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The veterinary uses of progestagens J.M. Evans M.R.C.V.S.
a
a
Glaxo Laboratories Ltd , Greenford, Middlesex, England Published online: 23 Feb 2011.
To cite this article: J.M. Evans M.R.C.V.S. (1976) The veterinary uses of progestagens, New Zealand Veterinary Journal, 24:3, 25-34 To link to this article: http://dx.doi.org/10.1080/00480169.1976.34277
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NEW ZEALAND VETERINARY JOURNAL VOLUME 24
MARCH, 1976
NUMBER 3
THE VETERINARY USES OF PROGESTAGENS* J. M. EVANSt
cycle, noting their effect on target organs and on each other.
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INTRODUCTION
THIS PAPER is very relevant to the theme of "Manipulation' of Populations", as set by the 1975 N.Z.V.A. Conference, because it concerns the use of progestagens in preventing conception and controlling ovula>tion for farm and domestic animals. It discusses first the basic principles behind the use of progestagens and then, by species, examines the applications that h~lVe been developed and some of the difficulties that have arisen. The periodicity of the oestrous cycle divides animals broadly into three groups: Polyoestrous - e.g. cows seasonally polyoestrous - e.g., ewes and monOestrous - e.g., bitches. Except when pregnancy or Dseudo-pregnancy intervenes, polyoestrous animals invariably follow the sequence of oestrus to metoestrus to dioestrus to pro-oestrus to oestrus. Seasonally polyoestrus animal occafrom metoestrus sionally proceed through a period of anoestrus before returning to pro-oestrus and on to oestrus. In monoestrous animals metoestrus is followed by anoestrus as part of their normal cycle. Parturition may be followe.d by pro-oestrus or may be preceded by a period of anoestrus. Pseudopregnancy in cats may occur after any non-fertile ovulation, whether brought about by a sterile mating, mechanical stimulation of the cervix, or hormonal treatment. Tables 1 and 2 list the hormones involve.d in bringing about the oestrous
PROGEST AGENS -
SYNTHESIS AND ROLE
Progesterone was first isolated from corpora lutea and purified in the midthirties. Since the discovery, in 1937, that in.iections of progesterone will inhibit ovulation in the rabbit, many derivatives have been synthesized in a quest for greater potency, slowe,I" excretion and oral activity. These synthetic compounds, which mimic the actions of progesterone, are called progestagens (or less commonly, progestins). Basically they fall into two main groups, oestranes and pregnanes. A recently discovered compound, norgestomet, is unique being a 19-nor pregnane. It can be regarded as a cross between oe,stranes and pregnanes. Of the pregnanes, megestrol acetate and medroxyprogesterone acetate have been mostly used in the bitch. Me:lengestrol acetate is particularly potent in cattle. In general, progestagens have numerous physiological actions but the following are the most important:
·Paper presented to the NZ. Veterinary Association Conference, February 1975. tT. M. EVANS. M.R.C.V.S., Glaxo Lahoratories Ltd. Greenford, Middlesex, England.
-
They inhibit FSH release and thus probably suppress the growth of ovarian follicles and oestrogen production. preventing the internal and external behaviour changes characteristic of oestrus.
-
They inhibit LH release and thus presumably prevent ovulation, organization of the corpora lutea and release of progesterone. They inhibit the release of luteotropic factors and so may affect the life of the corpus luteum.
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VOL. 24
TABLE 1; THE ACTION OF GONADOTROPHINS CONCERNED IN THE OESTROUS CYCLI. (Modified from Haas, 1961) Hormones
Follicle
FSH
Follicle Corpus luteum
LH Luteotrophic factors (prolactin)
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Target Organs
Corpus luteum Mammary glands
Effect
Stimulates oestrogen secretion Stimulates follicle growth Ovulation and formation of corpus luteum Initiates progesterone secretion
----------------------
Maintains progesterone secretion Stimulates lactation
TABLE 2; THE ACTION OF SEX HORMONES CONCERNED IN THE OESTROUS CYCLE (Modified from Haas, 1961) Hormones
Target Organs
Effect
-------------------------------------------------
Oestrogen
Progesterone
Anterior pituitary Endometrium Cervix Vagina Mammary glands Anterior pituitary Endometrium Mammary glands
They exert a peripheral antioestrogenic effect which, in bitches, may prevent vaginal haemorrhage during pro-oestrus. They cause thickening of vaginal mucus, rendering it hostile to spermatozoa. They produce a endometrium.
secretory uterine
They delay, in some species and in certain circumstances, the implantation of the fertilized ovum. They maintain pregnancy. Not all progestagens have. all the actions listed above; their relative activity in respect of each function may vary from compound to compound and species to species. Neverthe.Iess, their multiplicity of actions gives progestagens many potential applications in veterinary medicine. They can be used as contraceptive.s; to reduce libido in both males and females; to control the oestrouscycle -- i.e., synchronize oestrus, posipone oestrus, suppress heat; to trear false pregnancy in bitches; to control the
Positive and negative feedback Proliferation Relaxation Proliferation of lining Duct proliferation Negative feedback Progestational effect Alveolar proliferation
growth of certain tumors; to treat some skin conditions. These indications are listed for completeness but the brief here is to consider the use of proge.stagens only in manipulating the oestrous cycle -- i.e., to synchronize oestrus in,large animals, and to postpone it and suppress heat in small animals. APPLICATION IN LARGE ANIMALS CATTLE
The detection of heat in dairy cows is time-consuming and often difficult, because. in some animals the manifestations are not very marked. With beef herds the problem is further complicated by the impracticality of examining cows daily because the periods of oestrus are often very short and may occur overnight. Farmers in both industries, therefore, would welcome a technique whereby cows could be inseminated on a predetermined date and at a specified time without need to observe oestrous behaviour. Ideally the method should be simple to administer arid reasonably cheap: moreover, conce.ption rates following its use
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should not be lower than those normally obtained. The advantages of being able to inseminate at a predetermined time are: Labour saving - no oestrus dete:ction predictable calving dates; planned breeding programmes are possible; use of top quality A.1. bulls is facilitated; insemination is cheaper; compact calving season eases re.aring and ,fattening; seasonal milk production is eased. Oestrus control in cattle was first achieved by Christian and Casida (1948). These workers used daily injections of the naturally occurring hormone, progesterone. With the availability of proge.stagens many researchers all over the world set out to establish whether the compounds could be used to contrO'I ovulation very precisely and so satisfy the. need already mentioned. The literature is now filled with detailed descriptions O'f their experiments. In general, however, the method that has been fO'Ilowed is to give the, prO'gestagen to all the herd for a period equivalent to the life soan of the corpus luteum - i.e., 18 to 21 days. This has the effect of inhibiting oestrus if due whilst in other animals the corpora lutue,a regress spontaneously. The result is that, when the dosing period ends, the ovaries of all have no comora lutea, and the animals are ready to exhibit oestrus and ovulate synchronO'usly. Most experimenters have found that cows show oestrus 4 to 6 days after such treatment is withdrawn. However, at this first "rebound oestrus" fertility is lowered by about 20 to 55 %, depending on the progestagen used. Conception rates return to normality at the second oestrus following treatment, but the animals are not then so well synchronized because cycle length varies be,tween cows. All workers encountered this difficulty, regardless of the progestagen used and despite administering the compO'unds in a variety of ingenious and often impractical ways. Vaginal spon~es and implants were employed in the belief that steady progestagen levels and a sham cut-off at the end of treatment were necessary. HO'wever, such methOods did not helo and, fOor a time, the difficultv was thought to defy resOolution simply because agents designed basically as contraceptives were being used to
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contrO'I oestrus. Even so, a number of workers persisted. They investigated using progestagens in the ways described but with injections of human chorionic gonadotrophin given after the last dose. Such modifications were, hO'wever, found to interfere with normal expression of oestrus and led to very low levels of fertility. The ideal technique, remained elusive and, while some continued their efforts to resolve the problem, others increasingly abandoned proge,stagens in favour of the emerging prostaglandins. The decisive breakthrough came when Wiltbank et al. (1965) showed that fertility is unimpaired if the duration of progestagen administration is reduced to 12 or 9 days. This period is not long enough, however, for the dosage to synchronize all animals unless existing corpora lutea can be made to regress more rapidly than normal. Wiltbank showed that oestradiol vale,rate had the desired luteolytic effect from day 6 or 7 of the cycle onwards. By using an injectiO'n of 5 mg oestradiol valerate with a 9-day administration of norgestomet, he obtained an oe.strus response of approximately 80%, with normal levels of fertility in the responding animals. The hunt then started fOor a luteO'lytic agent that was effective early in the cycle. Like oestrodiol valerate, prostaglandins were. found to be luteolytic only after days 5 O'r 6 O'f the cycle. The progestagen norgestomet is antiluteotrophic and, in combination with oestradiO'I valerate, was found to PO'tentiate the, oestrogen's luteolytic effect. This finding really paved the way for the development of a svstem recently reported by Wishart and Young (1974) whereby a farmer can have, his heifers inseminated on a "bv the clock" basis without the need for detectiO'n O'f oestrus and without any adverse effect on fertility. These worke,rs describe exueriments which show that delayed embryo cleavage is a majO'r factO'r responsible for the lowered fertility associated with 18to 21-day administration of progestagens. This did not occur following a 9dav treatment periO'd. The authors also noted that, if !!ood results are to be obtained, onlv bulls of proven high fertility shO'uld be used and the cows should be maintained with sound nutrition.
