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E. L. Sheldrick and A. P. F. Flint

Summary. Concentrations of oxytocin in corpora lutea were reduced from 1706 to less than 15 ng/g wet wt after hysterectomy in sheep during the oestrous cycle. Hysterectomy also blocked the appearance of raised levels of oxytocin in ovarian and jugular venous plasma caused by cloprostenol. Administration of cloprostenol to hysterectomized ewes resulted in luteal regression, which occurred as rapidly as in intact animals. Therefore oxytocin in the corpus luteum during the oestrous cycle is unlikely to be involved in intraluteal events mediating prostaglandin-induced luteolysis.

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E. L. Sheldrick and A. P. F. Flint

Summary. The concentration of oxytocin in ovine corpora lutea dropped during pregnancy from 373 ng/g wet weight on Day 14 to < 5 ng/g between Day 50 and term. The major decrease occurred before Day 20 after mating. Circulating concentrations of oxytocin also decreased between Days 10 and 15 after mating, and were low in late gestation; however, concentrations of oxytocin in plasma on Days 16 and 17 were raised. Mean luteal concentrations of oxytocin ranged from 730 to 2482 ng/g between Days 8 and 14 of the oestrous cycle in non-pregnant sheep. Secretion of oxytocin by the corpus luteum is thought to be one of the mechanisms leading to luteal regression; therefore loss of oxytocin from the corpora lutea in early gestation may contribute to their maintenance.

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A. P. F. Flint and Marilyn B. Renfree

Summary. When lactating rats were mated at the post-partum oestrus, treated with a single dose of bromocriptine (2 mg/kg body wt) 7 days later, and killed on Day 11, implantation was induced in 8/24 animals. When the litter was removed at the time of bromocriptine treatment 5/9 rats had implantations compared with 9/10 after litter removal alone.

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A. P. F. Flint and E. L. Sheldrick

Summary. The secretion of oxytocin by the corpus luteum is thought to stimulate the episodic release of PGF-2α from the uterus, thereby contributing to luteolysis. In pregnancy corpus luteum function is maintained, and secretion of oxytocin, or its actions on the uterus, appear to be inconsistent with the successful establishment of gestation. Protection against the effects of oxytocin is ensured by a number of mechanisms, including the cessation of luteal oxytocin secretion, which is evident by Day 20 after mating in sheep, and the maintenance of low levels of the oxytocin receptor in the uterus.

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E. L. Sheldrick and A. P. F. Flint

Summary. Steroid-primed, ovariectomized ewes were treated intravenously with 2 doses of 1 μg oxytocin at intervals of 1, 2,4 or 6 h. The initial dose resulted in increases in 13,14-dihydro-15-keto-PGF-2α in the peripheral circulation from 173 to 667 pg/ml within 5 min; subsequent doses caused responses of 23 ± 1, 23 ± 6, 54 ± 12 and 62 ± 10% respectively of the initial dose. Concentrations of oxytocin receptor in myometrium, caruncular endometrium and intercaruncular endometrium were, respectively, 185 ± 33, 128 ± 7 and 105 ± 14 fmol/mg protein at 2 h after saline injection and 147 ± 27, 195 ± 52 and 170 ± 50 fmol/mg protein at 2 h after administration of 1 μg oxytocin. The dose of oxytocin administered was shown to raise circulating concentrations to levels characteristic of those observed during spontaneous episodes of release of oxytocin at luteolysis. Oxytocin administration therefore results in transitory uterine refractoriness which may be due to failure of a post-receptor response and this may contribute to the episodic nature of uterine prostaglandin secretion.

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J. E. Hixon and A. P. F. Flint

Summary. Administration of oestradiol-17β benzoate on Days 9 and 10 of the oestrous cycle resulted in episodic secretion of PGF-2α (as indicated by elevated circulating concentrations of 13,14-dihydro-15-ketoprostaglandin F-2α) and a decline in circulating progesterone. Release of PGF-2α 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-2α; 69% of pulses of oxytocin coincided with episodes of PGF-2α 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: (a) induction of the oxytocin receptor; (b) increased turnover of phosphoinositides; (c) onset of episodic secretion of PGF-2α; and (d) functional luteolysis.

