Luteolytic Effect Of PGF2α Research Articles

Luteoprotective Role of Equine Chorionic Gonadotropin (eCG) During Pregnancy in the Mare

The effects of repeated cloprostenol administration were compared in mares impregnated by horses and mares impregnated by donkeys in order to assess the role of eCG on the development of pregnancy-associated resistance to the luteolytic and abortifacient effects of PGF2α. Eleven mares impregnated by donkey (mule pregnancy) and 9 mares impregnated by horse (horse pregnancy) were used. Six mares with mule pregnancy and four with horse pregnancy were injected with cloprostenol (0.25mg) when they were between day 65 and day 75 of pregnancy, and the treatment was repeated 48, 72 and 96h latter. The rest of the mares remained as controls. Concentrations of eCG were 10 times higher (p<0.001) in mares impregnated by horses than in mares impregnated by donkeys, and they were not affected by cloprostenol treatment. Luteolysis was completed 30h after the first cloprostenol injection in mule pregnancies, while mares with horse pregnancies required 96h and three cloprostenol injections to complete luteolysis. Regression analysis revealed significant associations between eCG concentrations at time 0 and the time required for completion of luteolysis (p<0.001), foetal death (p<0.01) and foetal expulsion (p<0.05). It is concluded that high eCG concentrations in mares impregnated by horses protect the corpora lutea of pregnancy against the luteolytic effects of PGF2α. Low eCG concentrations in mares carrying mule foetuses afford them less protection against the luteolytic effect of PGF2α, and this may be a cause of the increased foetal mortality that occurs between days 60 and 90 of pregnancy in these mares.

Anti-luteogenic and luteolytic effects of PGF2α during the post-ovulatory period in mares

Anti-luteogenic and luteolytic effects of PGF2α during the post-ovulatory period in mares

Blood flow: A key regulatory component of corpus luteum function in the cow

Prostaglandin F2α (PGF 2α) is the primary luteolysin in the cow. During the early luteal phase, the corpus luteum (CL) is resistant to the luteolytic effect of PGF 2α. Once mature, the CL becomes responsive to PGF 2α and undergoes luteal regression. These actions of PGF 2α coincide with changes in luteal blood flow (BF): PGF 2α has no effect on BF in the early CL, but acutely increases BF in the peripheral vasculature of the mature CL within 30 min of PGF 2α injection. During spontaneous luteolysis, luteal BF increases on Days 17–18 of the estrous cycle, prior to any decrease in plasma progesterone (P). The increase in luteal BF is synchronous with an increase in plasma PGFM levels, suggesting that pulsatile release of PGF 2α from uterus stimulates the increase in luteal BF. Serial biopsies of these CL showed that mRNA expression for endothelial nitric oxide synthase (eNOS) together with endothelin-1 (ET-1) and angiotensin converting enzyme (ACE) increases on Days 17–18 when the luteal BF is elevated. On Day 19 when plasma P level firstly decreases, eNOS mRNA returns to the basal level whereas ET-1 and ACE mRNA remains elevated. Cyclooxygenase-2 (COX-2) mRNA expression increases on Day 19. In support of these data, an in vivo microdialysis study revealed that luteal ET-1 and angiotensin II (Ang II) secretion increases and precedes PGF 2α secretion during spontaneous luteolysis. In conclusion, we show for the first time that an acute increase of BF occurs in the peripheral vasculature of the mature CL together with increases in eNOS expression and ET-1 and Ang II secretion in the CL during the early stages of luteolysis in the cow. We propose that the increase in luteal BF may be induced by NO from large arterioles surrounding the CL, and simultaneously uterine or exogenous PGF 2α directly increases ET-1 and Ang II secretion from endothelial cells of microcapillary vessels within the CL, thereby suppressing P secretion by luteal cells. Taken together, our results indicate that an acute increase in luteal BF occurs as a first step of luteolysis in response to PGF 2α. Therefore, local BF plays a key role to initiate luteal regression in the cow.

