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The treatment of noncycling mares by oral application of chlormadinone acetate (CAP)
THERIOGENOLOGY
THE TREATMENT OF NONCYCLING MARES BY ORAL APPLICATION OF CHLORMADINONE ACETATE (CAP)
BY R. Hoppe, J. Biehkowski and A. Lipczyhski Faculty of Veterinary Medicine Grochowska 272, 03-849 Warsaw, Poland Received for publication July
1, 1974
ABSTRACT During 1970 to 1972, 55 anestrous mares were used to study the therapeutic effect of daily oral applications of 40 to 60 m chlormadinone acetate (CAP). Fourty animals received CAP, up to 18 9or 21) days, while 15 animals served as an untreated control group. During treatment, 19 of 40 animals showed heat and ovulated; CAP was discontinued and all animals bred. Sixteen out of 19 animals conceived. Within 21 days after CAP withdrawal, 12 mares came in heat and 11 conceived. Of 40 treated animals, 37 (92.5 %) came into estrus, and 31 became pregnant (77.5 %); while 8 of 15 control mares started cycling during the season (53.3 %) and only 5 (33.3 X) conceived. This treatment effect is significant (p < 0.01). INTRODUCTION The most common disorders of function of the ovaries in the mare are anestrus and prolonged heats with short irregular intervals, which often pass into continuous estrus. The economical losses, caused by these disorders, are severe since non-fertilized mares remain barren to the next breeding season. Although the literature concerning the influence of progestagens on the activity of the ovaries in mares is scanty, nevertheless the inhibitory effect of exogenous progesterone on estrus has been demonstrated. Loy and Swan (1966) and Van Niekerk, Couburgh and Doms (1973) showed that intramuscular application of progesterone to mares in the luteal phase of the cycle, in daily doses of 100 mg or higher (alternatively 400 mg every second day), blocks the onset of the next estrus and ovulation. Similarly, the onset of the so-called "foal heat" can be delayed by such a treatment. On the other hand, single injections of high doses of progesterone (500 mg) either cause only an insignificant delay of estrus or remain without any effect.
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THERIOGENOLOGY
Thus, the action of progesterone on the process of ovulation in mares seems to be of inhibitory character, as in cows and sheep. However, the effect of synthetic progestogens on this process seem to be different. In-cows and sheep, very low doses of synthetic progestogens inhibit the release of LH and partially FSH, although both these hormones are produced at this time in the pituitary. During the oral application of chlormadinone acetate (CAP),medroxyprogesterone acetate (MAP) or melengestrol acetate (MGA) in cattle and sheep, the corpus luteum becomes atrophic, and in spite of the formation of follicles ovulation does not occur since the ovulatory surge of LH is inhibited. If progestogens are administered in these animals throughout a period as long as the estrus cycle, sufficient quantities of LH and FSH in the pituitary are accumulated to induce ovulation after cessation of progestogen application. Until now, such a distinct action of the progestogens tested in the mare has not been observed. In the experiments of Loy and Swan (1966) the mares showed estrus after daily doses of medroxyprogesterone acetate (MAP) from 425 mg up to 1188 mg, while in the cow a daily oral dose of 180 mg inhibits estrus completely. Oral application of 100 to 200 mg (daily) of MGA, a much more active progestogen than CAP, in the mares did not block estrus and ovulation, while in the cow 0.6 mg per day of this substance is sufficient to inhibit ovulation. Both these progestogens applied in high doses in attempts at regulation of the disorders of the estrous cycle in the mare proved to be completely ineffective. Both the oral and systemic application in cases of continuous estrus did not inhibit estrus; sometimes the intensity was increased. In cases of anestrus, long periods of application of these progestogens did not provoke the expected release of the accumulated gonadotrophins and the onset of estrus. In some cases, estrus occurred during application of these progestogens. On the other hand, Bowen (1968) giving 0.5 mg/day of MGA orally to mares for 8 days, evoked ovarian cysts with continuous