Assessment of possible luteolytic effect of intra-ovarian injection of prostaglandin F2α in the human

A group of five patients awaiting laparoscopic tubal diathermy were followed by daily assay of luteinising hormone (LH) and progesterone. Between five and eight days after the LH peak, prostaglandin F_2α (PGF_2α) was injected into either the corpus luteum or the ovarian stroma. Doses of 100 μg into the corpus luteum, 1000 μg into the adjacent stroma and 500 μg into an indeterminate ovarian structure had no effect on peripheral plasma progesterone levels or uterine bleeding.An injection of 500 μg or 1000 μg given unequivocally into the corpus luteum produced a rapid and profound fall in plasma progesterone levels, the nadir coinciding with the onset of uterine bleeding which commenced 24 hours after the injection and persisted for more than seven days. Injection of 100 μg in the same volume of saline had no such effect. Despite continued bleeding plasma progesterone levels returned to normal luteal levels for three days and then fell again.     

The excretion of prostaglandin F-2ALPHA in milk of cows.

Prostaglandin F-2ALPHA (PGF-2ALPHA) was measured by immunoassay in plasma and milk of four cows (six experiments). After 30 mg PGF-2ALPHA im, plasma PGF-2ALPHA peaked at 15 minutes (2.4 plus or minus 0.7 ng/ml) and declined toward basal values by 3 hours; maxiumum milk PGF-2ALPHA (0.91 plus or minus 0.12 ng/ml) occurred at 1 hour. The average excretion rate in milk was 2.9 mu-g/day 0.9 mu-g (0.003%) of which was due to the 30 mg PGF-2ALPHA injected. In six nonpregnant control cows, daily changes of milk PGF-2ALPHA and progesterone were not consistently related.     

The effect of intra-uterine prostaglandin F-2alpha on corpus luteum function in the human.

Prostaglandin F-2alpha (PGF-2alpha) was administered via a Foley catheter over a 12 hour period to 8 healthy volunteers awaiting laparoscopic sterilisation. The amount of PGF-2alpha infused varied between 500 mu-g and 2000 mu-g every 2 hours for 6 doses. Plasma progestins and oestradiol 17beta, and urinary estrogens and pregnanediol were assayed throughout the study period. There was no evidence of luteolysis in any patient although vaginal bleeding of varying duration occurred in all women within 36 hours of administration of PGF-2alpha.     

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

The ability of human chorionic gonadotropin (HCG) to reduce the luteolytic effect of prostaglandin (PGF2 alpha) was demonstrated in cycling ewes. As expected, treatment with 10 mg of PGF2 alpha 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 PGF2 alpha 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 PGF2 alpha because plasma progesterone was reduced when the dose of PGF2 alpha was doubled. Whether CL regressed or continued to function after treatment with both HCG and PGF2 alpha appeared to depend upon a balance between the positive and negative effects of the two hormones.     

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.     

Direct effects of oestradiol-17 beta and prostaglandin E-2 in protecting pig corpora lutea from a luteolytic dose of prostaglandin F-2 alpha

Implants containing vehicle or oestradiol-17 beta (10 mg) were placed into pairs of corpora lutea (CL) with and without prostaglandin F-2 alpha (PGF-2 alpha) (100 micrograms) on Day 11 and CL were collected on Day 19, in cyclic gilts (Exp. 1). The results demonstrated that CL implanted with PGF-2 alpha with or without oestradiol-17 beta had a markedly lower (P less than 0.01) weight (mg) and progesterone concentration (ng/mg) than CL with vehicle-or oestradiol-17 beta-implanted or unimplanted CL, which were similar (149 and 7.2 vs. 304 and 49.6, respectively). In Exp. 2, CL implanted with vehicle, oestradiol-17 beta or PGE-2 remained fully functional until Day 19, whereas CL implanted with oestradiol-17 beta +/- PGF-2 alpha and PGE-2 + PGF-2 alpha exhibited lower (P less than 0.05) weight and progesterone concentrations; CL implanted with PGE-2 + PGF-2 alpha were heavier (P less than 0.05) and tended (P less than 0.10) to have greater progesterone concentrations than CL implanted with oestradiol-17 beta + PGF-2 alpha. In Exp. 3, a dose-dependent (P less than 0.05) effect of PGE-2 on preventing regression induced by PGF-2 alpha was observed on Day 19. These data demonstrate a direct effect of PGE-2, but not of oestradiol-17 beta in protecting the CL against luteolysis induced by PGF-2 alpha.     

