Failure of luteolysis and extension of the interoestrous interval in sheep treated with the progesterone antagonist mifepristone (RU 486) (original) (raw)
Related papers
Reproduction, 1991
Ewes were treated with exogenous follicle-stimulating hormone (FSH) and oestrus was synchronized using either a dual prostaglandin F-2\g=a\ (PGF-2\g=a\)injection regimen or pessaries impregnated with medroxy progesterone acetate (MAP). Natural cycling ewes served as controls. After oestrus or AI (Day 0), corpora lutea (CL) were enucleated surgically from the left and right ovaries on Days 3 and 6, respectively. The incidence of premature luteolysis was related (P < 0\m=.\05) to PGF-2\g=a\treatment and occurred in 7 of 8 ewes compared with 0 of 4 controls and 1 of 8 MAP-exposed females. Sheep with regressing CL had lower circulating and intraluteal progesterone concentrations and fewer total and small dissociated luteal cells on Day 3 than gonadotrophin-treated counterparts with normal CL. Progesterone concentration in the serum and luteal tissue was higher (P < 0\m=.\05) in gonadotrophin-treated ewes with normal CL than in the controls; but luteinizing hormone (LH) receptors/cell were not different on Days 3 and 6. There were no apparent differences in the temporal patterns of circulating oestradiol-17\g=b\, FSH and LH. High progesterone in gonadotrophin\x=req-\ treated ewes with normal CL coincided with an increase in total luteal mass and numbers of cells, which were primarily reflected in more small luteal cells than in control ewes. Gonadotrophin-treated ewes with regressing CL on Day 3 tended (P < 0\m=.\10) to have fewer small luteal cells and fewer (P < 0\m=.\05)low-affinity PGF-2\g=a\ binding sites than sheep with normal CL. By Day 6, luteal integrity and cell viability was absent in ewes with prematurely regressed CL. These data demonstrate that (i) the incidence of premature luteal regression is highly correlated with the use of PGF-2\g=a\;(ii) this abnormal luteal tissue is functionally competent for 2\p=n-\3 days after ovulation, but deteriorates rapidly thereafter and (iii) luteal-dysfunctioning ewes experience a reduction in numbers of small luteal cells without a significant change in luteal mass by Day 3 and, overall, have fewer low-affinity PGF-2\g=a\ binding sites.
Reproduction, 1987
Corpora lutea were collected from sheep on Days 6,10, and 15 of the oestrous cycle and Day 25 of pregnancy and dissociated into single cell suspensions. Purified preparations of large and small luteal cells were prepared by elutriation on all days except Day 6. Basal progesterone production by large cells was 6\p=n-\8-fold higher than by small cells (36\p=n-\65 vs 6\p=n-\9fg/cell/min). Oxytocin secretion was maximal on Day 6(1\m=.\0fg/cell/ min) and declined thereafter. The number of receptors for LH increased between Day 6 and Day 10 and the two cell types had an equal number of receptors on Days 10 and 15 (19 000\p=n-\23 000). Large cells on Day 25 of pregnancy had fewer receptors (12 000) than did small cells (26 000). Progesterone secretion by small luteal cells from all days examined was stimulated by LH (0\m=.\01\p=n-\1000ng/ml) in a dose-dependent manner; maximum sensitivity to LH occurred on Day 10. Despite the presence of receptors for LH on large cells, LH failed to stimulate progesterone production. Basal production of progesterone by large and small cells, and the response of small cells to LH, was not influenced by day examined. Re-combinations of large and small cells from Day 10 synergized to increase progesterone secretion. Prostaglandin E-2 (0\m=.\1\p=n-\1000ng/ml) did not stimulate progesterone secretion by large or small cells.