Progesterone and estradiol secretion by porcine luteal cells is influenced by individual and combined treatment with prostaglandins E 2 and F 2a throughout the estrus cycle

The present experiments were conducted to test whether the ratio of PGE 2:PGF 2α affects steroid secretion by porcine luteal cells. We examined the effect of separate and combined treatment with PGE 2 and PGF 2α on progesterone and estradiol secretion. Luteal cells were collected at three different stages of the luteal phase (1–3 days after ovulation; 10–12 days after ovulation and 14–16 days after ovulation). PGE 2 alone in a dose dependent manner increased progesterone production by cells collected from mature corpora lutea. On the other hand, PGF 2α in a dose dependent manner decreased progesterone secretion by cells of the same origin. Progesterone secretion by cells isolated from mature and regressing corpora lutea and treated with both prostaglandins increased in comparison to PGF 2α-treated cultures. However, in cells collected from regressing corpora lutea PGE 2 and PGF 2α in a ratio of 2:1 and 4:1 increased estradiol production when compared to control and both ratios increased estradiol secretion in comparison to PGF 2α-treated cells. These data 1) confirm the luteotropic effect of PGE 2 and the luteolytic effect of PGF 2α; 2) demonstrate that when the ratio of PGE 2 to PGF 2α changed from 1:1 to 2:1 or 4:1 cells were protected against the inhibitory effects of PGF 2α on progesterone secretion by cells collected during the mid- and late luteal phase; and 3) suggest that elevated estradiol production by luteal cells, isolated during late luteal phase, under the influence of increased doses of PGE 2 may serve as an additional source of estradiol to blastocysts, during early pregnancy in the pig.

Plasma concentration of progesterone during normal estrous cycles and following prostaglandin F 2α treatment of [formula omitted] and tropic-adapted [formula omitted][formula omitted] heifers

The introduction of the use of prostaglandin F 2α (PGF 2α) to synchronize estrus in cattle adapted to the tropics suggests a need to investigate the endocrine response to this treatment. Progesterone (P) concentrations in blood plasma of Bos indicus and tropic-adapted Bos taurus heifers during normal estrous cycles and following estrus synchronization were compared. After PGF 2α administration, the heifers were divided into two groups on the basis of response to treatment. Mean P levels in heifers showing estrus after the first injection ranged from 1.0–3.0 ng/ml, decreasing to 0.2–0.4 ng/ml 24 to 48 hr after treatment. The second group exhibited estrus only after the second PGF 2α injection and had low P (0.2–0.9 ng/ml) in plasma before the first injection. Mean peak P levels in both groups 8 to 12 d after the first injection in the periestrous period were not different from values in the same heifers at similar periods of the preceding control estrous cycle. Neither the tropical location nor breed affected the luteolytic effect of PGF 2α.

Luteal phase variations in endogenous concentrations of prosta-glandins PGE and PGF and in the capacity for their in vitro formation in the human corpus luteum

One evidence for a luteolytic role for prostaglandin F 2α in the human is the increase in luteal PGF at times corresponding to luteolysis as reported earlier by us and other groups. There have been other contradictory reports on this point. In the present experiments we have measured the concentrations of PGE and PGF in 16 more human corpora lutea and have determined the capacity of those tissues to form PGE and PGF in vitro. PGF concentrations were highest in the mid luteal phase but were accompanied by high PGE concentrations. On the other hand, in the late luteal phase PGF concentrations, lower than in mid luteal but generally higher than in early luteal phase, were significantly higher than PGE concentrations. This pattern in PGE and PGF concentrations was also evident in the capacity of these tissues to form these compounds in vitro. In view of the known capacity of PGE 2 to counteract the luteolytic effect of PGF 2α, these variations in the relative concentrations of PGE and PGF during the luteal phase may be of significance in the process of luteolysis in the human.

