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Attenuation of Antepartum Relaxin Surge and Induction of Parturition by Antiprogesterone RU 486 in Sheep O

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Attenuation of Antepartum Relaxin Surge and Induction of Parturition by Antiprogesterone RU 486 in Sheep O Attenuation of antepartum relaxin surge and induction of parturition by antiprogesterone RU 486 in sheep O. S. Gazal, Y. Li, C. Schwabe and L. L. Anderson 1 Department of Animal Science, Iowa State University, Ames, LA 50011, USA; and 2Department of Biochemistry, Medical University of South Carolina, Charleston, SC 29459, USA Pregnant ewes were injected with either the antiprogesterone, RU 486 (4 mg kg\m=-\1body weight, i.m.; n = 5), 3000 iu relaxin (i.m.; n = 9), or diluent (n = 8) at 12:00 h on days 144 and 145, to determine its effect on progesterone and relaxin secretion, and on induction of lambing. RU 486 induced earlier lambing (P < 0.01) compared with diluent treatment, but relaxin treatment did not significantly reduce the interval to parturition. Mean injection\p=n-\ lambing intervals were 31 \m=+-\2, 109 \m=+-\23 and 121 \m=+-\27 h for the RU 486, relaxin and diluent groups, respectively. There was no incidence of difficult birth (dystocia); all lambs were vigorous at birth; and placenta delivery was rapid (within 207 min) with RU 486 and relaxin treatments compared with diluent treated controls. Plasma progesterone concen- trations averaged 11 ng ml\m=-\1during the pretreatment period for all animals. RU 486 had a biphasic effect on progesterone concentrations, causing an initial increase (P < 0.05) within 2 h, and then an abrupt drop (P < 0.01) to 6 ng ml\m=-\1by 18:00 h on day 145. Progesterone concentrations remained consistently lower (P < 0.05) in relaxin-treated ewes than in diluent\x=req-\ treated controls from days 144 to 147 and then began a steady decrease to 4 ng ml\m=-\1on the day of parturition (days 149 and 150) in both groups. Immunoreactive relaxin concentrations in control ewes increased (P < 0.05) from 0.6 ng ml\m=-\1to a peak of 3.9 ng ml\m=-\1on day 146, but they were low (0.8 ng ml\m=-\1) at the time of parturition (day 150). RU 486 treatment abruptly increased (P < 0.05) circulating relaxin concentration, but the amplitude of this antepartum surge was greatly attenuated compared with that of diluent treated controls. Peak RU 486 concentrations in plasma were 7 and 9 ng ml\m=-\1within 2 h after first and second i.m. injection of the hormone, respectively, and stabilized at 4 ng ml\m=-\1at the time of induced lambing (day 145). The results reveal that an antepartum relaxin surge occurs in sheep 4 days before normal parturition (day 150), but that RU 486 greatly attenuates the relaxin surge and abruptly decreases circulating progesterone concentration with an induced parturition (day 145). The results indicate that RU 486 can precisely control the time of parturition in sheep in late pregnancy without detrimental effects of dystocia, retention of placenta or delayed postpartum fertility. Introduction contractility (Porter et al, 1981), thus suggesting a role for this hormone in pregnancy. Maintenance Relaxin is a peptide hormone produced in greatest concen¬ of pregnancy in mammals, including sheep, trations by female reproductive tissues, particularly during requires the binding of progesterone to its receptor in the uter¬ pregnancy (Anderson, 1987; Sherwood, 1988). Maximum peri¬ ine endometrium leading to the proliferation of the epithelial vascular decrease con¬ pheral blood concentrations of relaxin occur a few hours before and cells. A in circulating progesterone parturition in rats and pigs, but no similar evidence is available centrations must precede induced or spontaneous parturition in for sheep (Sherwood et al, 1980; Felder et al, 1986). Low relaxin ewes (Stabenfeldt el al, 1972; Ledger et al, 1985), and this immunoreactivity has been reported in placental, endometrial can be achieved by blocking progesterone synthesis with 3ß- inhibitors and ovarian tissues (0.05-11.00 ng g_I) of ewes from day 21 hydroxysteroid dehydrogenase (Taylor, 1987). RU 486 to parturition, but no obvious trend was found throughout (11 ß-[4-dimethyl-amino phenyl]l7ß-hydroxy-l7fX-[l-propynyl] pregnancy (Renegar and Larkin, 1985; Wathes et al, 1988). estra-4,9-dien-3-one) is a 19-norsteroid with potent antiproges- Relaxin increases cervical compliance in oestrogen-primed terone and antiglucocorticoid activities (Baulieu, 1989), and it ovariectomized ewes (Nemec et al, 1988) and reduces uterine reduces maternal progesterone concentrations in several species including pigs, cattle, monkeys (Rhesus and Macaca fascicularis), •Reprint requests. and humans (Nieman et al, 1987; Baulieu, 1989; Puri et al, 1990; Received 2 March 1992. Li et al, 1991a, b). RU 486 binds competitively to progesterone Downloaded from Bioscientifica.com at 09/28/2021 01:39:06PM via free access receptors and such binding either blocks the interaction between Relaxin for this experiment was extracted from the ovaries