Intrauterine pressure (IUP) changes were recorded in nonlactating, cyclic dairy cows using transcervically placed intraluminal pressure microtransducers. Spontaneous activity was recorded for the first 30 min. Prostaglandins (PG) F(2alpha) (5 mug/kg), E(2) (5 mug/kg), or cloprostenol (0.1 mug/kg) were then injected intravenously (i.v.) at diestrus, proestrus, estrus, and metestrus, and their effects were recorded. The drug administrations did not alter the duration of the estrous cycle of the cows. Single doses of PGF(2alpha) and E(2) significantly increased uterine activity at all stages of the estrous cycle, while cloprostenol had no effect. PGF(2alpha) and PGE(2) increased IUP, frequency, and amplitude during all stages of the estrous cycle. The spontaneous pattern resumed within 20 min postinjection. Partial uterine refractoriness occurred with both PGs. The results indicate that low doses of natural prostaglandins stimulate uterine activity during the estrous cycle in cattle.

Cloprostenol was deposited in the vaginal lumen of sows on Day 111 of pregnancy at dosages of 100, 125 or 175 g and volumes of 1, 2 or 5 ml, respectively. A control group was treated with physiological saline. In 92 out of 93 prostaglandin-treated sows, parturition commenced approximately 22 h after application, with no significant differences between dose levels or volumes. There were also no differences in the average size and weight of litters born, weaning weight, frequency of postpartum complications or post-weaning fertility. Intravaginal application of cloprostenol is thus a simple and efficient means of inducing parturition in sows.

Twenty-four to 36 hours after farrowing, 192 sows were treated with a single intramuscular injection (2 ml per animal) of a prostaglandin analogue; 102 were treated with cloprostenol racemate and 97 with dinoprost tromethamine, and 90 were left untreated. There were no statistically significant differences between the groups in the percentages of sows that came into oestrus by eight days after weaning or conceived by eight days after weaning. Significantly more piglets were born per litter (10.71 and 11.00 piglets in the cloprostenol and dinoprost groups, respectively) and born alive (10.22 and 10.41, respectively) than in the controls (9.24 piglets born per litter and 8.66 piglets born alive).

We verify the efficiency of a protocol for estrus synchronization in captive female collared peccaries (Pecaricari tajacu) using the prostaglandin analog D-cloprostenol. Five adult female collared peccaries received an intramuscular administration of 60 µg D-cloprostenol, which procedure was repeated after a 9-day interval. For 10 days after second the D-cloprostenol administration, females were monitored for changes in external genitalia, ovarian ultrasonography, vaginal cytology and reproductive hormonal dosage. As a result, four females synchronized their estrous at 9.5 ± 0.5 days after the second administration of the prostaglandin analog. Such females showed external signs of estrus, including vulvar opening, hyperemic vaginal mucosa, and vaginal mucus, concomitant with an increase in the proportion of superficial cells (52.2 ± 9.9%) verified through vaginal cytology. An estrogen peak of 22.7 ± 3.4 pg/ml was detected by hormonal dosage, and the presence of anechoic follicles measuring 0.29 ± 0.05 × 0.32 ± 0.07 mm were detected in the ovary by ultrasonography. Given these findings, we suggest that D-cloprostenol may be effective for use in estrus synchronization in collared peccaries.

OBJECTIVE

To assess the efficacy and safety of 2 protocols using bromocriptine mesylate and prostaglandins to terminate unwanted pregnancy in bitches.

METHODS

Prospective randomized single-blind controlled study.

METHODS

34 crossbred and purebred bitches referred for possible pregnancy termination. Seven additional pregnant bitches were used as controls.