Cellular and molecular mechanisms involved in luteolysis and maternal recognition of pregnancy in the ewe

The corpus luteum is composed of two distinct steroidogenic cell types, both of which contribute significantly to the total progesterone secreted during the luteal phase of the oestrous cycle. The small luteal cells secrete very little progesterone unless stimulated by luteinizing hormone (LH) while large luteal cells appear to spontaneously secrete progesterone at a high rate. Large luteal cells contain receptors for prostaglandin (PG)F 2α. Steroid secretion and viability of these cells in vitro are suppressed by PGF 2α. Prostaglandin F 2α may also reduce the ability of LH to stimulate steroidogenesis in the small cells, but this effect appears to be exerted through a signal originating from the large cells since the small cells are essentially devoid of receptors for PGF 2α. The corpus luteum of pregnancy was demonstrated to be resistent to the luteolytic effect of PGF 2α since higher doses of PGF 2α were required to cause luteolysis in pregnant than in non-pregnant ewes. In addition, more PGF 2α was required to cause luteolysis in ewes with two embryos when compared to ewes with one. Prostaglandin E 2, of embryonic and/or endometrial origin, is secreted from the uterus during early pregnancy and may be responsible for luteal resistence to the luteolytic effect of PGF 2α. Prostaglandin E 2 has been demonstrated to protect luteal tissue from the actions of PGF 2α both in vivo and in vitro .

Hormone receptor control of pulsatile secretion of PGF 2α from the ovine uterus during luteolysis and its abrogation in early pregnancy

Studies on the control of PGF 2α secretion by hormone receptors in the ovine uterus based on in vivo infusion experiments in the autotransplanted uterus are summarized. In addition, direct measurement of hormone receptor dynamics for oestradiol-17β, progesterone and oxytocin in the ovine uterus under experimental conditions are reported. Investigation of the antiluteolytic effect of early pregnancy in sheep was approached in two ways: (a) studies on the antiprostaglandin secreting effect of the embryo and (b) studies on a putative luteoprotective effect of the embryo. In the former study, the measurement of PGF 2α in samples of uterine venous plasma collected hourly from 5 sheep on days 12 to 17 postmating failed to reveal the presence of any major peaks of PGF 2α secretion. In the latter approach, several putative luteoprotective substances were examined for their ability to block the luteolytic effect of PGF 2α given as 5 separate hour-long pulses over 25 h into the arterial supply of the autotransplanted ovary. These substances included: day 14–15 uterine venous plasma from pregnant sheep, PGE 2, ovine prolactin, ovine LH, ovine placental lactogen and porcine relaxin. In no case was a convincing luteoprotective effect demonstrated suggesting that the antiprostaglandin secreting effect of the embryo may be the more important of these two antiluteolytic mechanisms. Experiments were performed to investigate circulating levels of endogenous oxytocin by monitoring intramyometrial pressure on a continuous basis in conscious sheep. These studies revealed the presence of hour-long periods of intense uterine activity at intervals of 5.5 to 6.5 hours on days 14 to 16 in the cyclic animal, but not in the early pregnant animal. Based on these results and on recent reports on the production of oxytocin by the corpus luteum, a hypothesis is presented to explain the hormone receptor control of episodic pulsatile secretion of PGF 2α in the cyclic sheep, including a possible mechanism for its abrogation during early pregnancy.

