significant quadratic increase (P≤0.05) was observed for PGF_2α and PGE in the vehicle and both PGF_2α treatment groups of intact ewes at the end of the 72-hr sampling period. It is concluded that the uterus and ovaries secrete significant quantities of PGE but little PGF_2α during midgestation. In addition, PGF_2α increased uterine secretion of PGE . PGE may be a placental stimulator of ovine placental secretion of progesterone or PGE may protect placental steroidogenesis from actions of PGF_2α.     

Role of progesterone in regulating uteroovarian venous concentrations of PGF2 α and PGE2 during the estrous cycle and early pregnancy in ewes

The role of progesterone in regulation of uteroovarian venous concentrations of prostaglandins F₂ α (PGF₂α) and E₂ (PGE₂) during days 13 to 16 of the ovine estrous cycle or early pregancy was examined. At estrus, ewes were either mated to a fertile ram or unmated. On day 12 postesturus, ewes were laparotomized and a catheter was inserted into a uteroovarian vein. Six mated and 7 unmated ewes received no further treatment. Fifteen mated and 13 unmated ewes were ovariectomized on day 12 and of these, 7 mated and 5 unmated ewes were given 10 mg progesteron sc and an intravaginal pessary containing 30 mg of progesterone. Uteroovarian venous samples were collected every 15 min for 3 h on days 13 to 16 postestrus. Mating resulted in higher mean daily concentrations of PGE₂ in the uterovarian vein than in unmated ewes. Ovariectomy prevented the rise in PGE₂ with day in mated ewes but had no effect in unmated ewes. Progesterone treatment restored PGE₂ in ovariectomized, mated ewes with intact embros. Mating had no effect on mean daily concentrations of PGF₂α or the patterns of the natural logarithm (ln) of the invariance of PGF₂α. Ovariectomy resulted in higher mean concentrations and ln invariances of PGF₂α on day 13 and lower mean concentrations and ln invariances of PGF₂α on days 15 and 16. Replacement with progesterone prevented these changes in patters of mean concentrations and ln variances of PGF₂α following ovariectomy. It is concluded that progesterone regulates the release of PGF₂α from the uterus, maintaining high concentrations while also preventing the occurrence of the final peaks of PGF₂α which are seen with falling concentrations of progesterone. This occurs in both pregnant and non-pregnant ewes. Progesterone is also needed to maintain increasing concentrations of PGE₂ in mated ewes.     

Interactions of prostaglandins with subpopulations of ovine luteal cells. II. Inhibitory effects of PGF2α and protection by PGE2

Purified preparations of ovine large luteal cells were utilized in a series of experiments to test the effects of prostaglandins (PG) E₂ abd F₂α on cell morphology, viability and secretion of progesterone. Luteal cells were allowed to attach to culture dishes overnight before experiments. In the first series of experiments incubation of large steroidogenic cells with PGF₂α for 6 hr resulted in morphological changes including a retraction of the cell cytoplasm and apparent extrusion of cytoplasmic components which became more pronounced after 12 hr. In a second series of experiments, PGF₂α decreased and PGE₂ increased progesterone accumulation in media after 6 hr when media were not replaced during the incubation period, while progesterone accumulation was not different than that observed in control dishes when both prostaglandins were present. Hourly replacement of the media negated the inhibitory effects of PGF₂α but had no effect on the stimulated secretion of progesterone induced by PGE₂. Finally, in incubations without media replacement, PGF₂α induced a dose-dependent decrease in progesterone accumulation while PGE₂ elicited a biphasic response with progesterone secretion increasing from 0.1 ng/ml to maximal levels at 10 ng/ml followed by a dose-dependent decrease at 100 and 1000 ng/ml. These data are compatible with the hypotheses that: 1) luteolysis is initiated, at least in part, by an action of PGF₂α on large luteal cells; and 2) the embryonic signal from the pregnant uterus which rescues the ovine corpus luteum may be PGE₂.     

The excretion of prostaglandin F2α in milk of cows

Prostaglandin F_2α (PGF_2α) was measured by immunoassay in plasma and milk of four cows (six experiments). After 30 mg PGF_2α im, plasma PGF_2α peaked at 15 minutes (2.4 ± 0.7 ng/ml) and declined toward basal values by 3 hours; maximum milk PGF_2α (0.91 ± 0.12 ng/ml) occurred at 1 hour. The average excretion rate in milk was 2.9 μg/day 0.9 μg (0.003%) of which was due to the 30 mg PGF_2α injected. In six non-pregnant control cows, daily changes of milk PGF_2α and progesterone were not consistently related.     