METHODS

Pregnancy was assessed by ultrasonographic examination from day 25 after mating in all bitches. Of the 34 bitches, 25 were pregnant and were randomly allocated to a treatment group. Group-1 dogs (n = 12) received a combination of increasing amounts of bromocriptine mesylate (15 to 30 microg/kg [6.8 to 13.6 microg/lb], p.o., q 12 h) and dinoprost tromethamine (0.1 to 0.2 mg/kg [0.045 to 0.09 mg/lb], s.c., q 24 h). Group-2 dogs (n =13) received a combination of increasing amounts of bromocriptine mesylate (the same schedule as group-1 dogs) and cloprostenol sodium (1 microg/kg [0.45 microg/lb], s.c., q 48 h). Both groups were treated until pregnancy termination. Results-Treatment success was 100% in both groups. Days of treatment required for pregnancy termination did not significantly differ between groups (5.0 +/- 0.6 vs 3.7 +/- 0.6 days, group-1 and group-2 dogs, respectively) although adverse effects only developed in group-1 dogs. At the end of the protocols, pseudopregnancy was observed in 3 of 12 and 6 of 13 group-1 and group-2 dogs, respectively. Pregnancy termination was followed by a mucoid sanguineous vulvar discharge for 3 to 10 days.

CONCLUSIONS

Results of this study indicate that protocols that combine the use of bromocriptine mesylate and prostaglandins for the termination of unwanted pregnancy in bitches are efficient and safe. The use of bromocriptine mesylate and cloprostenol had the best results and could be easily used on an outpatient basis.

The synthetic analogous of the prostaglandins are utilized in the obstetrical and gynecological therapy for multiple purposes. 4 lots with 12 nonpregnant female rats were use: the Ist received 25 g/kg/day isopropyl ester PGF2; the IInd lot received 50 g/kg/day isopropyl ester PGF2; the IIIrd lot received 50 g/kg/day optic active cloprostenol; the IVth lot was the witness lot. The medication was intraperitoneally (i.p.) administrated in a unique daily dose. Prostaglandin F2 analogous at small doses (25 micrograms/kg/day) induce vasodilating effects on the ovary blood vessels and functional luteolysis rather than structural luteolysis. Both of the prostaglandins analogous at doses of 50 micrograms/kg/day present obvious vasodilating and luteolytic effects, although the intensity of the phenomenon is not the same, cloprostenol is more active, inducing a more obvious vasodilatation and luteolysis.

The racemic cyclohexane-for-cyclopentane ring substitution analogue of the potent prostaglandin FP agonist cloprostenol (7) was synthesized from cyclohexenediol 11 in 21 steps and 0.07% yield. In a prostaglandin FP receptor-linked second-messenger assay, racemic analogue 7 exhibited an EC(50) value of 319 nM (72% response relative to cloprostenol); the corresponding values for PGF(2)(alpha) and cloprostenol were 23 nM (91% relative response) and 1 nM (defined as 100% response), respectively. Key features of the synthesis were the selective manipulation of four hydroxyl groups to direct independent elaboration of the alpha and omega chains and a new method for synthesis of aryloxy-terminated omega chains involving Horner-Emmons elongation of an aldehyde to a methyl enone, regioselective bromination adjacent to the carbonyl, and phenoxide displacement of bromide.

Numerous actions of the synthetic analogous of the prostaglandins were used in human and veterinary therapy. The action of these analogous (even, initially the prostaglandins were put in evidence in the seminal plasma) on the male reproductive system are little known. This is the reason for our study, which tried to emphasize the effects of analogous of the prostaglandin F2 alpha on the apoptosis of the rat and mouse testicular cells. Optic active Cloprostenol and Cloprostenol Isopropyl ester, in a dose of 100 micrograms/kg/day induces significant histopathologic modifications in the testis of rats and mice. These changes are evident after 14 days of treatment, but especially after 28 days of treatment.

The metabolic fate of the synthetic prostaglandin cloprostenol ('Estrumate') in the cow has been studied. Following intramuscular administration of 0.5 mg and 10 mg of [14C]cloprostenol to cows urinary excretion accounted for 58.2% and 56.3% of the dose respectively. Unchanged cloprostenol and its tetranor acid, probably formed by beta-oxidation, were the major components identified in urine. The tetranor acid was also present as a glucuronide conjugate. This synthetic prostaglandin analogue is apparently a poor substrate for the enzymes 15-hydroxyprostaglandin dehydrogenase and 13,14-reductase, which are responsible for the rapid metabolic deactivation of endogenous prostaglandins, as no components identified in urine were found to have undergone metabolic attack at the C-15 atom in the cloprostenol molecule.