estrus lasting up to 80 days. The same effect was obtained by Loy and Swan (19663, giving daily i-m. 50 mg of progesterone. JBchle and Merkt (1964) first obtained favorable results in the treatment of noncycling mares with progestogens by iving f.m. a large single dose of norethfndron enanthat; Mahler (19684 in continuation of these trials and using CAP in a 1 % oily solution observed ovulation in 66 4:of animals between the 6th and 18th day after a single injection of 125 mg CAP to 56 mares; of 42 treated animals, 34 ovulated between Day 2 and 71 after treatment (80 X). Sixty-three percent of all treated animals conceived. In especially resistant mares, the author performed additionally intrauterine infusions of saline solution to stimulate estrus. The majority of animals were treated in April and May. Zerobin (1969) treated 27 anestrous mares by oral administration of 5 mg CAP/day during a period of 14 days; 19 mares exhibited estrus between the 8th and 24th day after medication, and 12 (44 X) became pregnant. Arbeiter (1971) used in 15 noncycling mares CAP in the following doses: single i.m. injection of 80 to 150 mg, and oral administration of 15 mg during a lo-day period. Additionally, he performed intrauterine
2
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1974
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THERIOGENOLOGY infusions of saline to stimulate estrus by direct actions upon the uterus. All mares came into estrus within a period of 4 to 34 days after treatment. Total percentage of pregnancy after mating in three consecutive heats was 60 %. Baier, Bechtold and Brumner (1972) used CAP in 12 anestrous mares, starting the treatment by i.m. injection of 50 mg in 1 4;oil solution, and subsequently giving orally each day 10 mg CAP during a period of 20 days. Seven mares came into estrus within a period of 5 to 25 days after treatment, and four (33 %) became pregnant. All the above-mentioned authors used CAP for the treatment of noncycling mares and in their opinion this progestogen is the most suitable for the mare. The conception rates were rather low, although the authors applied additional treatment (intrauterine fnfusfons) and fncluded also as the posftfve result of treatment, estrus which were exhibited by the mares many weeks after the ending of medication. Unfortunately, none of these authors had a control group of noncycling mares during the period of observations and did not report on examinations of the ovaries of treated animals during and after treatment. Taking into consideration the fact that sterility in the mare due to anestrus causes serious economical losses in Polish horse studs, treatment of these disturbances was undertaken using CAP (mainly of Polish productfon). The main goal of this work was to investigate whether the administration of CAP for a period of time as long as an estrous cycle, would induce development of Graaffan follicles, estrus and ovulation. MATERIAL AND METHODS The animals consisted of 55 anestrous mares from five state horse studs. Fourty animals were treated with CAP while 15 served as the control group. The investigations were performed during a period of three years (1970 to 1972), mostly in the months of March and April and some in May. The breed and age of mares are given in Tables I and II. Fourty mares (16 lactating) in their anestrous period (lasting about 64 days) were given CAP once a day with oat grain. The daily doses were: 26 mares - 40 mg; 4 mares - 50 m ; and 10 mares - 60 mg. The CAP was obtained from VEB Jenapharm (GDR3 and Polfa (Poland). The period of medication lasted 18 to 21 days; in cases of the onset of estrus during administration of CAP, the medication was interrupted and the mares were served, according to the breeding plan of the stud, by stallions. previously examined for fertility. The mares were examined gynecologically and rectally before treatment, during the treatment every 4 to 5 days, and at end of medication as soon as they came into heat and were mated. The cervical mucus of 80 % of the mares was examined bacteriologically to exclude infection of the genital tract. In the 2nd and between the 3rd and 5th month after service, the mares were examfned for pregnancy. The course of pregnancy and parturition as well as the health of the foals were closely observed.