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Following the alternative route, other worke.rs have shown that two injections of prostaglandin F 2(J. or its synthetic analogues can be used to give a similar effect, but double insemination is needed if heat detection is to be avoided. The method of using norge.stomet, as described above, is somewhat complex but does offer three distinct advantages: First, it will not cause abortion in cattle already pregnant. Secondly, it can be used to induce a fertile oestrus in mepuberal and anoestrous heifers, and possibly also in acyc1ical beef cattle. Finally, it is free from a possible misuse hazard - namely, that of be.ing illegally adopted to induce abortion in women. SHEEP
The seasonal reproductive cycle of the ewe sets the seasonal pattern of lamb sales. In the northemhemisphere a premium is p'aid for spring~marketed lambs. The facility of being able to advance the breeding season bv one or two months is clearly financially advantageous to the farmer. Apart from using progestagens with ewes in late anoestrus, the compounds also have an application in the control of oestrus and ovulation of cyclical ewes within the breeding season, and in truly anoestrous ewes. Theoretically at le,ast, progestagens make A.I. or natural mating programmes possible at any time of the year, and enable lambings to be synchronized. The latter offe.rs advantages in respect of employment of staff, lamb survival, usage of pasture, handling for vaccination, marketing, and so on. Thanks principally to the work of Professor Robinson and his colleagues at Sydney University and the development of polyurethane sponge pessaries impregnated with cronolone, the theoretical uses of progestagens in ewe management can now be practical achievements. Early enthusiasm for controlling the. oestrous cycle in sheep by using cronolone-impregnated vaginal sponges was, however. short-lived. In the absence of A.I., ram fatigue and female selection by rams became a problem. Overcoming it requires approximately four times as many rams to cope with synchronized
VOL.
24
ewes. Another obstacle, as with cattle, is that a significant depression of fertility occurs in ewes at the synchronized oestrous period, with normal levels returning at the subsequent cycle. Quinlivan and Robinson (1967) have shown that the reduction in fertility of ewes is due. to an impairment of sperm transport. C~onolone-impregnated sponges have bee.n used successfully with and without PMS to stimulate earlier cyclical breeding during the latter part of the non-breeding se.ason (Wishart, 1966; Robinson and Smith, 1967). When combined with PMS, intra-vaginal sponges impregnated with the progestagen will control ovulation in cyclic ewes and will induce oestrus in anoestrous ewes, pe,rmitting A.I. at a predetermined time without reference to the signs of oestrus (McClelland and Quirke, 1971; Cooper et al., 1971). A slight variation of the me.thod is now being used very successfully in France, throughout the breeding and non-breeding seasons. The pessary is inserted and left in situ for 12 days. At the end of this pe,riod an iniection of PMS is given. The ewes are then hand-mated or inseminated and, a cycle's length after mating, a progesterone sample is taken to diagnose pregancy. If positive, parturition is induced using corticosteroids at 150 days. The lambs are early weaned and the ewes retreated. In conclusion, although only cronolone-impregnated sponges are mentioned above, the,re is little to choose in efficacy between these and sponges, impregnated with medroxy progesterone acetate. for the control of the reproductive cycle, in sheep. PIGS
As with other farm species, a convenient method of oestrus control would increase the numbe,r of pigs available to be inseminated from elite-performance and progeny-tested sires. Progesterone and synthetic steriods have not proved satisfactory; troubles have included variable dose response, pOQr synchronization of oestrus and ovulation, a tendencv to develop luteinized or cystic ovarian follicles, and reduced fertility at the synchronized heat. Although oestrogen or gonadotrophins increase the precision of
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ovulation control, no truly effective or practical method of using these, substances has been developed for the gilt or dry sow, A nOon-steroidal compound capable of suppressing pituitary gonadDtrophin release in pigs was described by Paget et ai, (1961), The substance, a thiourea derivative known as methallibure effectively synchronized oestrus in gilts when given daily mixed with food (Groves, 1967). However, the compound was eventually withdrawn from sale after the discovery by King (1969) that methallibure was a potent teratogenic agent when fed for a period of 20 days during the first 49 days of gestation, To date, no satisfactory treatment has been developed to take its place, USAGE IN SMALL ANIMALS BITCHES
The regular cyclic occurrence of heat, with its associated problems of haemorrhage, change of temperament and attraction Df dogs, has always worried and inconvenienced bitch owners, CDnsequently, the possible use of progestagens to control oestrus in bitches has been much studied (Bryan, 1960; Beard, 1961; Brodev and Fidler 1966; Christie and Bell, 1970; Cox, 1970) Employing these compounds for this purpose is, hDwever, a comparatively new aspect Oof veterinary practice and various complexities are only just being appreciated and explained, Many workers have shown that the bitch's uterus is particularly sensitive to the effects Oof progestagens and that these compounds can cause severe patholOogical changes (Dow, 1958; Anderson et ai" 1965; Whithers and Whitney, 1967), This matter is important to examine because it is fundamental to any discussion on the use of progestagens in bitches. For simplicity, the changes induced are of thre,e main types - cystic endometrial hyperplasia; mucome;tra; pyametra. Our studies have shown that the induction of uterine changes seems to depend not only on the, daily am aunt of prDgestagen given but also Dn the duration of its administratiDn (Austin and Evans, 1972). This emphasizes that
29
administration af progestagens to bitches is potentially dangerous and that strict attention should be paid to dosage, duration and method. Method is important because" ideally, veterinary surgeons· should be able to withdraw the drug if side-effects are observed, soo that pathological changes can be allDwed to reo:ress (Cox, 1970). ' The four phases Oof the bitch's oestrous cycle, are generally accepted to be 9 days of pro-Destrus, 9 of aestrus, 30 of metoestrus and 14 to 22 weeks of anoestrus. However, although the figures for the duration of each phase are reliable enough as averages, variation between individual animals can be considerable (Bell and Christie, 1971). Variation also occurs between animals in respect of external signs (bleeding and swelling), particularly at a first oestrus. Thankfully, ance a bitch has set a pattern it generally remains unchanged,although when several bitches are housed t~ether they can and do influence each other's cycles. Progestagens are used fOor bitches in two principal ways -during anoe.strus, tOo postpone the oestrus that would have naturally follDwed, - and, at the beginning of pro-oestrus, to suppress the signs of heat and prevent cOonception. Progestagen compounds are available as tablets for oral administration and as de,not injectians. The former can be used for both suppression of heat and postponement, the latter only for postponement. Depot injections are contraindicated during pro"oestrus, oestrus and metoestrus.