The prostaglandin F2 alpha analogue cloprostenol stimulates ovarian secretion of oxytocin in red deer hinds and Père David's deer hinds, as in cattle and sheep, but the response of the uterus to administered oxytocin has not been studied in deer. In the present experiment, oxytocin administered intravenously caused an increase in circulating concentrations of 13,14-dihydro-15-keto prostaglandin F2 alpha from 186 +/- 35 to 404 +/- 34 pmol L-1 within 5 min; concentrations in saline-treated hinds were unchanged (150 +/- 12 and 164 +/- 12 pmol L-1 before and after treatment respectively). This suggest that in red deer as in other ruminants, a positive feedback relationship between the corpus luteum and the uterus may operate to stimulate luteolytic episodes of prostaglandin F2 alpha.

The effects of oxytocin, prostaglandin F(2)alpha and a prostaglandin F(2)alpha analogue on uterine and vaginal pressures in the mare were measured using electronic catheter-tipped pressure transducers. Catheterisation for 70 minutes produced no significant change with time. Oxytocin caused a rapid rise in intrauterine pressure which had subsided 20 minutes later. Cloprostenol (prostaglandin F(2)alpha analogue) caused an increase in uterine pressure which started ten minutes after administration and lasted for the duration of the recording (60 minutes post-injection). Prostaglandin F(2)alpha produced a uterine pressure increase ten minutes after administration which declined over the next 40 minutes. The activity of the three drugs was not consistently affected by reproductive status (oestrus, dioestrus or anoestrus). There were no significant drug effects on intravaginal pressure.

Ethanol stimulates the production of prostaglandins in many species. The purpose of this study was to verify the effect of ethanol on the production of prostaglandin F2α (PGF2α) and luteolysis in bovine females. In the first experiment, Holstein cows at day 17 of the oestrous cycle were treated with 100% ethanol (0.05 ml/kg of body weight, IV; n = 5), saline (0.05 ml/kg of body weight, IV; n = 4) or synthetic prostaglandin (150 μg of D-cloprostenol/cow, IM; n = 4). The plasma concentrations of 13, 14-dihydro-15-keto PGF2α (PGFM; the main metabolite of PGF2α measured in the peripheral blood) were assessed by radioimmunoassay (RIA). There was an acute release of PGFM in response to ethanol comparing to other treatments (p ≤ 0.05). However, only cows treated with PGF2α underwent luteolysis. In the second experiment, endometrial explants of cross-bred beef cows (n = 4) slaughtered at day 17 of the oestrous cycle were cultured for 4 h. During the last 3 h, the explants were cultured with medium supplemented with 0, 0.1, 1, 10 or 100 μl of 100% ethanol/ml. Medium samples were collected at hours 1 and 4 and concentrations of PGF2α were measured by RIA. Ethanol did not induce PGF2α production by the endometrium. In conclusion, ethanol does not cause luteolysis in cows because it stimulates production of PGF2α in extra-endometrial tissues.

The use of cloprostenol sodium in puerperium is questionable, as both favorable and unfavorable responses during the uterine involution process have been reported in the literature. This study is based on the hypothesis that cloprostenol sodium promotes modifications in the prostaglandin F2α receptor (FP), caspase 3 (CASP-3), and cyclooxygenase 2 (COX-2) mRNA expression that may favor the process of postpartum uterine involution in multiparous Nelore (Bos taurus indicus) females. Additionally, we aimed to describe the presence and immunolocalization of the FP and COX-2 protein in endometrial tissue at different postpartum time points in these females. Multiparous Nelore cows (n = 24) were treated with cloprostenol sodium (n = 12) or saline solution (n = 12) on postpartum Days 1 and 4 (Day 0 = birth), and endometrial biopsies were performed with a Yomann biopsy instrument and collected on Days 1, 7, 14, 28, and 42 postpartum. The mRNA expression from samples on the Days 1, 7, 14, 28, and 42 and the protein expression from samples on the Days 1, 14, 28, and 42 were then analyzed. The treated cows had altered FP and CASP-3 mRNA expression, and FP and COX-2 protein were observed in the endometrial surface epithelium, the stroma, and the glandular epithelium, with cytoplasmic immunolocalization. Although we attribute the change in CASP-3 mRNA expression to physiological phenomena, the results obtained for FP mRNA expression opens new doors for the study of hormonal protocols associated with cloprostenol sodium in the puerperium of Zebu females.