Effect of PGF2α on progesterone secretion and adenylate cyclase activity in ovine luteal tissue

Ovine luteal slices were used to study the effects of prostaglandins (PG) F₂α on luteinizing hormone (LH)-stimulated secretion of progesterone and adenylate cyclase activity. The accumulation of progesterone in incubation medium and adenylate cyclase activity was similar after incubation of luteal slices with Medium 199 alone or Medium 199 containing PGF₂α (250 ng/ml) for 3 hr. Addition of luteinizing hormone (LH; 100 ng/ml) resulted in a 2–3 fold increase in both the rate of progesterone accumulation and adenylate eyclase activity by 3 hr. When luteal slices were incubated in the presence of both LH and PGF₂α the rates of progesterone accumulation and adenylate cyclase activity were identical to those in flasks containing LH alone after 1 hr; however, after 3 hr both LH stimulated progesterone accumulation and adenylate cyclase activity were inhibited to levels similar to those observed in control slices.In a second experiment, after 60–120 min of exposure to PGF₂α the rate of progesterone accumulation in the medium was not different from that in untreated control slices. In addition, after this experiment the luteal slices were homogenized and the basal, sodium fluoride, LH, isoproterenol (ISO) and PGE₂ sensitive adenylate cyclase activities were determined to evaluate the hormonal specificity of the negative effect of the pretreatment with PGF₂α. Both LH and ISO stimulated adenylate cyclase activities were reduced after PGF₂α pretreatment. However, fluoride ion stimulated adenylate cyclase activity was not significantly effected by PGF₂α pretreatment and PGE₂ sensitive adenylate cyclase was effected only slightly.     

Influence of low plasma progesterone concentrations on the release of prostaglandin F2α during luteolysis and oestrus in heifers

A study was conducted to determine the effect of suprabasal plasma concentrations of progesterone on the release of prostaglandin F_2α (PGF_2α) at luteolysis and oestrus. Heifers received silicone implants containing 2.5 (n = 4), 5 (n = 4), 6 (n = 3), 7.5 (n = 3), 10 (n = 4), or 15 (n = 3) g of progesterone, or an empty implant (controls, n = 4) between Days 8 and 25 post ovulation. Blood was collected frequently between Days 14 and 28 and assayed for progesterone and 15-ketodihydroprostaglandin F_2α. Basal progesterone concentrations in control heifers did not differ from those in heifers with 2.5- or 5-g implants and remained around 0.4−0.5 nmol l⁻¹ until ovulation in all three groups. In the heifers treated with 6–15 g of progesterone, basal concentrations were maintained at higher (P < 0.05) levels compared with those in the controls, ranging from 0.8 to 1.6 nmol 1⁻¹. The effect of these elevated progesterone levels was to delay ovulation by prolonging the growth of the ovulatory follicle, which continued growing until the implant was removed. In all experimental groups, the first significant increase of the PGF_2α metabolite occurred between Days 15.3 and 16.3 (P > 0.05) and was associated with the onset of a decrease in progesterone concentrations, which had reached levels below 3 nmol 1⁻¹ by Days 17.4−19.1. PGF_2α metabolite peaks associated with luteolysis were frequent until Day 20. In the period from Day 20 until implant removal, sporadic peaks were observed, ranging in number from 1.0 ± 1.2 (mean ± SEM) in the control group to 3.0 ± 1.4 peaks in the heifers treated with 7.5 g of progesterone (P > 0.05). The number of PGF_2α metabolite peaks during that period was higher (P < 0.05) in heifers treated with 10 and 15 g than in controls. A positive correlation was found between the basal concentration of progesterone and the number of PGF_2α peaks after luteolysis (r = 0.54; P < 0.01). Plasma progesterone concentrations above approximately 1.4 nmol l⁻¹ were able to maintain the release of PGF_2α until the progesterone implants were removed and plasma levels decreased to basal values. These heifers had a preovulatory PGF_2α release pattern resembling that found in repeat breeder heifers.     