Biology of Reproduction, 1993
Oxytocin stimulates secretion of endometrial prostaglandin (PG) F and induces endometrial phosphoinositide hydrolysis around the time of regression of the corpus luteum (CL) in cows. This study investigated the relationship between endometrial oxytocin receptors, oxytocin-stimulated phosphoinositide hydrolysis and PGF,, secretion in vitro, and plasma concentrations of ovarian steroids before and during CL regression in cyclic heifers (i.e., Days 13-19 post-estrus). Reproductive tracts were collected from 16 cyclic heifers on Days 13 (n = 5), 16 (n = 5), and 19 (n = 6). Decreases in mean CL weight (4.7, 4.6, and 3.0 + 0.6 g for Days 13, 16, and 19, respectively; p < 0.05) and plasma progesterone (12.2, 10.5, and 4.3 1.5 ng/ml for Days 13, 16, and 19, respectively; p < 0.01) were detected between Days 16 and 19, indicating that CL regression had been initiated in the group of Day 19 heifers. Mean concentration of plasma estradiol (3.4, 3.8, and 5.6 + 1.7 pg/ml for Days 13, 16, and 19, respectively) did not differ significantly (p > 0.5) among days of the estrous cycle. Concentration of endometrial oxytocin receptors increased (p < 0.06) during the estrous cycle (36, 49, and 789 234 fmol/mg protein on Days 13, 16, and 19, respectively), but the greatest increase (p < 0.05) occurred between Days 16 and 19. Similarly, incorporation of [ 3 H]inositol into endometrial inositol phosphates induced in vitro with 100 nM oxytocin also increased (p < 0.01) during the estrous cycle (5121 vs. 5819, 4529 vs. 7239, and 5888 vs. 68 096 18 564 dpm/g tissue for control vs. oxytocin-treated endometrium on Days 13, 16, and 19, respectively) with the greatest increase (p < 0.01) in responsiveness to oxytocin occurring between Days 16 and 19. Endometrial PGF, 0 secretion in response to 100 nM oxytocin increased linearly (p < 0.05) during the estrous cycle (905 vs. 1151, 783 vs. 1947, and 639 vs. 2485 510 pg/g tissue/min for control vs. oxytocin-treated endometrium on Days 13, 16, and 19, respectively). On Day 19, CL regression was not yet apparent in 3 of 6 heifers, whereas luteolysis was clearly occurring in the remaining 3 heifers (2.1 vs. 4.0 0.4 g, p < 0.05, for CL weight and 1.1 vs. 7.6 + 0.6 ng/ml, p < 0.01, for plasma progesterone in heifers with regressing and nonregressing CL, respectively). Mean concentrations of plasma estradiol did not differ significantly (p > 0.25) between heifers with a regressing CL (8.3 3.1 pg/ml) and heifers with a functional CL (2.8 + 3.1 pg/ml), although 2 of 3 heifers with a regressing CL and 0 of 3 heifers with a functional CL had elevated concentrations of estradiol. Concentration of endometrial oxytocin receptors was greater (p < 0.05) in heifers undergoing luteolysis than in heifers with CL maintained on Day 19 (1490 vs. 88 + 265 fmol/mg protein, respectively). Incorporation of [ 3 H]inositol into endometrial inositol phosphates in response to oxytocin also increased (p < 0.06) in those heifers undergoing luteolysis compared with those still having a functional CL (6170 vs. 120 353 and 5606 vs. 15 837 18 564 dpm/g tissue for control vs. oxytocin-treated endometrium from regressing and maintained heifers, respectively). In contrast, endometrial PGF,, secretion in response to oxytocin did not differ significantly between the two groups. These results indicate that 1) endometrial concentration of oxytocin receptors and oxytocin-induced phosphoinositide hydrolysis increased similarly during luteolysis with the greatest increases occurring around the time of onset of luteolysis; 2) endometrial PGF,. secretary response to oxytocin coincides with the early gradual increases in endometrial oxytocin receptor concentration and oxytocin-induced phosphoinositide hydrolysis between Days 13 and 16, but precedes the large increase in activity of the oxytocin receptor-phospholipase C system occurring 16-19 days post-estrus; and 3) oxytocin receptors and oxytocin-induced phosphoinositide hydrolysis are markedly increased during CL regression in cows. We suggest that a modest increase in the oxytocin receptor-phospholipase C system between Days 13 and 16 may be responsible for initiating endometrial sensitivity to oxytocin required for onset of luteolytic PGF,, secretion, whereas the large increase in the oxytocin receptorphospholipase C system occurs late in the estrous cycle as a consequence of luteolysis.
Ovulation and Corpus Luteum Maintenance in Ewes Treated with 17 -OESTRADIOL
Reproduction, 1968
Two experiments designed to measure the influence of oestradiol on ovulation and CL maintenance in cycling ewes are reported. All oestradiol-treated ewes were given a single injection of oestradiol on the 4th day of their oestrous cycle ; in addition, some ewes were given continuous daily injections of progesterone or oestradiol. Ovarian condition was determined by gross observations in Exp. 1 and by gross and histological observations in Exp. 2. Oestradiol induced ovulation in 72 and 73% of the ewes in Exps. 1 and 2, respectively. Progesterone blocked the ovulatory response to oestradiol. Continued daily injections of oestradiol were effective in maintaining the CL and inhibiting follicular development. The oestrous behaviour exhibited by oestradiol-treated ewes was not associated with ovulation. Induction of ovulation by oestrogen is probably due to a release of LH. The luteotrophic nature of oestrogen in the ewe may be caused by an increase in prolactin secretion. LH as a luteotrophic factor is suggested.