Rats with superluteinized ovaries were injected with the prostaglandin F2 alpha (PGF2 alpha) analogue cloprostenol to induce luteolysis. The treatment led to decreased adenylyl cyclase response to hCG and isoproterenol in ovarian homogenates while the response to forskolin remained unchanged indicating that the catalytic unit of the enzyme was not affected by the treatment. The activation of adenylyl cyclase by Mg2+ or the non-hydrolysable guanosine triphosphate (GTP) analogue guanosine-5'-(beta,gamma-imido)-triphosphate (GMP-P(NH)P) was not altered by the treatment with cloprostenol. Both basal and hormone-stimulated adenylyl cyclase activity increased with increasing concentration of GMP-P(NH)P. Unstimulated adenylyl cyclase continuously increased with increasing concentrations of Mg2+. The same applied to forskolin. The dependence of the adenylyl cyclase stimulation by hCG and isoproterenol on Mg2+ was complex. It is postulated that PGF2 alpha induces the attenuation of ovarian adenylyl cyclase by a modification in the coupling of the hormone-receptor to the N beta-component of the adenylyl cyclase complex while the catalytic unit remains unchanged.

1. Following subcutaneous administration of the synthetic prostaglandin analogue [14C]cloprostenol to the rat (200 micrograms/kg), the dose was quantitatively recovered from the excreta: 52% of the dose was present in the urine and 43% in faeces. After intravaginal administration (200 micrograms/kg) 42% of the dose was recovered from the excreta, equally divided between urine and faeces, and 40% (range 25--66%) of the dose was recovered from the site of application. The radiolabelled compounds present in faeces were eliminated initially via the bile. 2. The max. observed plasma concn. of total 14C in the rat was 84 ng equiv./ml at 30 min after subcutaneous administration of cloprostenol (200 micrograms/kg). A component which co-chromatographed with cloprostenol on t.l.c. was rapidly cleared from plasma with a half-life of 54 min. After intravaginal administration of cloprostenol (200 micrograms/kg), low and persistent plasma concn. of 14C were detected. 3. The metabolic fate of cloprostenol in the rat and marmoset has been studied with radiolabelled and non-labelled drug mixed such that fragments detected by mass spectrometry exhibited characteristic 12C:14C isotope clusters. Metabolites derived from cloprostenol contained these characteristic doublets. 4. In the rat cloprostenol is metabolized by beta-oxidation to tetranor-cloprostenol. Unchanged cloprostenol and a conjugate of tetranor-cloprostenol were minor urinary metabolites. In the rat biotransformation of cloprostenol in the cyclopentane ring occurred; the tetranor acid of 9-keto-cloprostenol was identified in urine. In the marmoset unchanged cloprostenol and dinor-cloprostenol were major urinary components.

Eleven dairy goats of several breeds were administered 0.5 mg of the prostaglandin analogue fenprostalene (0.5 mg s.c.) on Days 146 to 148 of pregnancy. Parturition was successfully induced in all does, with a mean interval to first kid of 31.6 h +/- 0.83 (SEM). The course and duration of labor were normal. All kids were delivered alive. The incidence of dystocia due to fetal posture was 1/11; the incidence of fetal membranes retained for longer than 6 h was 1/11. These data indicate fenprostalene is safe and efficacious for induction of parturition with an interval to effect not significantly different from that reported for dinoprost or cloprostenol.