Postponement of Oestrus For this, depot inje,ctions of progestagen have the advantage Df convenience. Bitches can be kept in anoestrus by injections given at 6-mDnthly intervals. No client error can arise. On the othe,r hand, variable duration of actiDn (Cax, 1970) makes these injectiDn prDducts too unpredictable fDr use in breeding animals. More,over, the risk of inducing pathological uterine changes cannot be ignored. Numerous authors (Anderson ct al., 1965; Joshua, 1965; Brodey and Fidler 1966; Withers and Whitney. 1967) have drawn attention tOo this situation and,
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althDugh reduced dO's age has lessened the incidence Df side-effects, the risk has nDt been entirely eliminated because uterine changes are related not Dnly to the amount of progestagen given but also to' the duratiDn Df its presence in the animal. FurthermDre, the possibility of additive effect shDuld nDt be overlooked if injectiDns are repeated. Alternatively, oestrus can be PDstpDned safely and effectively by administering progestagens by mouth. A daily dose is usually given fDr a cDntrolled periDd af time beginning just befDre an immine.nt oestrus. If the cDrrect dose is given, bitches will not come on heat whilst the tablets are being taken and, provided they are given only for the recDmmended period of time, no adverse effects shDuld occur. The principles that apnly to this method Df using megestrol acetate are: Dosage - O.S mg/kg daily. CDurse begins preferably 14 days, but at le.ast 7, befDre the effect is required. If found to' have begun ta'O near prooestrus to prevent follicular maturatiDn, the 14-day recommendation alIDWS the Dwner to' change to' a suppressiDn course in time. DuratiDn Df CDurse should not exceed 40 days, which is well within safety limits. Recurrence af heat cannot be, predicted. Occurrence Df the next oestrus depends Dn the duration of the CDurse and the stage of anoestrus at which dosage be,gan. The delay is unlikely to be more thaw 6 months but usually, if oestrus were imminent, it is about 3 months. Repeat courses may be given, but not more than two in any 12 months. Control Df heat between courses may be readily exercise.d. No matter how soon heat recurs after a pDstponement course, a supnressiDn course may be given if required. Of CDurse, the owner must be. relied upon to' give the tablets, but the recDmmended dosage Df 0.5 mg/kg is sufficient to overcome all but gross sins of omission.
VOL. 24
Suppression of Heat
Only Dral administration is anplicable for this purpose, A number of slightly different dosage regimes are recommended for the three Dral progestagen products available in the U.K. but, basically, the principle is too give a short caurse usually 8 to 21 days beginning when the signs af heat are first seen. Experiments, trials and results frDm the field in recent years have shDwn that 8 daily dases of 2 mg/kg of megestrDI acetate, begun at the onset of pro-oestrus as judged by the presence of bleeding and swelling af the vulva, will suppress that heat. Praaestrus bleeding ceases usually after 2 ar 3 days and the bitch then staps being attractive to' dogs. The dDse of 2 mg/kg is about ten times that needed to prevent conception. David et ai. (1963) shDwed that, although doses of 0.2 mg/kg did not prevent pro-oestral bleeding and bitches accepted the male normally, pregnancy did not result. The effect Df correct megestrol acetate administration at the onset of heat is to cut out all the days of oestrus, reduce the days Df nrO"Destrus, and renlace metoestrus with the administration and excretion time Df the drug. Thus the cycle length is effectively shDrtened by 4 to 6 weeks. Figure 1 shows when, after successful dosage, the next oestrus is likely to occur in bitches with cycles of variDUS lengths. Note, however, that these are mathematical calculatiDns based on the normal duratiDn Df the various stages Df the oestrous cycle. When pro-oestrus, oestrus Dr metoestrus are longer in individual animals, the effect will be for oestrus to occur even earlier. In general, the heat subsequent to a prevention course Df megestrol acetate will occur 4 to 6 weeks earlier than if medication had not been given. This fact must be recognized, and imnressed upon the Dwner, Dtherwise some dissatisfaction cDuld arise. Timinf!, of Dosage
Information received from veterinary surgeons in the field has indicated that the main difficulty arising in practice is cDncerned with the timing of dasage, particularly in the. young bitch whase
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cycle pattern has not yet been established. In general, if the drug is given too early, possibly because the bitch's normal pro-oestrus is prolonged, oestrus can occur early - usually 2 to 3 months after the dosage is stopped. This happens because the premature dosing postpones rather than prevents oestrus. Alternatively, if the drug is given too late" rebound oestrus can occur. Such an oestrus is often not preceeded by pro-oestral haemorrhage, or one of short duration only occurs. The p,robable mechanism is that a follicle too large to become atre,tic is present when dosage starts and is thus
held suspended and prevented from rupturing by the blocking effect of the proge,stagen on LHsecretion. The effect on the ovaries in the case of correct, too early or too late administration of megestrol acetate is illustrated in Fig. 2. Bitches can conceive at e.ither an early or a rebound oestrus. In either instance the timing of dosage should be adjusted at subsequent oestrous periods and vaginal smears may need to be, examined for the more accurate detection of prooestrus (Shorr, 1941; Gier, 1960; Schutte, 1967; Evans and Savage, 1970; Simmons, 1970; Christie etal., 1972). Such abnormal,
7 Anoestrus N1etoestrus 30 days
6
Oestrus
9 days
Pro-oestrus 9 days 5
(j)
Progestogen leVels effective about 15 days
4
g I
~ 3
2
o
A A B
B
A
B
Normal oestrous cycle Effect of M.A, on recurrence
A
B
A
B
of oestrus
FIG. 1: Return to oestrus after correct administration of megestrol acetate for suppression of heat.
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undesirable occurrences can be kept at a minimum if each bitch is considered individually and if an effort is made to obtain a detailed history from the owner. However, despite all possible checks, biological variation occurs. With bitches that have previously responded abnormally and for which additional information cannot be obtained, a more prolonged dosage re.gimen might be advantage6us. Earlv oestrus and rebound oestrus arise comparatively infrequently if candidates for medication are selected. with care. Given time, an intelligent owner and an accurate case history, the veterinary surgeon can identify a suitable dosage for most animals. He can also recognize those animals that are not suitable candidates. Figure. 3 gives a guide to the possible actions in various situations. In respect of general safety and the effect on breeding, experiments have shown that me,gestrol actetate exerts no
VOL.
teratogenic effect, nor does it prolong pregnancy if inadvertantly administered at the time of conception. Bitches have produced healthy normal-sized litters whe.n mated following the administration of a suppression course, a postponement course, or a combination of the two (Evans, 1972). When progestagens are used for the convenience of the owner, the. possible problems should be discussed at the time. If the owner has no intention of using the animal for breeding, the oe.tter course may to advise spaying, although this is also not without its problems. As with so many medical matters. the oros and cons need to be weighed fo-r each individual case. In short, vete.rinary surgeo-ns can no-w select whichever method or combination of methods is best in any particular case. In some ins,tances the desirable sequence. mav be first to co-ntrol heat by use of progestagens until the bitch is older, then let her produce a litter or two, and subsequently have he.r spayed.
o o
NORMAL CYCLE not dosed
o
o
CORRECT TIMING
o
o
ADMINISTRATION TOO EARLY
ADMINISTRATiON roo LATE
Anoestrus
Pro.cetrus
_
D::in
FIG.
g
0
Oestrus
1::1:1 CNuJotion
24
Metoestrus
·D
-
Effectiw levels of MA. .
f~:c=:=:~:~:~:~l Corpus Jute~
[ Days]
U
2: Effect of administering megestrol acetate ut different stages of the oestrus cycle.