Luteolysis in the hamster: Abrogation by gonadotropin and prolactin pretreatment

The luteolysis which terminated pseudopregnancy (PSP) in superovulated hamsters was studied. Spontaneous luteolysis occurred before 1100 on Day 7 of PSP and was characterized by a rapid decline in circulating progesterone levels. Luteolysis induced by prostaglandin F 2α (PGF 2α) on Day 5 of PSP displayed a similar rapid reduction in progesterone over 24 hours. In both cases levels of the progesterone metabolite 20α hydroxypregn-4-ene-3-one (20α-OHP) were less than 2 percent of progesterone levels and declined in a manner similar to progesterone. This suggests that conversion of progesterone or its precursors to 20α-OHP was not a functional aspect of luteolysis in the hamster. Pretreatment with either prolactin (PRL), luteinizing hormone (LH) or follicle stimulating hormone (FSH) failed to prevent PGF 2α-induced luteolysis on Day 5 in the superovulated PSP hamster. Combinations of PRL and LH, LH and FSH or PRL and FSH were also unsuccessful in abrogating luteolysis. However, pretreatment with a combination of PRL, FSH and LH prevented luteolysis in 11 14 animals. These results suggest that luteotropic agents can reverse the luteolytic effects of PGF 2α in the hamster.

Effects of prostaglandin on estrous cycles, behavior and blood progesterone levels of American Saddlebred mares

Twelve American Saddlebred mares ranging in weight from 365 to 450 kg were given intramuscular injections of 2.5, 5.0 and 7.5 mg of Prostaglandin (PGF 2α) on day 6 of diestrus a mean length of control estrus and diestrus were 6.5 ± .6, 16.9 ± 1.0 days, respectively. The 2.5, 5.0 and 7.5 mg PGF 2α doses significantly (P < .01) shortened the length of the treatment diestrus to 10.8 ± 1.8, 9.9 ± .7 and 9.9 ± .7, respectively. The 2.5 mg dose was 90% effective in shortening the duration of diestrus while doses of 5.0 and 7.5 mg were 100% effective. No effects were noted on the mean length of estrus or diestrus following treatment. Peripheral plasma progesterone concentrations were measured by radioimmunoassay to determine the luteolytic effect of PGF 2α. As compared to the non-treatment estrous cycles, all three treatments caused a significant (P < .01) decline in peripheral plasma progesterone concentrations 24 and 48 hr after treatment. The 2.5 mg PGF 2α dose caused a drop in progesterone from 7.7 ± .4 on day 6 to 2.6 ± 1.0 and 2.1 ± .9 ng/ml 24 and 48 hr later, respectively. Similarly, 5.0 mg lowered the progesterone level from 7.7 ± .3 to 1.6 ± .6 and 1.5 ± .5 ng/ml, and the 7.5 mg dose lowered the progesterone level 7.5 ± .3 to 1.2 ± .2 and 1.3 ± .3 PGF 2α. Abdominal cramps were noted in some mares after treatment. The incidence and severity of these reactions increased with the dose of PGF 2α.

Effects of prostaglandins on cultured granulosa cells from rhesus monkeys

It has repeatedly been demonstrated that administration of prostaglandin (PG) F-2α to nonprimates is luteolytic and inhibits progesterone synthesis, while administration of PGE-2 stimulates progesterone synthesis. The luteolytic effect of PGF-2α has not been conclusively demonstrated in vivo in the primate, variable effects on the circulating progesterone levels having been reported (Shaikh, 1972; Auletta, Speroff & Caldwell, 1973; Shaikh & Klaiber, 1974; Korda, Shutt, Smith, Shearman & Lyneham, 1975; Lyneham, Korda, Shutt, Smith & Shearman, 1975). PGE-2 has been reported to increase progesterone synthesis by the primate corpus luteum (Channing, 1971). It is becoming apparent that route of administration, dosage and other unknown factors can alter the effect of PGF-2α on progesterone synthesis (Channing, 1972; Auletta et al., 1973; Puri & Laumas, 1975; Henderson & McNatty, 1975). Attempts to isolate the factors whereby PGs affect granulosa cells by the use of in-vitro systems have met with limited success, because PGs in vitro frequently exhibit effects which differ from those seen in vivo (Lindner et al., 1974). We therefore examined the effect of the developmental state of the follicle on its response to PG and dibutyryl cyclic AMP in vitro. Dibutyryl cyclic AMP (dbcAMP) is considered to mimic the action of gonadotrophins, because synthesis of its analogue, cAMP, is believed to be a step in the intracellular action of gonadotrophins (Marsh, 1976).