Reproduction, 1984
Ovulation was induced in seasonally anoestrous ewes by repeated 2-h injections of 250 ng Gn-RH, after 12 days (Group 1, N = 7; Group 2, N = 8), 2 days (Group 3, N = 8) or no (Group 4, N = 7) progesterone pretreatment. A preovulatory LH peak occurred spontaneously at a mean (\m=+-\s.e.m.) time of 43\m=.\1 \ m=+-\ 2\m=.\0 h, 38\m=.\5\ m=+-\ 3\m=.\1h and 26\m=.\8\ m=+-\1\m=.\7 h after the start of Gn-RH treatment in Groups 1, 3 and 4 respectively, and was artificially induced in ewes in Group 2, after 24 h of treatment, by a single i.v. injection of 150 \g=m\g Gn-RH. Normal luteal function occurred in all progesterone\x=req-\ pretreated ewes, but in only 1/7 animals not treated with progesterone. These results demonstrate that, although normal luteal function in progesterone-primed ewes induced to ovulate with repeated injections of low doses of Gn-RH is associated with a delayed preovulatory LH peak, it is not this extended period of follicle development which is responsible for functional competence of the resultant corpus luteum. Since as little as 2 days of exposure to elevated plasma progesterone concentrations is effective, it is suggested that progesterone may act directly on the preovulatory follice. In those animals that do produce functionally normal corpora lutea after repeated injections of Gn-RH, the preovulatory LH peak occurs significantly (P < 0001) later, suggesting that the duration of follicle stimulation before the LH peak is critical. Furthermore, a 12-day period of © 1984 Journals of Reproduction & Fertility Ltd
Effect of intra-ovarian infusion of oxytocin on plasma progesterone concentrations in pregnant ewes
Reproduction, 1991
The function of oxytocin receptors in the corpus luteum of pregnant ewes was investigated by infusing saline or oxytocin (100 ng/min) into the utero\p=n-\ovarian artery of pregnant ewes (62 \m=+-\5 days, n = 12). During a 4-h infusion, plasma oxytocin (OT) concentration increased to 268 \ m=+-\ 80 pg OT/ml in the OT-infused group and remained unchanged at 2\m=.\5\m=+-\1\m=.\5 pg OT/ml in the saline-infused group. Progesterone concentration in jugular venous plasma (17 \m=+-\9 ng/ml) rapidly decreased during oxytocin infusion to 59 \m=+-\10% and 26 \ m=+-\ 9% of control at 1\m=.\5and 2 h, respectively; the utero\p=n-\ovarianvenous concentration of 64 \m=+-\38 ng/ml decreased by a similar magnitude during oxytocin infusion. Electron microscopy of corpora lutea, removed at the end of the experiments, showed no indication of luteolytic changes following oxytocin infusion. It was concluded that oxytocin markedly and rapidly reduces progesterone secretion in pregnant ewes.
Animal Reproduction Science, 1989
Berghorn, K.A., Edgerton, L.A., Cromwell, G.L. and Stahly, T.S., 1989. Serum progesterone and luteinizing hormone following prostaglandin Fz~ during the sow's estrous cycle. A nim. Thirty -six sows and gilts (hereafter called sows ) received one of three prostaglandin F2~ ( PGF~,~ ) treatments on day 6, 10, or 14 of the estrous cycle to determine the effect of prostaglandin treatment on subsequent concentrations of luteinizing hormone (LH) and progesterone. Also, the effect of treatment on estrous cycle lengths was evaluated. Blood was sampled every 15 min fl)r 6 h. Starting from time 0, sows received 25 mg of PGF2~ at 4 h (treatment 1), 50 mg at 4 h (treatment 2), or 25 mg at both I h and 4 h (treatment 3). Treatment and day of cycle that sows were treated modified estrous cycle lengths (P< 0.05). Release of LH was episodic prior to PGF~,~ treatment. After PGFz~ injection, progesterone in blood sera increased (P< 0.0001 ) with higher progesterone continuing for about 1 h. Concentrations of LH in blood sera decreased fbllowing PGF~,, suggesting negative feedback of progesterone. Initial response of LH and progesterone to PGF2,~. was not distinguishable (P > 0.05 ) among the three cycle stages nor altered by quantity of PGF2,~ although the response to a second injection (treatment 3) was diminished (P< 0.01 ). Correlations between LH and progesterone were not significant (P > 0.05 ) at any time. Therefore. it appears that resistance of naturally occurring corpora lutea (of the estrous cycle) in swine to the luteolytic action of PGF~ is not due to gonadotropic support from the pituitary.