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Mature Bitch
~
(Previously medicated
success fu lly)
Maturo Bitch (Previously medicated unsuccessfully)
~
,'"-
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:-
Mature Bitch ~o
previous medication)
f-----
r-r-
~
Abnormal Cycle Housed with other Bitches
NORMAL (8 day) COURSE
:J
Normal Cycle
r-!---
==>
f
Vaginal Smear
r-
f----
~
'"
Grossly abnormal Cycle
-r:> .,
Very short Cycle Diabetic
I\OT A CANDIDATE 1st Season
PROLONGED (4 + 16 days)
COl!=
I
~
FIG. 3: Suppression of heat -
decision chart for cd ministration of megestroi acetate.
ACKNOWLEDGEMENTS
CATS
Limitations of space permit me only to say briefly, of cats, that suppression and postponement of heat can be successfully achieved by the. use of either injectable or oral progestagens. When advising on the likely effects in this species, the veterinary surgeon must remembe.r that the cat is seasonally polyoestrous and that this factor can influence very considerably the time-interval between ce.ssation of dosage and the subsequent oestrus. CONCLUSION
In conclusion my hope is that this paper will be helpful in shedding some light on the rather complex and confusing subject of the use of progestagens in veterinary practice. Let me. stress, however, that these compounds are no more than additions to the veterinary surgeon's armoury, for specific purposes but not problem-free. They should be employed always with caution and with understanding.
I wish to thank Dr J. C. Hadley, H. G. Gilbert, A. M. R. Nelson, and D. F. Wishart for their valuable help in providing data, and P. G. Hendy and Mrs J. Jemmett, for their assisstance in producing diagrams and reviewing the text. REFERENCES Anderson, R. K.; Gilmore, C. E.; Schnelle, G. B. (1975): Utero-ovarian disorders associated with use of medroxyprogesterone in dogs. /. Am. vet. Med. Ass., 146: 1311-6. Austin, A. R.; Evans, J. M. (1972): Correspondence_ Vet. Rec., 191: 77. Beard, D. C. (1961): Hydroxyprogesterone acetate: use in estrogenic and progesterogenic states in the bitch. Small Anim. Clin., 1: 215-8. Bell, E. T.; Christie, D. W. (1971): Duration of proestrus, oestrus and vulval bleeding in the Beagle bitch. Br. vet. /., 127: xxv-xxvii. Brodey, R. S.; Fidler, I. J. (1966): Clinical and pathologic findings in bitches treated with progestational compounds. J. Am. vet. med. Ass., 149: 1406-\5.
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Bryan, H. J. (1960): Utility of 17 (l-acetoxyprogesterone in delaying estrus in the bitch. Proc. Soc. expo Bioi. Med., 105: 23-6. Christian, R. E.; Casida, L. E. (1948): The effects of progesterone in altering the estrus cycle ·Jf the cow. f. Anim. Sci., 7: 540. Christie, D. W.; Bailey, J. B.; Bell, E. T. (1972): Classification of cell types in vaginal smears during the canine oestrous cycle. Br. vet. f., 128: 301-10. Christie, D. W.; Bell, E. T. (1970): The use cf progestogens to control reproductive function 111 the bitch. Anim. Breed. Abstr., 38: 1-21. Cooper, R. J.; Wallace, D. N.; Wishart, D. P.; Hoskin, B. D. (1971): Artificial insemination cf sheep following induction of oestrus in the non-breeding season. Vet. Rec., 88: 381-3. Cox, J. E. (1970). Progestagens in bitches: A review. /. small Anim. Pract., 11: 759-78. David, A.; Edwards, K.; Fellows, K. P.; Plummer, J. M. (1963): Anti-ovulatory and other biological properties of megestroI acetate. f. Reprod. Fert .. 5: 331-6. Dow, C., (1958): The cystic hyperplasia- pyometra complex in the bitch. Vet. R.cc., 70: 1102-8. Evans, J. M. (1972): Oestrus control in the bitch. VII Int. Kongr. F. Tier. Fortpflanzung. II 106973. Evans, J. M.; Savage, T. J. (1970). The collection of vaginal smears from bitches. Vet. Rec., 87: 5989. Gier, H. T. (1960). Estrous cycle in the bitch: Vaginal fluids. Vet. Scope, 5: 1-7. Groves, T. W. (1967): MethaIlibure in the synchronisation of oestrus in gilts. Vet. Rec., 80: 470-5. Haas, K. B. (1961): Delaying estrus in the bitch. Illinois Vet., 4: 1-5. Joshua, Joan, O. (1965): The use of medroxyprogesterone. Vet. Rec., 77: 1192. King, G. J. (1969): Deformities in piglets following administration of methallibureduring specific stages of gestation. /. Reprod. Fert., 20: 551-3. McClelland, T. H.; Quirke, J. F. (1971): Artificial insemination and natural service at a predetermined time in cyclic sheep trea.ted with SC9880 - progesterone sponges. f. Anim. Prod., 13: 323-7.
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Paget, G. E.; Walpole, A. L.; Richardson, D. N. (1961): Non-steriod inhibitors of pituitary gonadotrophic function. Naturc, Lond.. 192: 1191-2. Quinlivan, T. D.; Robinson, T. J. (1967): The number of spermatozoa in the fallopian tubes of ewes at intervals after artificial insemination following withdrawal of SC9880 - impregnated intravaginal sponges. Paper XIII, pp. 177-94, in The Control of the Ovarian Cycle in the Sheep (Ed. T. J. Robinson). Sydney Univ. Press, Sydney. Robinson, T. J.; Smith, J. F. (1967). The evaluation of SC9880 - impregnated intravaginal sponges used with or without PMS for the advancement of the breeding season in British Breed Ewes. Paper X, pp. 144-57, in The Control of the Ovarian Cycle in the Sheep (Ed. T. J. Robinson). Sydney Univ. Press, Sydney. Schutte, A. P. (1967): Canine vaginal cytology-I. Technique and cytological morphology. f. small Anim. Pract., 8: 301-6. Shorr, E. (1941). A new technic for staining vaginal smears: Ill, A single difTerential stain. Science, 94: 545-6. Sim;n:;ns, J. (1970): The vaginal smcar and its practical application. Vet. Med. Small Anim. Clin., 65: 369-73. Wiltbank, J. N.; Zimmerman, D. R.; Ingalls, J. E.; Rowden, W. W. (1965): Use of progcstational compounds alone or in combination with estrogen for sy:nchronization of estrus. f. Anim. Sci., 24: 990-4. Wishart, D. F. (1966): The induction of earlier breeding activity in sheep: A comparison between the use of vasectomised rams and use of intravaginal pessaries impregnated with a new progestin. Vet. Rec., 79: 356-8. Wishart, D. F.; Young, I. M. (1974): Artificial insemination of progestin (SC21009) -treated cattle at predetermined times. Vet Rec., 95: 503-8. Withers, A. R.; Whitney, J. C. (1967): The response of the bitch to treatment with medroxyprogesterone acetate. f. small Anim. Pract., ~: 265-71.
