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Modulation of cyclic AMP formation and progesterone secretion by human chorionic gonadotropin, epinephrine, buserelin and prostaglandins in normal or human chorionic gonadotropin desensitized rat immature luteal cells in monolayer culture.

It is now well recognized that hCG-induced luteolysis is associated with hCG-induced desensitization, but the physiological significance of luteal cell GnRH, PGS and beta-receptors is still undefined. Therefore, we intend in this study to observe the effects of prostaglandin F2 alpha and prostaglandin E2 and the interactions between epinephrine, a potent LHRH agonist [(D-Ser-(TBu)6, des-Gly-NH2(10)) LHRH ethylamide: Buserelin] and hCG in normal and in vitro hCG-desensitized rat immature luteal cells in monolayer culture, on basal, hCG or cholera toxin stimulated intracellular and extracellular cyclic AMP and progesterone secretion. The present report shows that incubation of immature rat luteal cells in monolayer culture with Buserelin, led to 25-50% inhibition of the epinephrine--as well as PGE2--induced cyclic AMP and progesterone responses. The LHRH agonist can also reverse the stimulatory effects of cholera toxin in the presence of hCG and led with PGF2 alpha, to additive inhibitory effects on extracellular cyclic AMP accumulation induced by cholera toxin. Both Buserelin and PGF2 alpha can reverse the hCG-induced cyclic AMP and progesterone release but no effect could be observed when the incubation was carried out with either substance in the absence of hCG. Prostaglandin E2, in acute conditions of incubation, seems to share agonist properties with hCG when both were incubated with luteal cells. Buserelin reversed the stimulatory effects of PGE2, hCG, epinephrine, and cholera toxin on cyclic AMP and progesterone responses to these substances. These results suggest that Buserelin and PGF2 alpha have luteolytic-like effects and that there may be a complementary action for the two substances. Preincubation of rat luteal cells in monolayer culture with 1 nM hCG for a 24 h period led to the inhibition of cyclic AMP and progesterone responses after a subsequent exposure to hCG and epinephrine. Luteal cells were no longer responsive to hCG while the presence of epinephrine in hCG-desensitized cells led to a 40% stimulation of cAMP and progesterone production. These observations suggest that there occurred a partial alteration of the N component activity of the adenylyl cyclase system.

Animals↗

The effects of progesterone receptor blockade in the luteal phase of normal fertile women.

The effects of a single, variable dose (5 to 200 mg) of RU38486 (RU486) (Roussel-Uclaf, Paris, France) in the first half of the luteal phase of the menstrual cycle were studied in 30 normal fertile volunteers. Quantitative histologic techniques were employed, and the results were compared with normal ranges derived from a separate, normal, fertile population. It was found that RU486 inhibited glandular secretory activity, accelerated degenerative changes, induced various vascular changes, increased stromal but not glandular mitotic activity, and did not affect the predecidual reaction. The superiority of morphometric analysis over traditional dating criteria was demonstrated in this study of endometrial responses to an exogenously administered agent. In addition, it was found that temperature drop occurred in 56%, menstrual induction in 43%, luteolysis in 24%, mood change in 23%, and thirst sensation in 3% of women studied. Both menstrual induction and changes in hypothalamic function after the administration of RU486 occurred independently of luteolysis and so were likely to be the direct result of progesterone receptor blockade in these organs. Menstrual induction was significantly related to the dose given and the day on which RU486 was administered. Mood change was significantly related to the day on which RU486 was given. Most of the effects of RU486 occurred around 48 hours after its administration.

Adolescent↗

Infusion of exogenous tumor necrosis factor dose dependently alters the length of the luteal phase in cattle: differential responses to treatment with indomethacin and L-NAME, a nitric oxide synthase inhibitor.

We examined whether prostaglandins (PGs) and nitric oxide (NO) mediate tumor necrosis factor (TNF) actions in the estrus cycle. On Day 14 of the cycle, the following solutions were infused into the aorta abdominalis of a total of 51 heifers (Experiments 1 and 2): saline; 1 or 10 microg of TNF; 480 mg indomethacin (INDO), an inhibitor of prostaglandin H synthase; 800 mg L-NAME, an inhibitor of NO synthase; and TNF (1 or 10 microg) in combination with INDO or L-NAME. TNF at 1 microg infused directly into aorta abdominalis increased the level of PGF(2alpha) and decreased the level of progesterone (P4) in the peripheral blood and shortened the estrus cycle. The high TNF dose stimulated P4 and PGE(2) and prolonged the corpus luteum (CL) lifespan. INDO blocked the effects of both TNF doses on the CL lifespan and hormone output. L-NAME completely blocked the effects of the luteolytic TNF dose, whereas the effects of the luteotropic TNF dose were not inhibited. In Experiment 3 (Day 14), saline or different TNF doses were infused into the jugular vein (n = 9) or into the uterine lumen (n = 18). The CL lifespans of the different groups were not different when TNF was infused into the jugular vein. Although high TNF doses (1 and 10 microg) infused into the uterine lumen prolonged the CL lifespan, low doses (0.01 and 0.1 microg) induced premature luteolysis. We suggest that the actions of exogenous TNF on the CL lifespan depend on PG synthesis stimulated by TNF in the uterus. TNF at low concentrations initiates a positive cascade between uterine PGF(2alpha) and various luteolytic factors, including NO, to complete premature luteolysis. PGE(2) is a good candidate mediator of the luteotropic actions of exogenous TNF action.