Dependence on prolactin of the luteolytic effect of prostaglandin F2alpha in rat luteal cell cultures

Luteal regression is a multistep, prolonged process, and long-term luteal cultures are required for studying it in vitro. Cell suspensions from ovaries of superovulated rats were enriched with steroidogenic cells, seeded on laminin or fibronectin, and maintained in defined medium for up to 10 days. Progesterone secretion was much lower than that of 20alpha-dihydroprogesterone, a product of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD). Prolactin added throughout the incubation period gradually increased the percent progesterone out of total progestins to fourfold, while reducing 20alpha-HSD mRNA by 73%. Luteinizing hormone accelerated the establishment of higher percent progesterone by prolactin but by itself had no effect. Prolactin did not increase total progestin production or cytochrome P450 side-chain cleavage (P450(scc)) mRNA. Cell viability was unaffected by prolactin and/or LH. Prostaglandin F2alpha (PGF2alpha) was added 7-8 days after seeding. In prolactin-treated cells, PGF2alpha reduced steroidogenesis after 4-45 h, and at 45 h total progestins and P450(scc) mRNA were reduced by 45%. At 8-45 h PGF2alpha reduced the percent progesterone out of total progestins, and at 45 h 20alpha-HSD mRNA was doubled. In contrast, in prolactin-deprived cultures, PGF2alpha had little effect on total progestins or 20alpha-HSD mRNA but doubled P450(scc) mRNA. Phospholipase C activity was stimulated by PGF2alpha regardless of prolactin. Thus, when prolactin-treated, our cultures are a good model for mature corpora lutea challenged with PGF2alpha; the finding that without prolactin PGF2alpha has an alternative set of actions could help in identifying the signaling pathways of PGF2alpha responsible for its luteolytic effects.     

Clearance of prostaglandin F2ALPHA during circulatory shock.

The rate of disappearance of total circulating radioactivity following an intravenous bolus injection of 3HPGF_2α was determined during splanchnic artery occlusion (SAO) shock in the dog. In addition, the pattern of PGF_2α metabolite formation was assessed in both shocked and nonshocked animals. Although the clearance of circulating prostaglandin metabolites is significantly impaired during SAO shock as a result of decreased renal function, neither the pattern nor the time course of PGF_2α metabolite formation appears to be altered. Thus, increases in circulating prostaglandin concentrations during SAO shock reflect an increase in the rate of $\text{de novo}$ synthesis and release of these materials, and are not the result of decreased prostaglandin degradation.     

Intrauterine instillation of prostaglandin F2ALPHA IN EARLY PREGNANCY.

Intrauterine PGF2alpha (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidience of infection was high occuring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF2alpha instillation and 90iod and 75% over the next 14 days.     

Action of prostaglandin F2alpha on pregnancy in hamsters: luteolytic and extra-ovarian effects.

Pregnancies in hamsters may be terminated by 10 mug PGF2alpha administered b.i.d. on days 4, k and 6 of gestation. Small (250 mug and above) daily injections of progesterone on the same days will reverse this PG effect; in contradistinction, 10 mg of progesterone per day failed to maintain normal pregnancies in hamsters spayed on day 5. Daily administration of 3 mg of progesterone and 1 mug of estrone essentially normalized the gestation; administration of PGF2alpha at 10 mg on days 5, 6 and 7 of pregnancy in steroid-maintained rats, resulted in pregnancy termination in all animals, while 1 mg was partly effective. These data demonstrate an extra-ovarian site of action of prostaglandin F2alpha on pregnancy in hamsters.     