New Zealand Veterinary Journal Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tnzv20
The veterinary uses of progestagens J.M. Evans M.R.C.V.S.
a
a
Glaxo Laboratories Ltd , Greenford, Middlesex, England Published online: 23 Feb 2011.
To cite this article: J.M. Evans M.R.C.V.S. (1976) The veterinary uses of progestagens, New Zealand Veterinary Journal, 24:3, 25-34 To link to this article: http://dx.doi.org/10.1080/00480169.1976.34277
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NEW ZEALAND VETERINARY JOURNAL VOLUME 24
MARCH, 1976
NUMBER 3
THE VETERINARY USES OF PROGESTAGENS* J. M. EVANSt
cycle, noting their effect on target organs and on each other.
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INTRODUCTION
THIS PAPER is very relevant to the theme of "Manipulation' of Populations", as set by the 1975 N.Z.V.A. Conference, because it concerns the use of progestagens in preventing conception and controlling ovula>tion for farm and domestic animals. It discusses first the basic principles behind the use of progestagens and then, by species, examines the applications that h~lVe been developed and some of the difficulties that have arisen. The periodicity of the oestrous cycle divides animals broadly into three groups: Polyoestrous - e.g. cows seasonally polyoestrous - e.g., ewes and monOestrous - e.g., bitches. Except when pregnancy or Dseudo-pregnancy intervenes, polyoestrous animals invariably follow the sequence of oestrus to metoestrus to dioestrus to pro-oestrus to oestrus. Seasonally polyoestrus animal occafrom metoestrus sionally proceed through a period of anoestrus before returning to pro-oestrus and on to oestrus. In monoestrous animals metoestrus is followed by anoestrus as part of their normal cycle. Parturition may be followe.d by pro-oestrus or may be preceded by a period of anoestrus. Pseudopregnancy in cats may occur after any non-fertile ovulation, whether brought about by a sterile mating, mechanical stimulation of the cervix, or hormonal treatment. Tables 1 and 2 list the hormones involve.d in bringing about the oestrous
PROGEST AGENS -
SYNTHESIS AND ROLE
Progesterone was first isolated from corpora lutea and purified in the midthirties. Since the discovery, in 1937, that in.iections of progesterone will inhibit ovulation in the rabbit, many derivatives have been synthesized in a quest for greater potency, slowe,I" excretion and oral activity. These synthetic compounds, which mimic the actions of progesterone, are called progestagens (or less commonly, progestins). Basically they fall into two main groups, oestranes and pregnanes. A recently discovered compound, norgestomet, is unique being a 19-nor pregnane. It can be regarded as a cross between oe,stranes and pregnanes. Of the pregnanes, megestrol acetate and medroxyprogesterone acetate have been mostly used in the bitch. Me:lengestrol acetate is particularly potent in cattle. In general, progestagens have numerous physiological actions but the following are the most important:
·Paper presented to the NZ. Veterinary Association Conference, February 1975. tT. M. EVANS. M.R.C.V.S., Glaxo Lahoratories Ltd. Greenford, Middlesex, England.
-
They inhibit FSH release and thus probably suppress the growth of ovarian follicles and oestrogen production. preventing the internal and external behaviour changes characteristic of oestrus.
-
They inhibit LH release and thus presumably prevent ovulation, organization of the corpora lutea and release of progesterone. They inhibit the release of luteotropic factors and so may affect the life of the corpus luteum.
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VOL. 24
TABLE 1; THE ACTION OF GONADOTROPHINS CONCERNED IN THE OESTROUS CYCLI. (Modified from Haas, 1961) Hormones
Follicle
FSH
Follicle Corpus luteum
LH Luteotrophic factors (prolactin)
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Target Organs
Corpus luteum Mammary glands
Effect
Stimulates oestrogen secretion Stimulates follicle growth Ovulation and formation of corpus luteum Initiates progesterone secretion
----------------------
Maintains progesterone secretion Stimulates lactation
TABLE 2; THE ACTION OF SEX HORMONES CONCERNED IN THE OESTROUS CYCLE (Modified from Haas, 1961) Hormones
Target Organs
Effect
-------------------------------------------------
Oestrogen
Progesterone
Anterior pituitary Endometrium Cervix Vagina Mammary glands Anterior pituitary Endometrium Mammary glands
They exert a peripheral antioestrogenic effect which, in bitches, may prevent vaginal haemorrhage during pro-oestrus. They cause thickening of vaginal mucus, rendering it hostile to spermatozoa. They produce a endometrium.
secretory uterine
They delay, in some species and in certain circumstances, the implantation of the fertilized ovum. They maintain pregnancy. Not all progestagens have. all the actions listed above; their relative activity in respect of each function may vary from compound to compound and species to species. Neverthe.Iess, their multiplicity of actions gives progestagens many potential applications in veterinary medicine. They can be used as contraceptive.s; to reduce libido in both males and females; to control the oestrouscycle -- i.e., synchronize oestrus, posipone oestrus, suppress heat; to trear false pregnancy in bitches; to control the
Positive and negative feedback Proliferation Relaxation Proliferation of lining Duct proliferation Negative feedback Progestational effect Alveolar proliferation
growth of certain tumors; to treat some skin conditions. These indications are listed for completeness but the brief here is to consider the use of proge.stagens only in manipulating the oestrous cycle -- i.e., to synchronize oestrus in,large animals, and to postpone it and suppress heat in small animals. APPLICATION IN LARGE ANIMALS CATTLE
The detection of heat in dairy cows is time-consuming and often difficult, because. in some animals the manifestations are not very marked. With beef herds the problem is further complicated by the impracticality of examining cows daily because the periods of oestrus are often very short and may occur overnight. Farmers in both industries, therefore, would welcome a technique whereby cows could be inseminated on a predetermined date and at a specified time without need to observe oestrous behaviour. Ideally the method should be simple to administer arid reasonably cheap: moreover, conce.ption rates following its use
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should not be lower than those normally obtained. The advantages of being able to inseminate at a predetermined time are: Labour saving - no oestrus dete:ction predictable calving dates; planned breeding programmes are possible; use of top quality A.1. bulls is facilitated; insemination is cheaper; compact calving season eases re.aring and ,fattening; seasonal milk production is eased. Oestrus control in cattle was first achieved by Christian and Casida (1948). These workers used daily injections of the naturally occurring hormone, progesterone. With the availability of proge.stagens many researchers all over the world set out to establish whether the compounds could be used to contrO'I ovulation very precisely and so satisfy the. need already mentioned. The literature is now filled with detailed descriptions O'f their experiments. In general, however, the method that has been fO'Ilowed is to give the, prO'gestagen to all the herd for a period equivalent to the life soan of the corpus luteum - i.e., 18 to 21 days. This has the effect of inhibiting oestrus if due whilst in other animals the corpora lutue,a regress spontaneously. The result is that, when the dosing period ends, the ovaries of all have no comora lutea, and the animals are ready to exhibit oestrus and ovulate synchronO'usly. Most experimenters have found that cows show oestrus 4 to 6 days after such treatment is withdrawn. However, at this first "rebound oestrus" fertility is lowered by about 20 to 55 %, depending on the progestagen used. Conception rates return to normality at the second oestrus following treatment, but the animals are not then so well synchronized because cycle length varies be,tween cows. All workers encountered this difficulty, regardless of the progestagen used and despite administering the compO'unds in a variety of ingenious and often impractical ways. Vaginal spon~es and implants were employed in the belief that steady progestagen levels and a sham cut-off at the end of treatment were necessary. HO'wever, such methOods did not helo and, fOor a time, the difficultv was thought to defy resOolution simply because agents designed basically as contraceptives were being used to
27
contrO'I oestrus. Even so, a number of workers persisted. They investigated using progestagens in the ways described but with injections of human chorionic gonadotrophin given after the last dose. Such modifications were, hO'wever, found to interfere with normal expression of oestrus and led to very low levels of fertility. The ideal technique, remained elusive and, while some continued their efforts to resolve the problem, others increasingly abandoned proge,stagens in favour of the emerging prostaglandins. The decisive breakthrough came when Wiltbank et al. (1965) showed that fertility is unimpaired if the duration of progestagen administration is reduced to 12 or 9 days. This period is not long enough, however, for the dosage to synchronize all animals unless existing corpora lutea can be made to regress more rapidly than normal. Wiltbank showed that oestradiol vale,rate had the desired luteolytic effect from day 6 or 7 of the cycle onwards. By using an injectiO'n of 5 mg oestradiol valerate with a 9-day administration of norgestomet, he obtained an oe.strus response of approximately 80%, with normal levels of fertility in the responding animals. The hunt then started fOor a luteO'lytic agent that was effective early in the cycle. Like oestrodiol valerate, prostaglandins were. found to be luteolytic only after days 5 O'r 6 O'f the cycle. The progestagen norgestomet is antiluteotrophic and, in combination with oestradiO'I valerate, was found to PO'tentiate the, oestrogen's luteolytic effect. This finding really paved the way for the development of a svstem recently reported by Wishart and Young (1974) whereby a farmer can have, his heifers inseminated on a "bv the clock" basis without the need for detectiO'n O'f oestrus and without any adverse effect on fertility. These worke,rs describe exueriments which show that delayed embryo cleavage is a majO'r factO'r responsible for the lowered fertility associated with 18to 21-day administration of progestagens. This did not occur following a 9dav treatment periO'd. The authors also noted that, if !!ood results are to be obtained, onlv bulls of proven high fertility shO'uld be used and the cows should be maintained with sound nutrition.