Effect of in vivo prostaglandin treatment on H-PGF2α uptake in hamster corpora lutea

Pregnant hamsters were administered (SC) prostaglandin or vehicle on the morning of the 4th day of pregnancy. Serum progesterone was significantly depressed (p<.01) at 0.5, 2, and 6 hours after treatment with 100 μg PGF_2α. Serum progesterone levels were unchanged 2 hours and 6 hours after treatment with 100 μg PGF_2β and 2 hours after treatment with 1 mg PGF_2β. Progesterone levels were depressed to less than 1 ng/ml 6 hours after treatment with 1 mg PGF_2β. The specific uptake of ³H-PGF_2α in whole hamster corpora lutea was significantly depressed 2 hours and 6 hours following 100 μg PGF_2α treatment. A 15% depression in specific uptake occurred 0.5 hour post-treatment. Treatment with 100 μg PGF_2β resulted in no change. Administration of 1 mg PGF_2β resulted in depressed ³H-PGF_2α uptake at both 2 and 6 hours post-treatment.Prostacyclin (PGI₂) treatment resulted in no change in either ³H-PGF_2α specific uptake or serum progesterone 2 hours after 100 μg treatment SC. These parameters were both reduced approximately 30% 6 hours post-treatment. Treatment with 6-keto-PGF_1α resulted in a complete lack of measurable ³H-PGF_2α uptake and serum progesterone levels less than 1 ng/ml at both 2 and 6 hours after treatment with 1 mg SC.     

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.     

Prostaglandin biosynthesis by the rat uterus during the oestrus cycle, temporal correlation with plasma oestradiol and progesterone concentrations, identification of 6 keto PGF1α as the major metabolite

Prostaglandin biosynthesis was studied in the rat uterus during the oestrous cycle. Uterine homogenates were incubated for 20 minutes in the presence of exogenous substrate (2.10⁻⁵M). PGF_2α and PGE₂ were measured by R.I.A.. A sharp peak PGF_2α and a smaller peak of PGE₂ were observed at prooestrus, 20 h. Another small PGE₂ peak occurred at dioestrus II, 15 h. The lowest values of both PGs were found on dioestrus, 15 h. Plasma oestradiol concentration were highest at proestrus, 15 h and 20 h. A sharp progesterone peak occurred at prooestrus, 20 h. The PGF_2α peak is next to the oestradiol peak and is superimposable or lags slightly beyond the progesterone peak.Incubation with ¹⁴C arachidonic acid and subsequent analysis of extracts by TLC and scanning showed that the major metabolite is PGI₂, identified as 6 keto PGF_1α. The conversion rate of arachidonic acid into 6 keto PGF_1α is 5 times higher than into PGF_2α. 6 keto PGF_1α was further identified by GC/MS. No significant difference was observed between 6 keto PGF_1α production during oestrus and dioestrus.     

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.     

Reversal of indomethacin blockade of ovulation in gilts by prostaglandins

Prepubertal gilts given 750 IU pregnant mares′ serum gonadotropin (PMSG) followed 72 h later by 500 IU human chorionic gonadotropin (hCG) to induce follicular growth and ovulation fail to ovulate when 10 mg/kg indomethacin (INDO) is injected 24 h after hCG administration. This study examines the effects of administration of exogenous prostaglandins F_2α and E₂ (PGF_2α and PGE₂) alone or in combination, and at various times prior to the expected time of ovulation, on the INDO blockade of ovulation in PMSG/hCG-treated gilts. Occurrence of ovulation was determined by visual observation at laparotomy 48 h after hCG. When 5 mg or 10 mg PGF_2α was injected at each of 38, 40 and 42 h after hCG injection, 63% and 79%, respectively, of preovulatory follicles ovulated. In contrast, injection of 5 mg PGE₂ or 5 mg PGE₂ plus 5 mg PGF_2α induced ovulation in 0% and 24% of preovulatory follicles, respectively. In control groups, 100% of folicles in PMSG/hCG-treated gilts ovulated whereas none did so in PMSG/hCG/INDO-treated animals. These results indicate that administration of PGF_2α can induce ovulation in the PMSG/hCG/INDO-treated prepubertal gilt and suggest that PGE₂ is ineffective and may be antagonistic to PGF_2α in overcoming the ovulation blocking effect of INDO.     

Blood LH after PGF2α in diestrous and ovariectomized cattle

Two experiments were conducted to determine whether the increased serum LH which occurs within 12 hr after a luteolytic dose of PGF_2α is dependent upon changes in progesterone or estradiol secretion. In the first experiment, exogenous progesterone abolished the increase in serum LH caused by a subcutaneous injection of 25 mg PGF_2α in diestrous heifers, but not in ovariectomized heifers. In the second experiment, progesterone pessaries were removed at 6 hr after a subcutaneous injection of 25 mg PGF_2α. LH remained at pre-PGF_2α values while the pessaries were in place, but began to increase within 1 hr after they were removed. Blood estradiol also remained at pre-PGF_2α values until the pessaries were removed, and began to increase at 2 hr after pessary removal. We conclude that the increase in serum LH within 12 hr after PGF_2α treatment in diestrous cattle is dependent upon withdrawal of progesterone; it is not due to increased serum estradiol.     