INFLUENCE OF THYROTROPIN-RELEASING HORMONE (TRH) ON PLASMA PROGESTERONE AND PITUITARY HORMONE CONCENTRATIONS IN CATTLE

Four Friesian heifers 14–16 mo of age were injected through jugular catheters six times per day (0600, 0900, 1200, 1500, 1800 and 2100 h) with 100 μg thyrotropin-releasing hormone or saline (control). TRH and saline treatment continued for 14 days beginning 1 day after a luteolytic dose of prostaglandin (PGF2α, 30 mg) which was given during diestrus. Blood samples were collected via the catheters at 0900 and 2100 h each day for progesterone prolactin and LH determinations and before and 10, 20, 30, 40 and 60 min after the 0600 and 2100 h TRH injections on the 1st, 7th and 13th days of treatment for growth hormone (GH) and prolactin analysis. After 14 days, heifers were injected with 10 mg PGF2α and changes in blood progesterone were measured for 24 h. There were two treatment periods; hence, each animal was subjected to both TRH and saline injections. Results support the following conclusions: (1) Prolactin secretion in response to TRH did not diminish with time. (2) Plasma progesterone of TRH-treated animals was lower (P &lt; 0.05) from approximately day 5 of the cycle (estrus = day 0) until corpora lutea were destroyed with PGF2α; this provides no support for a luteotrophic role for prolactin. (3) Corpora lutea of all animals regressed after 10 mg PGF2α, suggesting that TRH had not increased the resistance of the corpus luteum to the luteolytic effects of PGF2α.

Prolactin release induced by prostaglandin F2 in pregnant rats.

PROSTAGLANDIN (PGF2α) induces lactogenesis and advanced parturition when injected into pregnant rats1. A luteolytic effect of PGF2α has also been demonstrated in pseudopregnant and pregnant rats3,4, normal guinea-pig5, autotransplanted sheep ovary6 and pregnant hamster7. The decrease of plasma progesterone concentration before parturition8–10 will trigger the release of prolactin and other hormones from the hypophysis and induce lactogenesis11–13 which in the normal pregnant rat occurs around 12 h before parturition13.

Intravenous infusion of prostaglandin F 2α in the mid-luteal phase of the normal human menstrual cycle

The luteolytic effect of PG-F 2α was studied in three normal women. Plasma levels of estrogens, progesterone and gonadotropins were measured daily. Following a control cycle, an infusion of 100μg/min of PG-F 2α over an eight hour period was given. Two subjects received the PG-F 2α on the ninth and one on the fifth post-ovulatory day. The steroid patterns during the control and treatment cycles were not significantly different and the length of the luteal phases was identical. To accentuate luteal activity, two subjects received, in subsequent cycles, 10,000 i.u. HCG 48 hours prior to the PG-F 2α infusion. In these cycles, despite the PG-F 2α, the steroids continued to rise and then gradually declined in a normal fashion. The luteal phase was not curtailed. All subjects experienced nausea, vomiting, painful uterine contractions, staining and temperature elevations above 100°F during the infusion. It is concluded that in the human PG-F 2α at the given dose was not luteolytic.

Effects of prostaglandin F2-alpha on pituitary luteinizing hormone content of pregnant rats: a possible explanation for the luteolytic effect.

Summary. Prostaglandin F2α induced degeneration of embryos in intact pregnant rats but not in ovariectomized rats maintained on progesterone. The pituitary lh stores in the intact, treated rats were significantly higher than those in the pregnant, pseudopregnant or cyclic controls. The prostaglandin failed to inhibit the ovulatory release of lh in the cyclic rat. It is suggested that the luteolytic effect of PGF2α may be mediated in part by the increased synthesis and secretion of lh.