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Following the alternative route, other worke.rs have shown that two injections of prostaglandin F 2(J. or its synthetic analogues can be used to give a similar effect, but double insemination is needed if heat detection is to be avoided. The method of using norge.stomet, as described above, is somewhat complex but does offer three distinct advantages: First, it will not cause abortion in cattle already pregnant. Secondly, it can be used to induce a fertile oestrus in mepuberal and anoestrous heifers, and possibly also in acyc1ical beef cattle. Finally, it is free from a possible misuse hazard - namely, that of be.ing illegally adopted to induce abortion in women. SHEEP
The seasonal reproductive cycle of the ewe sets the seasonal pattern of lamb sales. In the northemhemisphere a premium is p'aid for spring~marketed lambs. The facility of being able to advance the breeding season bv one or two months is clearly financially advantageous to the farmer. Apart from using progestagens with ewes in late anoestrus, the compounds also have an application in the control of oestrus and ovulation of cyclical ewes within the breeding season, and in truly anoestrous ewes. Theoretically at le,ast, progestagens make A.I. or natural mating programmes possible at any time of the year, and enable lambings to be synchronized. The latter offe.rs advantages in respect of employment of staff, lamb survival, usage of pasture, handling for vaccination, marketing, and so on. Thanks principally to the work of Professor Robinson and his colleagues at Sydney University and the development of polyurethane sponge pessaries impregnated with cronolone, the theoretical uses of progestagens in ewe management can now be practical achievements. Early enthusiasm for controlling the. oestrous cycle in sheep by using cronolone-impregnated vaginal sponges was, however. short-lived. In the absence of A.I., ram fatigue and female selection by rams became a problem. Overcoming it requires approximately four times as many rams to cope with synchronized
VOL.
24
ewes. Another obstacle, as with cattle, is that a significant depression of fertility occurs in ewes at the synchronized oestrous period, with normal levels returning at the subsequent cycle. Quinlivan and Robinson (1967) have shown that the reduction in fertility of ewes is due. to an impairment of sperm transport. C~onolone-impregnated sponges have bee.n used successfully with and without PMS to stimulate earlier cyclical breeding during the latter part of the non-breeding se.ason (Wishart, 1966; Robinson and Smith, 1967). When combined with PMS, intra-vaginal sponges impregnated with the progestagen will control ovulation in cyclic ewes and will induce oestrus in anoestrous ewes, pe,rmitting A.I. at a predetermined time without reference to the signs of oestrus (McClelland and Quirke, 1971; Cooper et al., 1971). A slight variation of the me.thod is now being used very successfully in France, throughout the breeding and non-breeding seasons. The pessary is inserted and left in situ for 12 days. At the end of this pe,riod an iniection of PMS is given. The ewes are then hand-mated or inseminated and, a cycle's length after mating, a progesterone sample is taken to diagnose pregancy. If positive, parturition is induced using corticosteroids at 150 days. The lambs are early weaned and the ewes retreated. In conclusion, although only cronolone-impregnated sponges are mentioned above, the,re is little to choose in efficacy between these and sponges, impregnated with medroxy progesterone acetate. for the control of the reproductive cycle, in sheep. PIGS
As with other farm species, a convenient method of oestrus control would increase the numbe,r of pigs available to be inseminated from elite-performance and progeny-tested sires. Progesterone and synthetic steriods have not proved satisfactory; troubles have included variable dose response, pOQr synchronization of oestrus and ovulation, a tendencv to develop luteinized or cystic ovarian follicles, and reduced fertility at the synchronized heat. Although oestrogen or gonadotrophins increase the precision of
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ovulation control, no truly effective or practical method of using these, substances has been developed for the gilt or dry sow, A nOon-steroidal compound capable of suppressing pituitary gonadDtrophin release in pigs was described by Paget et ai, (1961), The substance, a thiourea derivative known as methallibure effectively synchronized oestrus in gilts when given daily mixed with food (Groves, 1967). However, the compound was eventually withdrawn from sale after the discovery by King (1969) that methallibure was a potent teratogenic agent when fed for a period of 20 days during the first 49 days of gestation, To date, no satisfactory treatment has been developed to take its place, USAGE IN SMALL ANIMALS BITCHES
The regular cyclic occurrence of heat, with its associated problems of haemorrhage, change of temperament and attraction Df dogs, has always worried and inconvenienced bitch owners, CDnsequently, the possible use of progestagens to control oestrus in bitches has been much studied (Bryan, 1960; Beard, 1961; Brodev and Fidler 1966; Christie and Bell, 1970; Cox, 1970) Employing these compounds for this purpose is, hDwever, a comparatively new aspect Oof veterinary practice and various complexities are only just being appreciated and explained, Many workers have shown that the bitch's uterus is particularly sensitive to the effects Oof progestagens and that these compounds can cause severe patholOogical changes (Dow, 1958; Anderson et ai" 1965; Whithers and Whitney, 1967), This matter is important to examine because it is fundamental to any discussion on the use of progestagens in bitches. For simplicity, the changes induced are of thre,e main types - cystic endometrial hyperplasia; mucome;tra; pyametra. Our studies have shown that the induction of uterine changes seems to depend not only on the, daily am aunt of prDgestagen given but also Dn the duration of its administratiDn (Austin and Evans, 1972). This emphasizes that
29
administration af progestagens to bitches is potentially dangerous and that strict attention should be paid to dosage, duration and method. Method is important because" ideally, veterinary surgeons· should be able to withdraw the drug if side-effects are observed, soo that pathological changes can be allDwed to reo:ress (Cox, 1970). ' The four phases Oof the bitch's oestrous cycle, are generally accepted to be 9 days of pro-Destrus, 9 of aestrus, 30 of metoestrus and 14 to 22 weeks of anoestrus. However, although the figures for the duration of each phase are reliable enough as averages, variation between individual animals can be considerable (Bell and Christie, 1971). Variation also occurs between animals in respect of external signs (bleeding and swelling), particularly at a first oestrus. Thankfully, ance a bitch has set a pattern it generally remains unchanged,although when several bitches are housed t~ether they can and do influence each other's cycles. Progestagens are used fOor bitches in two principal ways -during anoe.strus, tOo postpone the oestrus that would have naturally follDwed, - and, at the beginning of pro-oestrus, to suppress the signs of heat and prevent cOonception. Progestagen compounds are available as tablets for oral administration and as de,not injectians. The former can be used for both suppression of heat and postponement, the latter only for postponement. Depot injections are contraindicated during pro"oestrus, oestrus and metoestrus.