Animals↗

Why does RU486 fail to prevent implantation despite success in inducing menstruation?

The administration of RU38486 (RU486) in the luteal phase may induce menstruation, but it may not be associated with shedding of the functional layer of the endometrium. This provides an explanation why, in some cases of successful menstrual induction by RU486, pregnancy continues undisturbed. The ability of RU486 to interrupt a very early pregnancy is more likely to be related to its ability to cause shedding of the endometrium than its ability to induce menstruation.

Adult↗

Endocrine basis for the initiation, maintenance and termination of pregnancy in humans.

Channels of hormonal communication between the embryo and the mother are established early in the conceptual process. The preimplantation embryo exerts local uterine and systemic effects on the maternal organism to provide a suitable environment for embryonic development, to enable the development of a receptive endometrium for implantation, and to maintain corpus luteum function. In primates, implantation can be induced with progesterone alone if the proliferative effects of estrogens on the endometrium have already been achieved; estrogens may have a priming effect for progesterone on the endometrium, but it is not obligatory for implantation. Progesterone secretion from the corpus luteum is essential for the maintenance of early pregnancy until the placenta takes over the major role of steroidogenesis. This luteo-placental shift is completed at about the 50th day of human gestation. Withdrawal of progesterone effects by the administration of the competitive progesterone antagonist, RU 486, within 24 days after conception will terminate 85% of human pregnancies. Other nonsteroidal functions of the corpus luteum have been recently suggested. Relaxin and prorenin are peptides secreted by corpus luteum of pregnancy but their role remains putative at the present time.

Abortion, Spontaneous↗

Induction of luteolysis by luteinizing hormone-releasing factor (LRF) agonist: sensitivity, reproducibility, and reversibility.

The reproducibility, reversibility, and the maximal effectiveness of the luteolytic action of [D-Trp6,Pro9NEt]-LRF (luteinizing hormone-releasing factor) (LRF-agonist) were evaluated during 43 treatment cycles in 15 normal women. LRF-Ag (50 microgram) administration subcutaneously on 1 or 2 days at varying times during the luteal phase of consecutive cycles was made. Successful luteolysis was achieved in 26 of 27 cycles (96%) in which LRF-Ag was administered between 5 and 8 days after the luteinizing hormone (LH) peak. However, LRF-Ag treatment failed to induce luteolysis in 10 of 13 cycles (77%) when treatment began within 5 days of the LH peak. The luteal phase of posttreatment cycles was functionally unaffected by prior LRF-Ag treatment. The present study has thus demonstrated the reproducibility and reversibility of LRF-Ag as a potent luteolytic agent, although its action is dependent upon the timing of administration with a window of maximal effectiveness on days 5 to 8 of the luteal phase.

Adult↗

[Effects of natural and synthetic PGF2 alpha preparations on the uterine contractility of cattle].

The effects of luteolytic doses of PGF2 alpha (25 mg Dinoprost) and its synthetic analogues Cloprostenol (500 micrograms), Luprostiol (15 mg) and Tiaprost (525 micrograms) on bovine myometrial activity were investigated using a miniature pressure transducer placed in one uterine horn. The compounds were administered intravenously to 4 lactating cyclic cows at diestrus, proestrus, estrus and metestrus. Intrauterine pressure changes were assessed by computerized planimetry of the pressure tracings 30 minutes before and 60 minutes after treatment. Baseline intrauterine pressure was set at zero and treatment effects were expressed as percent change from an equivalent control period (= 100%). Following administration of Dinoprost there was a significant increase of uterine contractility in diestrus (515%), proestrus (198%) and metestrus (256%), but not in estrus. In comparison to PGF2 alpha the analogues Luprostiol and Tiaprost were less effective (Luprostiol: 195% and 154% in diestrus and proestrus resp., Tiaprost: 215% during diestrus), while Cloprostenol did not cause a significant change of intrauterine pressure in any stage of the estrous cycle. The results indicate that the myotonic effects which F2 alpha-prostaglandins exert on the uterus of cycling cows is affected both by the type of prostaglandin and the stage of the estrous cycle.

Animals↗

Prostaglandin injection for termination of tubal pregnancy: preliminary results.

A variety of conservative surgical techniques is available for the termination of ectopic pregnancy with preservation of the tube. We report on a new treatment by means of intratubal prostaglandin F2 alpha application followed by intramuscular administration of a prostaglandin E2 derivative (sulprostone) for 3 days. Only 5 of the 30 patients enrolled had to undergo laparotomy later. The results were compared with those obtained by different surgical procedures during the 2 preceding years. Hysterosalpingography was performed in 12 patients of the prostaglandin treated group and 14 of the surgically treated group. Tubal patency was demonstrated in 11 patients of the PG group but only in two patients of the surgically treated group.

Abortifacient Agents↗

Effects of a luteinizing hormone-releasing hormone agonist on luteal function in women.

The potent stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRH was administered once daily during the luteal phase of the human menstrual cycle. The treatment was instituted in the early or mid-luteal phase of the cycle. Early luteal phase institution of intranasal treatment with 600 micrograms of the LRH agonist once daily reduced the basal progesterone levels during the luteal phase in 4 women but did not cause premature onset of menstruation. Mid-luteal phase institution of subcutaneous treatment with 10 micrograms of the LRH agonist once daily did not affect the progesterone levels or reduce the length of the luteal phase in 5 women. Thus, daily postovulatory administration of the LRH agonist D-Ser(TBU)6-EA10-LRH did not cause luteolysis in normally cycling women.

Adult↗