An intra-corpus luteum site for the luteolytic action of prostaglandin F2α in the rhesus monkey

It has not been possible to demonstrate prostaglandin F₂α (PGF₂α) participation in primate luteolysis under conditions of systemic administration or of acute intraluteal injection. These study designs were hampered by the short biological half-life in the first instance and brevity of administration in the latter. In this study, luteolysis has resulted from chronic, intraluteal delivery of PGF₂ α. Using the Alzet osmotic pump-cannula system, normally cycling rhesus monkeys were continuously infused, until menses occurred, with PGF₂ α (10 ng/1/hr) directly into the corpus luteum (CL, n=6), into the stroma of the ovary bot bearing the corpus luteum (NCL, n=3), or subcutaneously (SC, n=5). An additional 5 monkeys received vehicle (V) into the corpus luteum. All experiments commenced 5–7 days after the preovulatory estradiol surge. Luteal function was assessed by the daily measurements of plasma progesterone, estradiol, and LH. Intraluteal PGF₂α caused premature functional luteolysis in all monkeys, as reflected by a highly significant decline in circulating progesterone and estradiol and the early onset of menstruation, when compared to the other groups. V, NCL, and SC infusions had no effect on either circulating steroid levels or luteal phase lengths. None of the experimental groups showed any change in plasma LH concentrations. These are the first data to indicate that PGF₂α can induce functional luteolysis in the primate, and the site of action appears to be the corpus luteum.     

Effects of oestradiol, progesterone, hydrocortisone and oxytocin on prostaglandin output from the guinea-pig endometrium maintained in tissue culture

The effects of oestradiol, oxytocin, progesterone and hydrocortisone on prostaglandin (PG) output from guinea-pig endomerium, removed on days 7 and 15 of the oestrous cycle and maintained in tissue culture for 3 days, have been investigated. Oetradiol (3.7 to 3700nM) and oxytocin ( 2 to 200pM) did not stimulate endometrial PGF_2α output, thus not confirming the findings of a previous report (Leaver & Seawright, 1928), nor did they stimulate the outputs of PGE₂ and 6-keto-PGF_1α. In fact, oestradiol (3700nM) inhibited the outputs of PGF_2α, PGE₂ and, to a lesser extent, 6-keto-PGF_1α. Progesterone (3.2 to 3200nM) inhibited the outputsof PGF_2α and PGE₂; hydrocortisone (2.8 to 2800nM) had no effect on endometrial PG output. These findings indicate that the inhibitory effect of progesterone on endometrial PG synthesis and release in the guinea-pig is not due to progesterone having a glucocorticoid-like action. Furthermore, progesterone had no effect on 6-keto-PGF_1α output, suggesting that the mechanisms controlling endometrial PGI₂ synthesis (as reflected by measuring 6-keto-PGF_1α) are different from those controlling endometrial PGF_2α and PGE₂ synthesis.     

Luteolysis, estrus and ovulation, and blood prostaglandin F after intramuscular administration of 15, 30 or 60 mg prostaglandin F2α

During diestrus in three consecutive estrous cycles, each of six heifers was given (im) 30 mg, 15 mg (twice at 6-hr intervals) and 60 mg prostaglandin F_2α (PGF_2α) tham salt. Neither the decline in blood progesterone, the increase in blood estradiol, the duration or the peak of the LH surge, the interval to onset of estrus, nor the interval to ovulation was affected significantly by dose of PGF_2α. Thus, relative to that after 30 mg PGF_2α im, two injections of 15 mg at 6-hr intervals or 60 mg PGF_2α did not hasten luteolysis. Thirty mg was an ample im dose of PGF_2α to cause luteolysis. Regardless of im dose of PGF_2α, blood PGF peaked at about 6.0 ng/ml within 10 minutes and returned to basal values (<1.0 ng/ml) within 90 minutes. In another trial, after a single iv injection of 5 mg PGF_2α, blood PGF peaked (25 ng/ml) within 5 minutes and returned to basal values within 15 minutes. During a 30-minute infusion (0.5 mg/minute) of PGF_2α, blood PGF plateaued at 29.5 ng/ml with a metabolic clearance rate of 17.0 liters per minute.