Postponement of Oestrus For this, depot inje,ctions of progestagen have the advantage Df convenience. Bitches can be kept in anoestrus by injections given at 6-mDnthly intervals. No client error can arise. On the othe,r hand, variable duration of actiDn (Cax, 1970) makes these injectiDn prDducts too unpredictable fDr use in breeding animals. More,over, the risk of inducing pathological uterine changes cannot be ignored. Numerous authors (Anderson ct al., 1965; Joshua, 1965; Brodey and Fidler 1966; Withers and Whitney. 1967) have drawn attention tOo this situation and,
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althDugh reduced dO's age has lessened the incidence Df side-effects, the risk has nDt been entirely eliminated because uterine changes are related not Dnly to the amount of progestagen given but also to' the duratiDn Df its presence in the animal. FurthermDre, the possibility of additive effect shDuld nDt be overlooked if injectiDns are repeated. Alternatively, oestrus can be PDstpDned safely and effectively by administering progestagens by mouth. A daily dose is usually given fDr a cDntrolled periDd af time beginning just befDre an immine.nt oestrus. If the cDrrect dose is given, bitches will not come on heat whilst the tablets are being taken and, provided they are given only for the recDmmended period of time, no adverse effects shDuld occur. The principles that apnly to this method Df using megestrol acetate are: Dosage - O.S mg/kg daily. CDurse begins preferably 14 days, but at le.ast 7, befDre the effect is required. If found to' have begun ta'O near prooestrus to prevent follicular maturatiDn, the 14-day recommendation alIDWS the Dwner to' change to' a suppressiDn course in time. DuratiDn Df CDurse should not exceed 40 days, which is well within safety limits. Recurrence af heat cannot be, predicted. Occurrence Df the next oestrus depends Dn the duration of the CDurse and the stage of anoestrus at which dosage be,gan. The delay is unlikely to be more thaw 6 months but usually, if oestrus were imminent, it is about 3 months. Repeat courses may be given, but not more than two in any 12 months. Control Df heat between courses may be readily exercise.d. No matter how soon heat recurs after a pDstponement course, a supnressiDn course may be given if required. Of CDurse, the owner must be. relied upon to' give the tablets, but the recDmmended dosage Df 0.5 mg/kg is sufficient to overcome all but gross sins of omission.
VOL. 24
Suppression of Heat
Only Dral administration is anplicable for this purpose, A number of slightly different dosage regimes are recommended for the three Dral progestagen products available in the U.K. but, basically, the principle is too give a short caurse usually 8 to 21 days beginning when the signs af heat are first seen. Experiments, trials and results frDm the field in recent years have shDwn that 8 daily dases of 2 mg/kg of megestrDI acetate, begun at the onset of pro-oestrus as judged by the presence of bleeding and swelling af the vulva, will suppress that heat. Praaestrus bleeding ceases usually after 2 ar 3 days and the bitch then staps being attractive to' dogs. The dDse of 2 mg/kg is about ten times that needed to prevent conception. David et ai. (1963) shDwed that, although doses of 0.2 mg/kg did not prevent pro-oestral bleeding and bitches accepted the male normally, pregnancy did not result. The effect Df correct megestrol acetate administration at the onset of heat is to cut out all the days of oestrus, reduce the days Df nrO"Destrus, and renlace metoestrus with the administration and excretion time Df the drug. Thus the cycle length is effectively shDrtened by 4 to 6 weeks. Figure 1 shows when, after successful dosage, the next oestrus is likely to occur in bitches with cycles of variDUS lengths. Note, however, that these are mathematical calculatiDns based on the normal duratiDn Df the various stages Df the oestrous cycle. When pro-oestrus, oestrus Dr metoestrus are longer in individual animals, the effect will be for oestrus to occur even earlier. In general, the heat subsequent to a prevention course Df megestrol acetate will occur 4 to 6 weeks earlier than if medication had not been given. This fact must be recognized, and imnressed upon the Dwner, Dtherwise some dissatisfaction cDuld arise. Timinf!, of Dosage
Information received from veterinary surgeons in the field has indicated that the main difficulty arising in practice is cDncerned with the timing of dasage, particularly in the. young bitch whase
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cycle pattern has not yet been established. In general, if the drug is given too early, possibly because the bitch's normal pro-oestrus is prolonged, oestrus can occur early - usually 2 to 3 months after the dosage is stopped. This happens because the premature dosing postpones rather than prevents oestrus. Alternatively, if the drug is given too late" rebound oestrus can occur. Such an oestrus is often not preceeded by pro-oestral haemorrhage, or one of short duration only occurs. The p,robable mechanism is that a follicle too large to become atre,tic is present when dosage starts and is thus
held suspended and prevented from rupturing by the blocking effect of the proge,stagen on LHsecretion. The effect on the ovaries in the case of correct, too early or too late administration of megestrol acetate is illustrated in Fig. 2. Bitches can conceive at e.ither an early or a rebound oestrus. In either instance the timing of dosage should be adjusted at subsequent oestrous periods and vaginal smears may need to be, examined for the more accurate detection of prooestrus (Shorr, 1941; Gier, 1960; Schutte, 1967; Evans and Savage, 1970; Simmons, 1970; Christie etal., 1972). Such abnormal,
7 Anoestrus N1etoestrus 30 days
6
Oestrus
9 days
Pro-oestrus 9 days 5
(j)
Progestogen leVels effective about 15 days
4
g I
~ 3
2
o
A A B
B
A
B
Normal oestrous cycle Effect of M.A, on recurrence
A
B
A
B
of oestrus
FIG. 1: Return to oestrus after correct administration of megestrol acetate for suppression of heat.
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undesirable occurrences can be kept at a minimum if each bitch is considered individually and if an effort is made to obtain a detailed history from the owner. However, despite all possible checks, biological variation occurs. With bitches that have previously responded abnormally and for which additional information cannot be obtained, a more prolonged dosage re.gimen might be advantage6us. Earlv oestrus and rebound oestrus arise comparatively infrequently if candidates for medication are selected. with care. Given time, an intelligent owner and an accurate case history, the veterinary surgeon can identify a suitable dosage for most animals. He can also recognize those animals that are not suitable candidates. Figure. 3 gives a guide to the possible actions in various situations. In respect of general safety and the effect on breeding, experiments have shown that me,gestrol actetate exerts no
VOL.
teratogenic effect, nor does it prolong pregnancy if inadvertantly administered at the time of conception. Bitches have produced healthy normal-sized litters whe.n mated following the administration of a suppression course, a postponement course, or a combination of the two (Evans, 1972). When progestagens are used for the convenience of the owner, the. possible problems should be discussed at the time. If the owner has no intention of using the animal for breeding, the oe.tter course may to advise spaying, although this is also not without its problems. As with so many medical matters. the oros and cons need to be weighed fo-r each individual case. In short, vete.rinary surgeo-ns can no-w select whichever method or combination of methods is best in any particular case. In some ins,tances the desirable sequence. mav be first to co-ntrol heat by use of progestagens until the bitch is older, then let her produce a litter or two, and subsequently have he.r spayed.
o o
NORMAL CYCLE not dosed
o
o
CORRECT TIMING
o
o
ADMINISTRATION TOO EARLY
ADMINISTRATiON roo LATE
Anoestrus
Pro.cetrus
_
D::in
FIG.
g
0
Oestrus
1::1:1 CNuJotion
24
Metoestrus
·D
-
Effectiw levels of MA. .
f~:c=:=:~:~:~:~l Corpus Jute~
[ Days]
U
2: Effect of administering megestrol acetate ut different stages of the oestrus cycle.
