Lack of effect of the uterus on the luteolytic effect of luteinizing hormone in the rat.
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Comparison of the luteolytic action of gonadotrophin-releasing hormone antagonist and cloprostenol, and the ability of human chorionic gonadotrophin and melatonin to override their luteolytic effects in the marmoset monkey.
The effects of the luteolytic and luteotrophic agents cloprostenol, human chorionic gonadotrophin (hCG) and melatonin on the corpus luteum have been investigated in marmoset monkeys treated with an LHRH antagonist to reduce endogenous LH secretion. This has allowed the effects of these agents to be investigated in the absence of the principal endogenous luteotrophin. Administration of the LHRH antagonist ([N-acetyl-D beta Nal1-D-pCl-Phe2-D-Phe3-D-Arg6-Phe7-Arg8-D-Ala10]NH2-LHRH) or cloprostenol between days 7 and 11 after ovulation (preimplantation) resulted in luteolysis. A significant (P less than 0.05) decrease in progesterone concentrations had occurred by 4 h after administration of the LHRH antagonist and was indeed preceded by a fall in LH concentrations. Coadministration of hCG with the LHRH antagonist prevented the fall in progesterone. In contrast, administration of cloprostenol resulted in an immediate fall in progesterone concentrations, to less than half the initial level within 1 h, and co-administration with hCG did not prevent the fall. Administration of hCG stimulated progesterone production when given 8 h after the LHRH antagonist but not after 24 h. Cloprostenol prevented the stimulation by hCG. Co-administration of melatonin with the LHRH antagonist did not prevent the decrease in progesterone concentrations. Melatonin was also not effective in preventing the fall in progesterone induced by cloprostenol. However, co-administration of melatonin and cloprostenol between days 17 and 21 after ovulation (post-implantation) significantly (P less than 0.05) delayed the fall in progesterone seen with cloprostenol alone. These results suggest that while the LHRH antagonist and cloprostenol have different sites of action their effect is similar at the corpus luteum, that is in depriving the corpus luteum of luteotrophic support. The results also suggest that melatonin may be able to influence the luteolytic action of cloprostenol but that its effect varies with the stage of the cycle. The physiological role for such an action, if any, remains unknown.
Animals↗
Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase expression and activity in the hypophysectomized rat ovary: interactions between the stimulatory effect of human chorionic gonadotropin and the luteolytic effect of prolactin.
The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) catalyzes an obligatory step in the conversion of pregnenolone and other 5-ene-3 beta-hydroxysteroids into progesterone as well as precursors of all androgens and estrogens in the ovary. Since 3 beta-HSD is likely to be an important target for regulation by pituitary hormones, we have studied the effect of chronic treatment with LH (hCG), FSH, and PRL on ovarian 3 beta-HSD expression and activity in hypophysectomized adult female rats. Human CG (hCG) [10 IU, twice a day (bid)], ovine FSH (0.5 microgram, bid), and ovine PRL (1 mg, bid) were administered, singly or in combination, for a period of 10 days starting 15 days after hypophysectomy. In hypophysectomized rats, PRL exerted a potent inhibitory effect on all the parameters studied. In fact, PRL caused a 81% decrease in ovarian 3 beta-HSD mRNA content accompanied by a similar decrease in 3 beta-HSD activity and protein levels. In addition, ovarian weight decreased by 40% whereas serum progesterone fell dramatically from 1.92 nmol/liter to undetectable levels after treatment with PRL. Whereas hCG alone had only slight stimulatory effects on 3 beta-HSD mRNA, protein content and activity levels, treatment with the gonadotropin partially or completely reversed the potent inhibitory effects of oPRL on all the parameters measured. FSH, on the other hand, had no significant effect on 3 beta-HSD expression and activity. In situ hybridization experiments using the 35S-labeled rat ovary 3 beta-HSD cDNA probe show that the inhibitory effect of PRL is exerted primarily on luteal cell 3 beta-HSD expression and activity. On the other hand, it can be seen that hCG stimulates 3 beta-HSD mRNA accumulation in interstitial cells. The present data show that hCG and PRL exert potent and opposite cell-specific effects on ovarian 3 beta-HSD expression, activity, and content in the rat ovary. Moreover, the present study could suggest that female infertility associated with hyperprolactinemia in women could well be related, at least in part, to the potent inhibitory effect of PRL on ovarian 3 beta-HSD expression and activity.
