Further Studies on the Use of Synthetic Prostaglandin Analogues for Inducing Luteolysis in Mares

Abstract

SUMMARY ICI‐81008, a synthetic prostaglandin analogue structurally related to Prostaglandin F2α, was shown to be a safe and effective luteolytic agent in mares. It consistently induced luteolysis in Welsh Pony mares at a dose of 125 μg and only produced detectable adverse side effects when given at more than six times this dose. Of 63 Thoroughbred mares in prolonged dioestrus which were treated with ICI‐81008, 55 returned to oestrus and ovulated; 40 per cent of the mares covered during the induced oestrus conceived. A total of 144 Thoroughbred mares in prolonged dioestrus were treated with another prostaglandin analogue, ICI‐79939; 134 returned to oestrus and ovulated and 46 per cent of those covered during the induced oestrus conceived. However, ICI‐79939 produced marked adverse side effects in mares when given at only three to four times the normal therapeutic dose. This study supported previous findings that the majority of non‐pregnant mares which are not showing regular oestrous cycles during the breeding season are in prolonged dioestrus rather than anoestrus. RÉSUMÉ On a démontré l'innocuité et l'efficacité du produit, ICI 81,008, un analogue synthétique de la prostaglandine et qui est structurellement apprenté avec la prostaglandine F2α, comme agent luteolytique chez les juments. En administration dans une dose de 125 mcg (microgrammes) la substance induit une répons luteolytic constante chez les juments de la race poney gallois. Des effets collaterau néfastes sont decelables seulement après l'administration des doses 6 fois plus grandes. De 63 juments pur sang en dioestrus prolongé, qui ont reçu ce traitment avec l'ICI 81,008, 55 sont revenues en oestrus avec ovulation ulterieure. 40% des juments couvertes pendant cet oestrus induit ont conçu. Un total de 144 juments pur sang en dioestrus prolongé ont reçu un traitement avec un autre analogue de prostaglandine (le composé denommé ICI 79,939); 134 sont revenu en oestrus, avec ovulation; 46% des juments couvertes pendant cet oestrus induit sont devenues gravides. Pourtant le composé ICI 79,939 produisit des effets collateraux indésirables marqués chez les juments même dans les doses qui ne depassent le niveau therapeutic normal que par un facteur de 3 à 4. Cette investigation confirme les observations anterieures; elle montre que la plupart des juments non‐gravides qui ne presentente pas des cycles d'oestrus regulaires pendant la monte se trouvent en effet en dioestrus prolongé, plutôt que dans un état d'anoestrus. ZUSAMMENFASSUNG Es wurde gezeigt, dass ICI‐81008, ein synthetisches Prostaglandin, strukturanalog zum Prostaglandin F2α ein sicheres und wirksames luteolytisches Agens für Stuten darstellt. Eine Dosis von 125 μg löste bei Welsh‐Pony‐Stuten durchweg Luteolyse aus und verursachte nachweisbare nachteilige Nebenwirkungen erst nach einer sechsfachen Dosierung. Von 63 Vollblut‐Stuten mit verlängertem Diöstrus, die mit ICI‐81008 behandelt wurden, kamen 55 in Brunst und ovulierten: 40% der Stuten, die während dieser induzierten Brunst belegt wurden, kon...

Control of the oestrous cycle of the mare

“…Prostaglandin F-2a, in spite of mild side effects (Miller, Lauderdale & Geng, 1976), can be used for this purpose. Synthetic analogues (Allen et al, 1974;Witherspoon, Lamond, Thompson & Stevenson, 1975) allow the same luteolytic effect without side effects. In almost all animals treated at an appropriate time of the luteal phase, oestrus will begin 2-5 days later.…”

Half a century of equine reproduction research and application: A veterinarytour de force

“…These tests established that a much lower dose of prostaglandin was effective as a luteolytic agent in the mare than the cow, the CL was relatively insensitive to the actions of prostaglandin until 5 days after ovulation and intramuscular administration was as effective as intrauterine. At the same time, numerous noncycling Thoroughbred mares in Newmarket were treated with ICI 79939 with equally startling and pleasing results – mares that had not cycled for weeks showed strong oestrous behaviour and good follicle growth only 2–4 days after a single intramuscular injection of the drug (Fig ; ).…”

The 50 year veterinary revolution in equine stud management

“…The discovery during the early 1970s that a small dose of either natural PGF2a (Douglas and Ginther 1972) or any of three ICI Pharmaceuticals PGF2a analogues (Allen and Rowson 1973, Allen and Rossdale 1973, Allen et al 1974, either infused into the uterus or injected intramuscularly, would rapidly induce luteolysis of the cycling or persistent corpus luteum followed by a return to fertile oestrus in 2-4 days was a considerable revelation. It led the following year to a largescale clinical trial on Thoroughbred studfarms in the Newmarket area of England in which some 300 non-cycling maiden, barren and lactating mares which showed an elevated serum progesterone concentration were treated with a single dose of an ICI Pharmaceuticals prostaglandin F analogue.…”

“…Prior to the discovery in the late 1960s that prostaglandin F2a (PGF2a) secreted by the endometrium is the luteolytic agent that controls the oestrous cycle in all the large domestic animal species (see McCracken et al 1973 for review), and the parallel synthesis of natural PGF2a by Upjohn Limited in the USA and a number of potent PGF analogues by ICI Pharmaceuticals in the UK, failure to show regular oestrous cycles during the arbitrary covering season (mid-Februarymid-July) was by far the commonest cause of infertility in Thoroughbred mares (Allen et al 1974. As mentioned previously, in the absence of the rapid progesterone assay and transrectal ultrasound scanning this lack of cyclicity was mistakenly assumed to be persistence of winter or lactation-related anoestrus and treatment was limited to "washing out" the uterus by infusing a large volume of warmed physiological saline , Arthur 1975.…”

“…That is, abnormal prolongation of luteal lifespan beyond the normal 14 -16 days in the absence of pregnancy due, presumably, to insufficient release of endometrial prostaglandin (PGF2a) at the end of dioestrus, leading to a 60 -85 day period of acyclicity akin to "pseudopregnancy" in the bitch , Allen et al 1974. This persisting luteal tissue, situated deep within the ovarian stroma was not palpable per rectum so that mares which passed into prolonged dioestrus early in the breeding season or, more commonly, had passed through the previous winter in prolonged dioestrus, were usually considered to be still in seasonal anoestrus and therefore "given more time" to respond to the natural increases in daylength and ambient temperature of Spring.…”