Maiden heifers and lactating cows of known ovarian status and of several breeds were treated with a synthetic prostaglandin, cloprostenol, or a synthetic progestagen, norgestomet, at the start of an artificial insemination (AI) program. Animals in the cloprostenol treatment received 2 injections 10 days apart. Over the next 26 days those animals that showed oestrous behaviour were inseminated. Synchronisation rates and calving rates to insemination over the first 7 days were calculated. Those in the norgestomet treatment received an implant of norgestomet plus an injection of norgestomet and oestradiol valerate. The implant was removed 10 days later and the animals were given an injection of pregnant mare serum gonadotrophin (PMSG). They were inseminated at 48 h (maiden heifers) or 56 h (lactating cows) after implant removal. Calving rates to fixed-time insemination were recorded. After completion of the AI program the animals in both treatments were joined with bulls. Overall calving rates (AI plus bulls) were calculated. By day 7 of the program, 82% of the maiden heifers and 76% of the lactating cows in the cloprostenol treatment had been detected in oestrus. By day 21 the respective figures were 99% and 81%. Norgestomet treatment had an immediate and a prolonged effect on ovarian activity in those females classified as having inactive ovaries at the start of the AI program. Calving rates of those females to fixed-time AI and overall were similar to those of the females with active ovaries in both treatments. Their calving rates to fixed-time insemination, and overall calving rates for the lactating females, were significantly higher than the corresponding values of their contemporaries treated with cloprostenol and inseminated on observed oestrus over 7 days. For those females classified as having active ovaries at the start of the AI program, calving rates to first insemination and overall were similar for both treatments. Overall calving rates of lactating cows of each breed were, with one exception, higher in the norgestomet treatment than in the cloprostenol treatment. Although norgestomet treatment was more expensive than cloprostenol treatment, the advantage in calf crop resulted in an overall monetary advantage to the norgestomet treatment.

Prostaglandin F2α (PGF) is considered to be the main luteolysin in cattle. We have previously demonstrated that cortisol (Cr) suppresses PGF production in non-pregnant bovine endometrium. This study was carried out to test whether exogenous PGF increases ovarian and/or uterine PGF production and to determine the temporal relationship between PGF and Cr in ovarian and uterine circulations during PGF-induced luteolysis in cows. Catheters were inserted into the ovarian vein (OV), uterine vein (UV) and jugular vein (JV) of 10 cows on Day 9 of the oestrous cycle (Ovulation = Day 0) for frequent blood collection. On Day 10, the cows were divided randomly into two groups and treated with a luteolytic dose of a PGF analogue (cloprostenol) or saline solution. Blood samples were collected at -0.25, 0, 0.25, 0.5, 1 and 2 h and then at 2-h intervals until 12 h after treatment (0 h). The basal concentrations of PGF and Cr in OV and UV plasma were not significantly different. Injection of a PGF analogue induced more than twofold increases in the levels of PGF between 0.25 and 1 h in UV plasma, but not in OV plasma. PGF increased (p < 0.05) the concentrations of Cr in OV, UV and JV plasma between 0.5 and 1 h. The Cr levels in OV, UV and JV plasma were similar. The PGF levels in UV plasma decreased after Cr reached its highest levels. The overall results suggest that the uterus rather than the ovary increases PGF production in response to PGF injection. Based on the temporal changes of PGF and Cr in the ovarian and uterine circulations, Cr may act to reduce uterine PGF production in non-pregnant cows in vivo.

The authors describe the synchronization of farrowing by the induction of parturition with a prostaglandin F2alpha analogue (Cloprostenol). The time sequence of the beginning of parturitions was recorded in 147 sows after administration of 175 microgram Cloprostenol. 93.7% of the parturitions take place between the 14th and 39th hour after administration, the peak time being between the 24th and 27th hour (31.2%). The schedule of the farrowing days is described as a prerequisite for a qualitative change in the organization of work in large pig herds.

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.

Recipient age at transfer (less than 525 d old or more than 525 d old), season (fall, winter, spring, summer), method of synchronization (natural or induced), and transfer technique (surgical or nonsurgical transfer) were associated with success of embryo transfer in a log-linear analysis. In a separate analysis, no significant association was found between success of transfer and transfer to the left or right uterine horn. Summer had the lowest proportion of successful transfers (58.9%). Pregnancy rates were 83% using the surgical transfer method and 68% with transcervical transfers. Proportion of pregnancies following a second transfer was not different from the proportion after first transfers. Success of embryo transfer was highest if recipients were greater than 525 d old and if transfers were performed surgically in spring following synchronization of recipients with cloprostenol, an analog of prostaglandin F2 alpha. Probability of success was lowest for transfers to young, prostaglandin-synchronized recipients, performed nonsurgically in summer.