3-Hydroxysteroid Dehydrogenases↗
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.
Animals↗
Prostaglandin F2 alpha and its 13-dehydro analogs: comparative luteolytic effects in vivo.
Prostaglandin F2 alpha (PGF2 alpha) was identified as a luteolytic hormone in sheep (Nature, New Biol. 238, 129, 1972). Attempts to use PGF2 alpha for the pharmacological control of luteolysis in normal cycling sheep met with only partial success due to the rapid clearance of PGF2 alpha from the blood. In addition treated animals showed moderate to severe cardiovascular and gastrointestinal side effects. Accordingly, experiments were carried out to determine whether PG analogs might be more effective as pharmacological luteolytic agents. These compounds, which consisted of a number of the 13-dehydro analogs of PGF2 alpha, were administered to both sheep and monkeys either directly into the ovary or into the systemic circulation to examine them respectively for direct luteolytic activity and for resistance to metabolism. In addition in both the sheep and the monkey smooth muscle activity of the analogs was determined by recording uterine contractions in vivo. Several 13-dehydro analogs including some 16-fluoro derivatives were shown to have luteolytic activity equal to, or in some cases greater than, PGF2 alpha itself. Furthermore most of these compounds showed a marked resistance to the 15-OH-PG-dehydrogenase enzyme in vivo as evidenced by their luteolytic activity when infused intravenously. In terms of uterine contractions, several luteolytic analogs showed markedly diminished smooth muscle activity, and in some cases, complete absence of activity. These results suggest that the receptors governing the luteolytic effect on the one hand, and the smooth muscle effect on the other, possess different structural specificities. Recent studies which we have carried out on the effect of PGF2 alpha on corpus luteum (CL) blood flow support this conclusion. CL capillary blood flow was continuously monitored by means of a miniaturized Geiger-Müller probe inserted through the center of the CL in both the in situ and the autotransplanted ovary of the sheep. Capillary blood flow was measured by the clearance rate of 85Krypton injected periodically into the ovarian artery before and during the induction of luteolysis with PGF2 alpha. It was concluded that the initiation of luteolysis is not dependent on a smooth muscle effect of PGF2 alpha on the capillaries of the CL, a finding which supports the results with the synthetic analogs devoid of smooth muscle activity. More recently, in the primate model used (Macaca fascicularis) we have demonstrated that certain metabolically stable analogs are luteolytic when given intravenously, subcutaneously, or orally. These results demonstrate a rational approach to both drug synthesis and biological evaluation and suggest that a once-a-month contraceptive agent, based on a luteolytic analog of PGF2 alpha, devoid of smooth muscle activity (side effects) and metabolically stable in the bloodstream may become a reality.
Animals↗
A phorbol ester, phorbol 12-myristate 13-acetate, and a calcium ionophore, A23187, can mimic the luteolytic effect of prostaglandin F2 alpha in isolated rat luteal cells.