of progesterone receptors and DNA or impairs gene transactivation. pregnant pigs and purified according to procedures described Substitution of glycine by cysteine at position 5 75 in the human previously (Büllesbach and Schwabe, 1985). Sequential blood progesterone receptor abrogates binding of RU 486, but not that of samples were collected at intervals of 15 min for 1 h after treat¬ an agonist (Benhamou et al, 1992). Relaxin administered to cattle ment and 2, 3, 9 and 15 h later. Ewes not lambing by 11:00 h on late in pregnancy decreases circulating progesterone and also day 145 received a second injection of RU 486 or relaxin and advances parturition (Musah et al, 1986; Bagna et al, 1991) and were bled using the same regimen as described for day 144. it decreases progesterone in cyclic ewes (Akinbami et al, 1990). From day 146 to 2 days post partum, blood samples were col¬ RU 486 can modulate both progesterone and relaxin secretion lected once a day at 12:00 h. The catheter was flushed with in pigs, but responses depend on the presence or absence of the heparinized saline (100 iu ml- ) after each blood collection. uterus (Li et al, 1991b). In pregnant pigs, RU 486 advanced the Blood samples (10 ml) were collected in 16 x 100 mm borosili- time and increased the amplitude of peak relaxin release and cate culture tubes maintained on ice. Tubes were centrifuged at abruptly decreased circulating progesterone concentrations, 2000 # for 10 min and the plasma was immediately harvested whereas in hysterectomized animals the same RU 486 treatment into 12 X 75 mm culture tubes, frozen on dry ice and stored at delayed the time of peak relaxin release and abruptly increased 20°C until required for radioimmunoassay of progesterone, progesterone secretion. relaxin— and RU 486. Our studies in pigs and cattle indicate that RU 486 is a useful Ewes exhibiting signs of imminent lambing were kept in probe for determining the physiological roles of progesterone the maternity barn for continuous observation. Duration of during pregnancy. The mechanism by which progesterone and gestation, exact time of lambing, time of placental delivery and relaxin secretion are regulated during late pregnancy in sheep is sex and body weights of lambs were recorded at lambing. The undefined. It is hypothesized that RU 486 could decrease pro¬ interval from first hormone or diluent injection to parturition gesterone secretion in pregnant sheep, but it is not known was calculated to determine the injection—lambing interval. whether the drug can alter endogenous relaxin secretion. Whether exogenous relaxin could alter progesterone secretion in this species is undefined. This study was designed to deter¬ Radioimmunoassays of RU 486, relaxin and progesterone in mine the effects of both RU 486 and relaxin on antepartum progesterone and relaxin secretion in late pregnant sheep. peripheral plasma Furthermore, the effects of RU 486 and relaxin on the time and RU 486 concentrations in the plasma were determined by ease of parturition as well as viability of lambs were determined. radioimmunoassay procedures as previously described (Salmon and Mouren, 1985; Heikinheimo et al, 1986) with modifications (Li et al, 1991a, b, c). The specific activity of [3H]RU 486 was Materials and Methods 46.8 Ci mmol"1 (433.59 molecular weight). The anti-RU 486- 3-carboxylmethyloxime-BSA antiserum was raised in New Zealand White rabbits to described Animals according procedures pre¬ viously (Raynaud et al, 1974). Plasma samples (50 µ ) in Twenty-two ewes of Suffolk and Hampshire breeds, averag¬ duplicate were added to 0.25 ml distilled water and extracted ing 97 + 2 kg body weight (mean + SEM) were maintained at with 3.0 ml diethyl ether (spectrophotometric grade; Aldrich, the Sheep Teaching Farm, Iowa State University. Animals Milwaukee, WI). The recovery of radioactivity was 79.3% (n = received 1.8 kg of chopped hay and 0.5 kg of corn daily. Water 2). Total incubation volume was 0.4 ml tube-1 in which anti- was provided ad libitum. Ewes were naturally mated at oestrus serum was diluted to 1:10 000 and total [3H]RU 486 was (day = 0). The average duration of gestation in this flock is 150 10 000 cp.m. The standard curve contained 0, 20, 40, 80, 125, days. 250, 1000 and 2000 pg tube"1 RU 486 in duplicate. Separation of unbound fraction was obtained by dextran-coated charcoal. Sensitivity of the assay was 10 pg tube-1, and the intra- and interassay coefficients of variation were 8.0% (n = 2) and 18% Experimental groups = (n 2), respectively; non-specific binding was 9.0%. The ewes were randomly allocated to one of three treat¬ A homologous double antibody radioimmunoassay for porcine ments: RU 486 group (n = 5); relaxin group (n = 9); and relaxin was used as described by O'Byrne and Steinetz (1976) with diluent group (n = 8). On day 140 of gestation, one external modifications to quantify relaxin concentration in ovine plasma jugular vein of each ewe was fitted with an indwelling catheter in duplicate aliquots of 50-200 µ .
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