Biology of Reproduction
Oxytocin stimulates secretion of endometrial prostaglandin (PG) F and induces endometrial phosphoinositide hydrolysis around the time of regression of the corpus luteum (CL) in cows. This study investigated the relationship between endometrial oxytocin receptors, oxytocin-stimulated phosphoinositide hydrolysis and PGF,, secretion in vitro, and plasma concentrations of ovarian steroids before and during CL regression in cyclic heifers (i.e., Days 13-19 post-estrus). Reproductive tracts were collected from 16 cyclic heifers on Days 13 (n = 5), 16 (n = 5), and 19 (n = 6). Decreases in mean CL weight (4.7, 4.6, and 3.0 + 0.6 g for Days 13, 16, and 19, respectively; p < 0.05) and plasma progesterone (12.2, 10.5, and 4.3 1.5 ng/ml for Days 13, 16, and 19, respectively; p < 0.01) were detected between Days 16 and 19, indicating that CL regression had been initiated in the group of Day 19 heifers. Mean concentration of plasma estradiol (3.4, 3.8, and 5.6 + 1.7 pg/ml for Days 13, 16, and 19, respectively) did not differ significantly (p > 0.5) among days of the estrous cycle. Concentration of endometrial oxytocin receptors increased (p < 0.06) during the estrous cycle (36, 49, and 789 234 fmol/mg protein on Days 13, 16, and 19, respectively), but the greatest increase (p < 0.05) occurred between Days 16 and 19. Similarly, incorporation of [ 3 H]inositol into endometrial inositol phosphates induced in vitro with 100 nM oxytocin also increased (p < 0.01) during the estrous cycle (5121 vs. 5819, 4529 vs. 7239, and 5888 vs. 68 096 18 564 dpm/g tissue for control vs. oxytocin-treated endometrium on Days 13, 16, and 19, respectively) with the greatest increase (p < 0.01) in responsiveness to oxytocin occurring between Days 16 and 19. Endometrial PGF, 0 secretion in response to 100 nM oxytocin increased linearly (p < 0.05) during the estrous cycle (905 vs. 1151, 783 vs. 1947, and 639 vs. 2485 510 pg/g tissue/min for control vs. oxytocin-treated endometrium on Days 13, 16, and 19, respectively). On Day 19, CL regression was not yet apparent in 3 of 6 heifers, whereas luteolysis was clearly occurring in the remaining 3 heifers (2.1 vs. 4.0 0.4 g, p < 0.05, for CL weight and 1.1 vs. 7.6 + 0.6 ng/ml, p < 0.01, for plasma progesterone in heifers with regressing and nonregressing CL, respectively). Mean concentrations of plasma estradiol did not differ significantly (p > 0.25) between heifers with a regressing CL (8.3 3.1 pg/ml) and heifers with a functional CL (2.8 + 3.1 pg/ml), although 2 of 3 heifers with a regressing CL and 0 of 3 heifers with a functional CL had elevated concentrations of estradiol. Concentration of endometrial oxytocin receptors was greater (p < 0.05) in heifers undergoing luteolysis than in heifers with CL maintained on Day 19 (1490 vs. 88 + 265 fmol/mg protein, respectively). Incorporation of [ 3 H]inositol into endometrial inositol phosphates in response to oxytocin also increased (p < 0.06) in those heifers undergoing luteolysis compared with those still having a functional CL (6170 vs. 120 353 and 5606 vs. 15 837 18 564 dpm/g tissue for control vs. oxytocin-treated endometrium from regressing and maintained heifers, respectively). In contrast, endometrial PGF,, secretion in response to oxytocin did not differ significantly between the two groups. These results indicate that 1) endometrial concentration of oxytocin receptors and oxytocin-induced phosphoinositide hydrolysis increased similarly during luteolysis with the greatest increases occurring around the time of onset of luteolysis; 2) endometrial PGF,. secretary response to oxytocin coincides with the early gradual increases in endometrial oxytocin receptor concentration and oxytocin-induced phosphoinositide hydrolysis between Days 13 and 16, but precedes the large increase in activity of the oxytocin receptor-phospholipase C system occurring 16-19 days post-estrus; and 3) oxytocin receptors and oxytocin-induced phosphoinositide hydrolysis are markedly increased during CL regression in cows. We suggest that a modest increase in the oxytocin receptor-phospholipase C system between Days 13 and 16 may be responsible for initiating endometrial sensitivity to oxytocin required for onset of luteolytic PGF,, secretion, whereas the large increase in the oxytocin receptorphospholipase C system occurs late in the estrous cycle as a consequence of luteolysis.