To explore the possible role of protein kinase C and calcium in the luteolytic process, we treated luteal cells with a protein kinase C activator, the phorbol ester, phorbol 12-myristate 13-acetate (PMA), and with the calcium ionophore, A23187. Lower concentrations of PMA could clearly mimic the inhibitory, luteolytic effects of prostaglandin F2 alpha (PGF2 alpha) on LH-induced cAMP and progesterone production. A nontumor promoting phorbol ester, 4 alpha-phorbol 12,13-didecanoate, had no inhibitory effect, indicating a specific PMA effect. The calcium ionophore, A23187, also gave a marked inhibition of LH-induced cAMP and progesterone production. Hormone-stimulated adenylate cyclase activity was markedly impaired after preincubation of the cells with PGF2 alpha, PMA, or A23187, but no effect was seen when the substances were added to isolated membranes. In addition, the stimulation of progesterone production in the luteal cells with the cAMP analogs, 8-bromo-cAMP and (Bu)2cAMP, was almost totally abolished when PMA or A23187 was present. We conclude that PMA and A23187 in many ways mimic the effect of PGF2 alpha in luteal cells. The inhibition of steroidogenesis is partly dependent on depressed activity of the hormone-sensitive adenylate cyclase, but also obtained by inhibiting steps distal to cAMP formation. Both points of action seem to be calcium and/or protein kinase C dependent. In contrast, higher concentrations of PMA markedly stimulated steroidogenesis without affecting the cAMP level, a stimulation not seen after incubation with 4 alpha-phorbol 12,13-didecanoate, suggesting again a specific PMA effect. The stimulation of steroidogenesis by higher concentrations of PMA seems to be specific, but the interpretation of this finding is unclear at present. In conclusion, PMA and A23187 mimic some of the luteolytic properties of PGF2 alpha, not only inhibiting the luteal cAMP system, but also by inducing lesions in the steroidogenic steps beyond the cAMP system.
8-Bromo Cyclic Adenosine Monophosphate↗
Luteolytic effect of D-Trp6-luteinizing hormone-releasing hormone in the rhesus monkey (Macaca mulatta).
A potent agonist of luteinizing hormone, D-Trp6-LRH, was administered at different stages during the luteal phase of rhesus monkeys (Macaca mulatta). Luteolysis, evidenced by short luteal phases and decreased serum progesterone concentrations, was consistently induced when the analog was injected on days 3 or 5 post ovulation; however, no effect was observed when it was given on day 7 post ovulation. Increasing doses of hCG administered from days 6-10 post ovulation prevented the luteolytic effect of D-Trp6-LRH. The possible mechanisms of action and the potential uses of LRH analogs as contraceptive agents are discussed.
Animals↗
Luteolytic effect of oestrone sulphate on cyclic beef heifers.
The action of oestrone sulphate on luteal function was tested in cyclic beef heifers. Once daily injection of 28 or 56 mg oestrone sulphate in corn oil beginning on Day 10 of the cycle had a significant luteolytic effect as compared to corn oil-treated controls.
Animals↗
A luteolytic effect of a prostaglandin F2 alpha analogue in non-pregnant women?
Four healthy non-pregnant volunteers with regular cycles were exposed to vaginal suppositories containing a PGF2 alpha analogue (ICI 81.008, 500-600 microgram) twice at 24-hour intervals in the early or mid-luteal phase. In comparison to serum progesterone levels of ovulatory control cycles, this treatment caused a significant decrease of serum progesterone combined with a shortening of the length of the luteal phase by 1.4 days. No gastrointestinal or other adverse effects were noticed during this treatment. Administration of ICI 81.008 in the follicular phase interfered neither with ovulation nor with the length or shape of the following luteal phase. Although limited, these data suggest a luteolytic effect of ICI 81.008 in women.
Adult↗
The non-luteolytic effect of prostaglandin F(2)alpha at the beginning of the bovine oestrous cycle: the role of oestrogen?
After the preovulatory gonadotrophin surge, antral follicles ovulate or become atretic; whatever their evolution, they stop secreting oestradiol. Since it was demonstrated that oestrogens were necessary for luteolysis to occur after PGF(2)alpha treatment, their absence could explain the non-luteolytic effect of PGF(2)alpha injected early in the cycle. Thus, cyclic cows received a PGF(2)alpha analogue and oestradiol valerate together on day 3. This treatment did not affect the life span of the corpus luteum. The absence of oestrogens in the blood does not explain the failure of PGF(2)alpha to cause luteolysis in young corpora lutea.