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A. P. F. Flint and E. L. Sheldrick

Summary. Continuous intravenous infusion of oxytocin (3 μg/h) between Days 13 and 21 after oestrus delayed return to oestrus by 7 days (length of cycle 23·3 ± 0·6 days compared to 16·6 ± 0·2 days in control ewes). At a lower infusion rate (0·3 μg/h) oxytocin delayed luteolysis in only 2 of 5 ewes. Treatment from Day 14, when luteolysis had already begun, was ineffective. Delay of luteal regression by oxytocin had no effect on the length of subsequent cycles. Measurement of circulating progesterone concentrations and luteal weight showed that prolongation of the oestrous cycle was due to prevention of luteal regression. Luteal regression and behavioural oestrus were induced during continuous oxytocin administration begun on Day 13 when cloprostenol was given on Day 15 (mean cycle length, 17·3 ± 0·21 days).

Continuous oxytocin infusion from Day 13 blocked the rise in uterine oxytocin receptor concentrations which normally precedes oestrus. Mean receptor concentrations in caruncular and intercaruncular endometrium and in myometrium were 76, 36 and 9 fmol/mg protein on Day 17 in ewes receiving continuous oxytocin (3 μg/h); in control ewes these values were 675, 638 and 130 fmol/mg protein respectively at oestrus. Receptor concentrations on the day of oestrus in ewes receiving oxytocin and cloprostenol were not significantly different from those in control ewes (649, 852, and 109 fmol/mg protein respectively).

Since cloprostenol, a PGF-2α analogue, overcame the antiluteolytic action of oxytocin, it is suggested that continuous oxytocin treatment may inhibit uterine production of PGF-2α, possibly by down regulating the uterine oxytocin receptor. Failure of oxytocin to prevent the rise in oxytocin receptor after cloprostenol may indicate that the process of down regulation is progesterone dependent.

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A. P. F. Flint and E. L. Sheldrick

Summary. Jugular venous concentrations of oxytocin and progesterone changed in parallel during the oestrous cycle in the ewe, falling at luteal regression and rising with formation of the new corpus luteum. These fluctuations in the circulating concentration of oxytocin were not caused by changes in its metabolic clearance rate. On Days 6–9 of the cycle circulating oxytocin concentrations exhibited a diurnal rhythm, peaking at 09:00 h; this rhythm was absent on Days 11–14. Although there was no evidence for increased production of oxytocin at or preceding luteal regression in samples taken daily, more frequent sampling revealed that two thirds of detected surges of uterine secretion of prostaglandin (PG) F-2α were accompanied by raised levels of oxytocin. This oxytocin was not of pituitary origin. Luteal regression induced with cloprostenol on Day 8 after oestrus caused a decrease in circulating progesterone level followed after 24 h by a fall in oxytocin. Measurements of oxytocin in the ovary and other organs before and after treatment with cloprostenol identified the corpora lutea as a major potential source of oxytocin, and suggested that 98% of luteal oxytocin was available for secretion in response to prostaglandin stimulation. The data are consistent with a role for ovarian secretion of oxytocin in response to uterine release of PGF-2α in the control of luteal regression.

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E. L. Sheldrick, A. P. Ricketts and A. P. F. Flint

Summary. Pregnant goats were ovariectomized or lutectomized and treated with medroxyprogesterone acetate. The circulating concentration of progesterone, which was reduced by 85% after ovariectomy or lutectomy, increased almost 3-fold between 120 and 140 days gestation, suggesting increased placental secretion. Measurement of veno-arterial differences across the uterus confirmed that an intrauterine organ was secreting progesterone at this time. Progesterone levels decreased (by 38%) in intact animals treated with medroxyprogesterone acetate alone. Concentrations of total unconjugated oestrogens were not altered by ovariectomy or lutectomy or by medroxyprogesterone acetate alone, but were related to the birth weight of the kids. Chronic treatment with medroxyprogesterone acetate reduced milk yield during lactation by up to 64%.

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Penelope A. Steele, A. P. F. Flint and A. C. Turnbull

Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, U.K.