Effects of a luteolytic dose of oestradiol benzoate on uterine oxytocin receptor concentrations, phosphoinositide turnover and prostaglandin F-2 alpha secretion in sheep

Administration of oestradiol-17 beta benzoate on Days 9 and 10 of the oestrous cycle resulted in episodic secretion of PGF-2 alpha (as indicated by elevated circulating concentrations of 13,14-dihydro-15-ketoprostaglandin F-2 alpha) and a decline in circulating progesterone. Release of PGF-2 alpha began 35 +/- 3 h after first injection of oestrogen and progesterone concentrations declined from 42 +/- 3 h. Secretion of oxytocin, which was first observed 26 +/- 3 h after oestrogen treatment, preceded secretion of PGF-2 alpha; 69% of pulses of oxytocin coincided with episodes of PGF-2 alpha secretion. Uterine oxytocin receptor concentrations were raised in ewes treated with oestrogen, increases occurring in caruncular endometrium and myometrium by 12 h after treatment and in intercaruncular endometrium by 24 h. Raised receptor concentrations were followed at 24 h by increases in the incorporation of [3H]inositol into phosphatidylinositol and in the hydrolysis of labelled tissue phosphoinositides in response to oxytocin in slices of caruncular endometrium incubated in vitro. The following sequence of events is therefore suggested to occur at oestrogen-induced luteolysis: induction of the oxytocin receptor; increased turnover of phosphoinositides; onset of episodic secretion of PGF-2 alpha; and functional luteolysis.     

Release of prostaglandin F-2alpha during foaling in mares.

The concentrations of PGF-2alpha in the peripheral blood of five foaling mares were measured by radioimmunoassay. Low levels of PGF-2alpha were detected as early as 1 week before foaling in two of the mares. These levels increased steadily, reaching a peak (1-74 +/- 0-44 ng/ml) during fetal expulsion. A relatively high PGF-2alpha level was found in samples collected 60 min after foaling.     

15-Methylation augments the cardiovascular effects of prostaglandin F-2alpha.

Intramuscular injection of the 15-methyl analogue of prostaglandin F-2alpha (15-ME-PGF-2alpha) is being used to initiate second trimester abortion. The natural prostaglandin F-2alpha (PGF-2alpha) is a known pulmonary pressor agent but there is little information about the cardiovascular effects of the analogue. Consequently, we compared the hemodynamic responses to the two forms in twenty-three anesthetized dogs. Given I.M. or I.V. 15-me-PGF-2alpha produced a greater and more sustained rise in pulmonary arterial pressure than PGF-2alpha. Intramuscular 15-me-PGF-2alpha also elicited a more prolonged increase in pulmonary vascular resistance than prostaglandin F-2alpha given I.M. or I.V. The methyl analogue (I.M. or I.V.) causes a greater initial fall in systemic arterial oxygen tension and cardiac output, and a greater increase in systemic resistance than I.M. PGF-2alpha. Breathlessness seen during abortion induced by prostaglandin F-2alpha or its methyl analogue may be caused by acute pulmonary hypertension in addition to bronchoconstriction.     

Effect of prostaglandin F-2 alpha on ovarian enzyme activity in the hysterectomized guinea-pig.

The enzymes studied were cholesterol esterase, cholesterol ester synthetase 3 beta-hydroxysteroid dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase. PGF-2 alpha reduced the activities of 3 beta-hydroxysteroid dehydrogenase and cholesterol esterase but did not affect those of cholesterol ester synthetase of 20 alpha-hydroxysteroid dehydrogenase.     

Plasma progesterone and LH concentrations in ewes after injection of an analogue of prostaglandin F-2alpha

Plasma progesterone and LH concentrations were monitored throughout a natural oestrous cycle in 12 Clun Forest ewes and compared to those following treatment with a single i.m. injection of 100 microng ICI 80,996, an analogoue of prostaglandin F-2alpha, given during the luteal phase of the cycle. After injection of the analogue there was a high degree of synchrony in the return of oestrus (440 +/- 1-9 h; mean +/- S.E.M.) and the timing of the LH peak (48-5 +/- 2-0 h) from injection. There were no significant differences in the plasma progesterone concentrations or in the height and duration of the preovulatory LH peak between control and treatment cycles. The technique offers the possibility of controlled ovulation in the ewe.