Journal Article↗
Luteolytic effect of azastene in the nonhuman primate.
The ability to block steroidogenesis with 4,4,17-alpha-trimethylandrost-5-eno[2,3,-d]isoxazol-17-ol (azastene) was studied in 3 different models. Oral administration of 500 mg to rhesus monkeys on different days of their luteal phase induced marked depression of circulating progesterone concentrations, and in some cases early onset of menses. Simultaneous administration of human chorionic gonadotropin (hCG) during the midluteal phase did not overcome the luteolytic effect of azastene. Concentrations of 50 micrograms/ml of azastene inhibited testosterone secretion by decapsulated mice testes in vitro in response to hCG [controls, 1165 +/- 196 ng/ml, azastene, 306 +/- 40 ng/ml (P less than .01)]. Production of progesterone by dispersed luteal cells from rhesus monkey corpora lutea was markedly inhibited by the presence of 25 and 50 micrograms/ml azastene in the incubation media (P less than .05 and less than .01, respectively). The availability of a compound that blocks in vivo and in vitro gonadal steroidogenesis opens a new approach to postcoital contraception in primates because of its luteolytic and interceptive activity. The possible mechanisms of action of azastene are discussed.
Abortifacient Agents↗
Paracrine regulation of insulin-like growth factor I (IGF-I) an IGF-II on prostaglandins F2alpha and E2 synthesis by human corpus luteum in vitro: a possible balance of luteotropic and luteolytic effects.
The existence of a complete intraovarian insulin-like growth factor (IGF) system replete with ligands, receptors, and binding proteins has been demonstrated as well as the ability of IGF-I to positively affect steroidogenesis in human granulosa cells. Furthermore, we recently showed that IGF-I and IGF-II stimulate progesterone secretion by human luteal cells. As the PGs, PGE2 and PGF2alpha, are classically known to have luteotropic and luteolytic effects, we wanted to determine whether the IGFs could affect the human luteal phase by influencing the PG system. For this reason, human luteal cells were cultured for different times (12, 24, and 48 h) with IGF-I, IGF-II (10-100 ng/mL), and GH (100 ng/mL), and both PGs were assayed in the medium culture. We found that both IGF-I and IGF-II were able to stimulate PGE2 synthesis in a time- and dose-dependent way, whereas they both inhibited PGF2alpha production. GH, too, significantly reduced PGF2alpha synthesis; this effect was IGF-I mediated because it was reverted by increasing dilutions of an anti-IGF-I antibody. On the contrary, no GH effect was observed on PGE2 production. In conclusion, based on these data and on our previous results, we speculate that IGFs could influence luteal steroidogenesis through PG system.
Adult↗
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.
20-Hydroxysteroid Dehydrogenases↗
The possible mode of action of iproniazid. I. Differential luteolytic effect of iproniazid before and after the establishment of placental adolescence.
Iproniazid, a very specific monoamine oxidase inhibitor, at a dose level of 200 mg/kg body weight induced luteolysis and caused lysis of deciduomata as well as resorption of the established embryos. Exogenous replacement of prolactin, a most consistent stimulant of the endocrine functioning of corpus luteum, or progesterone absolutely reversed the adversity developed following iproniazid injection. Moreover, failure of iproniazid even at a higher dose level in the deviation of the normal sequence of pregnancy after the establishment of placental adolescence strongly tempting to suggest that iproniazid could only show its luteolytic effect when the hypothalamic-pituitary complex is exclusively involved in the maintennance of pregnancy.
Animals↗
Possible luteolytic effects of luteinizing hormone-releasing hormone in normal women.