1976
33
NEW ZEALAND VETERINARY JOURNAL
Mature Bitch
~
(Previously medicated
success fu lly)
Maturo Bitch (Previously medicated unsuccessfully)
~
,'"-
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:-
Mature Bitch ~o
previous medication)
f-----
r-r-
~
Abnormal Cycle Housed with other Bitches
NORMAL (8 day) COURSE
:J
Normal Cycle
r-!---
==>
f
Vaginal Smear
r-
f----
~
'"
Grossly abnormal Cycle
-r:> .,
Very short Cycle Diabetic
I\OT A CANDIDATE 1st Season
PROLONGED (4 + 16 days)
COl!=
I
~
FIG. 3: Suppression of heat -
decision chart for cd ministration of megestroi acetate.
ACKNOWLEDGEMENTS
CATS
Limitations of space permit me only to say briefly, of cats, that suppression and postponement of heat can be successfully achieved by the. use of either injectable or oral progestagens. When advising on the likely effects in this species, the veterinary surgeon must remembe.r that the cat is seasonally polyoestrous and that this factor can influence very considerably the time-interval between ce.ssation of dosage and the subsequent oestrus. CONCLUSION
In conclusion my hope is that this paper will be helpful in shedding some light on the rather complex and confusing subject of the use of progestagens in veterinary practice. Let me. stress, however, that these compounds are no more than additions to the veterinary surgeon's armoury, for specific purposes but not problem-free. They should be employed always with caution and with understanding.
I wish to thank Dr J. C. Hadley, H. G. Gilbert, A. M. R. Nelson, and D. F. Wishart for their valuable help in providing data, and P. G. Hendy and Mrs J. Jemmett, for their assisstance in producing diagrams and reviewing the text. REFERENCES Anderson, R. K.; Gilmore, C. E.; Schnelle, G. B. (1975): Utero-ovarian disorders associated with use of medroxyprogesterone in dogs. /. Am. vet. Med. Ass., 146: 1311-6. Austin, A. R.; Evans, J. M. (1972): Correspondence_ Vet. Rec., 191: 77. Beard, D. C. (1961): Hydroxyprogesterone acetate: use in estrogenic and progesterogenic states in the bitch. Small Anim. Clin., 1: 215-8. Bell, E. T.; Christie, D. W. (1971): Duration of proestrus, oestrus and vulval bleeding in the Beagle bitch. Br. vet. /., 127: xxv-xxvii. Brodey, R. S.; Fidler, I. J. (1966): Clinical and pathologic findings in bitches treated with progestational compounds. J. Am. vet. med. Ass., 149: 1406-\5.
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NEW ZEALAND VETERINARY JOURNAL
Bryan, H. J. (1960): Utility of 17 (l-acetoxyprogesterone in delaying estrus in the bitch. Proc. Soc. expo Bioi. Med., 105: 23-6. Christian, R. E.; Casida, L. E. (1948): The effects of progesterone in altering the estrus cycle ·Jf the cow. f. Anim. Sci., 7: 540. Christie, D. W.; Bailey, J. B.; Bell, E. T. (1972): Classification of cell types in vaginal smears during the canine oestrous cycle. Br. vet. f., 128: 301-10. Christie, D. W.; Bell, E. T. (1970): The use cf progestogens to control reproductive function 111 the bitch. Anim. Breed. Abstr., 38: 1-21. Cooper, R. J.; Wallace, D. N.; Wishart, D. P.; Hoskin, B. D. (1971): Artificial insemination cf sheep following induction of oestrus in the non-breeding season. Vet. Rec., 88: 381-3. Cox, J. E. (1970). Progestagens in bitches: A review. /. small Anim. Pract., 11: 759-78. David, A.; Edwards, K.; Fellows, K. P.; Plummer, J. M. (1963): Anti-ovulatory and other biological properties of megestroI acetate. f. Reprod. Fert .. 5: 331-6. Dow, C., (1958): The cystic hyperplasia- pyometra complex in the bitch. Vet. R.cc., 70: 1102-8. Evans, J. M. (1972): Oestrus control in the bitch. VII Int. Kongr. F. Tier. Fortpflanzung. II 106973. Evans, J. M.; Savage, T. J. (1970). The collection of vaginal smears from bitches. Vet. Rec., 87: 5989. Gier, H. T. (1960). Estrous cycle in the bitch: Vaginal fluids. Vet. Scope, 5: 1-7. Groves, T. W. (1967): MethaIlibure in the synchronisation of oestrus in gilts. Vet. Rec., 80: 470-5. Haas, K. B. (1961): Delaying estrus in the bitch. Illinois Vet., 4: 1-5. Joshua, Joan, O. (1965): The use of medroxyprogesterone. Vet. Rec., 77: 1192. King, G. J. (1969): Deformities in piglets following administration of methallibureduring specific stages of gestation. /. Reprod. Fert., 20: 551-3. McClelland, T. H.; Quirke, J. F. (1971): Artificial insemination and natural service at a predetermined time in cyclic sheep trea.ted with SC9880 - progesterone sponges. f. Anim. Prod., 13: 323-7.
VOL. 24
Paget, G. E.; Walpole, A. L.; Richardson, D. N. (1961): Non-steriod inhibitors of pituitary gonadotrophic function. Naturc, Lond.. 192: 1191-2. Quinlivan, T. D.; Robinson, T. J. (1967): The number of spermatozoa in the fallopian tubes of ewes at intervals after artificial insemination following withdrawal of SC9880 - impregnated intravaginal sponges. Paper XIII, pp. 177-94, in The Control of the Ovarian Cycle in the Sheep (Ed. T. J. Robinson). Sydney Univ. Press, Sydney. Robinson, T. J.; Smith, J. F. (1967). The evaluation of SC9880 - impregnated intravaginal sponges used with or without PMS for the advancement of the breeding season in British Breed Ewes. Paper X, pp. 144-57, in The Control of the Ovarian Cycle in the Sheep (Ed. T. J. Robinson). Sydney Univ. Press, Sydney. Schutte, A. P. (1967): Canine vaginal cytology-I. Technique and cytological morphology. f. small Anim. Pract., 8: 301-6. Shorr, E. (1941). A new technic for staining vaginal smears: Ill, A single difTerential stain. Science, 94: 545-6. Sim;n:;ns, J. (1970): The vaginal smcar and its practical application. Vet. Med. Small Anim. Clin., 65: 369-73. Wiltbank, J. N.; Zimmerman, D. R.; Ingalls, J. E.; Rowden, W. W. (1965): Use of progcstational compounds alone or in combination with estrogen for sy:nchronization of estrus. f. Anim. Sci., 24: 990-4. Wishart, D. F. (1966): The induction of earlier breeding activity in sheep: A comparison between the use of vasectomised rams and use of intravaginal pessaries impregnated with a new progestin. Vet. Rec., 79: 356-8. Wishart, D. F.; Young, I. M. (1974): Artificial insemination of progestin (SC21009) -treated cattle at predetermined times. Vet Rec., 95: 503-8. Withers, A. R.; Whitney, J. C. (1967): The response of the bitch to treatment with medroxyprogesterone acetate. f. small Anim. Pract., ~: 265-71.