The administration of five subcutaneous 250-microgram doses of lutienizing hormone (LH)-releasing hormone (LHRH) at 4-hour intervals, the first injection being given at 8 A.M. on 1 or 2 consecutive days between days 1 and 9 following the LH surge in normal women, shortened the luteal phase from 1 to 4 days in 16 of 17 treatment cycles. There was a better efficiency of treatment when LHRH was administered on days 6 to 9 after the LH surge as compared with days 1 to 5. In fact, the luteal phase was shortened from 3.3 +/- 0.2 days versus 1.4 +/- 0.2 days (P less than 0.01) and the serum progesterone level was decreased to 44% +/- 6% versus 71% +/- 6% of control levels (P less than 0.01) when the neurohormone was injected late as compared with early in the luteal phase. The present data raise the possibility of a luteolytic effect of LHRH in normal women and indicate the interest of such a near-physiologic approach for the control of luteal function and time of appearance of menses.
Adult↗
Luteolytic effects of DL111-IT in pregnant rats.
The present studies were conducted to evaluate the effects of DL111-IT [3-(2-ethyl phenyl)-5-(3-methoxy phenyl)-1H-1,2,4 triazol] on ovaries of pregnant rats. Pregnant rats were i.m. treated with DL111-IT 2.5 mg kg(-1) day(-1) or camellia oleum (vehicle control) 0.2 ml/day from day 6 of pregnancy for 1, 3 or 5 days. Blood and ovaries were collected 24 h after the last injection. Ovarian fresh weight and protein contents, activities of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) in ovaries, and cell apoptosis of corpus luteum (including hematoxylin-eosine stain, in situ 3'-end labeling and nucleosomal banding) were estimated. Compared with that in the control group, ovarian fresh weight declined 11% and 22% after DL111-IT-3 days and -5 days; protein content dropped 29% after 5-day administration. DL111-IT for 3 days provoked a marked decrease of serum progesterone, by 31% of the control; the activity of 3beta-HSD decreased 34.4% after i.m. DL111-IT for 5 days, while that of 20alpha-HSD increased dramatically after only one injection of DL111-IT (P < 0.01). Histological analysis and in situ 3'-end DNA labeling indicated that DL111-IT induced the pyknosis of cells and the formations of apoptotic bodies and intense oligonucleosomes in luteal cells of pregnant rats. The cell apoptosis induced by DL111-IT was further confirmed by evaluation of nucleosomal DNA fragmentation by agarose gel electrophoresis in cultured luteal cells exposed to DL111-IT for 24 h. In conclusion, all results, including shrunken luteal cells, decreased concentration of protein content and serum progesterone, changed activities of 3beta-HSD and 20alpha-HSD and formation of DNA fragments in luteal cells, showed the luteolytic effect of DL111-IT in pregnant rats.
20-Hydroxysteroid Dehydrogenases↗
Comparative luteolytic effects of prostaglandin F2 alpha and its 13-dehydro analogs in vivo.
Several 13-dehydro analogs were shown to be luteolytic in both the cyclic sheep and cyclic primate models studied. The fact that these luteolytic analogs have diminished uterine smooth muscle activity suggests that the receptors governing the smooth muscle effect on the one hand, and the luteolytic effect on the other, may possess different structural specificities. In both species studied, the analogs showed marked resistance to the PG-15-OH-dehydrogenase in vivo as shown by their activity when infused intravenously. In the early pregnant monkey, the reduced luteolytic activity of the 13-dehydro analogs suggests that mCG may have a protective effect on the corpus luteum to PGs in general. Thus, the early pregnant monkey, or possibly the hCG-treated cyclic monkey, would appear to be "essential" models in the study of luteolytic agents in the primate. Finally, previous reports of termination of early pregnancy in monkeys with luteolytic PG analogs may have depended, at least in part, on their intrinsic smooth muscle activity on the uterus.
Animals↗
The luteotrophic effect of estrogen in the rat: prevention by estradiol of the luteolytic effect of an antiserum to luteinizing hormone in the pregnant rat.
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Animals↗