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THERIOGENOLOGY RESULTS The effects of treatment with a dose of 40, 50 or 60 mg CAP did not differ; so the results are combined. In mares in which at the beginning of the treatment ovarian follicles of about 3 cm in diameter could > be palpated, or in which the ovaries were larger than normal and of spongy consistence ("shallow anestrus"), the adminfstration of CAP Induced estrus after 2 to 3 days (6 mares - see Table III). In mares in which at the beginning of the treatment no function of the ovaries could be palpated, a gradual enlargement of the ovarfes occurred during the period of 5 to 8 days of CAP application. These changes fnvolved one or both ovaries. Within the next few days, the ovarfes became pear-shaped with formation of Graafian follicles (Table III). Thirteen mares responded fn this way and they exhibited estrus with ovulation between the 7th and 16th day of application and all animals were mated. Out of all treated animals (19). which were mated after an incomplete period of CAP administration, 16 mares conceived. In the mares which did not exhibit estrus during the adminfstratfon of CAP, ovaries which became enlarged before cessation of the treatment either then reduced in size or remained without changes of site and consistency until the end of treatment (+ 20 days). Twelve mares showed estrus with ovulation between the fira and 18th day after the end of treatment without any distinct synchronization effect. Mating of these mares.gave the highest fertilization rate (91.7 %). Incidence of estrus fn mares after the perfod of 21 days from the end of administration of CAP (after one estrous cycle) cannot be attributed to the immediate action of the progestogen. However, since estrus in the control mares after the same period occurred in a consfderably lower percentage as compared to those which received CAP, the results of mating performed later than 21 days after the end of medication was taken into account for the final comparison of the percent of pregnancy in both groups. There were only 4 mares in this class which showed estrus, and 2 of them conceived; 3 mares did not exhibit estrus, while 9 mares (29 %) which did not conceive during the induced estrus, conceived at the 2nd estrus (16 X) or the 3rd (13 %). Out of 40 anestrous mares treated with CAP, 37 (92.5 %) were considered as cured; 31 out of these became regnant (77.5 %). Out of 15 control mares, 8 exhibited estrus (53.3 %P and 5 conceived (33 %) (Table IV). Both the differences in the percentage of estrus observed and the percentage of conceptions between the groups of treated and control mares are statistically highly significant (p < 0.01). The course of pregnancy and sex ratio of foals in both groups of mares are shown in Tables V and VI. In 4 treated mares (3 lactating) embryonic death, and in 2 mares early abortions, were observed. In the control grou , embryonic mortality occurred in 2 lactating mares (40 4 of all pregnant5 . No twin pregnancies occurred; the sex ratio was 10 males to 12 females, which mfght be accepted as normal. The high percentage of embryonic mortality in lactating mares is pointed out by the majority of authors workfng on this problem; the observations of the first author in this paper showed the same phenomenon in Poland (1968).
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THERIOGENOLOGY
Since the effect of the treatment with doses of 40, 50 or 60 mg of CAP were the same, the lowest dose, i. e. 40 mg per day, should be accepted as sufficient for the therapeutic effect.
DISCUSSION Our studies revealed that CAP at dose levels of 40 to 60 mg per day either initiated ovarian responses resulting in estrus, ovulation and conception (16 out of 19); or estrus, ovulation and conception during 20 days after drug withdrawal (11 out of 12). Overall, a significantly higher number of mares treated with CAP showed heat and conceived as the untreated control group. Progesterone, at the same dose level supplied systematically to cattle (JHchle, 1969) or horses (Loy & Swan, 1966; Van Niekerk et al., 1973) interrupts cyclic functions; 10 mg CAP, given orally, controls the cycle in cattle (Jdchle, 1969) while in the mare 40 to 60 mg of CAP are only partially active in controlling the cycle. However, our clinical observations clearly.indicate that at these dose levels CAP either caused an immediate gonadotrophin release (positive feedback) or temporarily a negative feedback with an increase in gonadotrophin release after CAP withdrawal (rebound phenomenon). Further discussions about the CAP effects on FSH or LH release are hypothetical and should await data forthcoming in a foreseeable future from blood level determinations of FSH and LH by irmnunoassays. These future studies should also take the effect of CAP on dry or lactating mares and on mares early or late in season into consideration, effects whfch may explain some of the differences in responsiveness seen by us and reported by others in the literature (Arbeiter, 1971; Baier et al., 1972; Zerobin, 1969). In cattle, conceptions at the first heat after cycle synchronization with orally applied progestogens are generally lower than in untreated controls (Jdchle, 1969; 1972). In the mare, our data and some of those published previously (Mahler, 1968; Arbeiter, 1971) do not indicate any fertility reducing effect of CAP when animals are bred at the first heat during the drug administration period or shortly thereafter.
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THERIOGENOLOGY
REFERENCES
1.
ARBEITER, K.: Therapeutische Steroidhormon-Anwendung beim Pferd. Wien. Tierdrztl. Mschr., -58(10):328, 1971.
2.
BAIER, W., M. Bechtold and H. Brusnner: Erfahrungen Uber die Behandlung von ZyklusstBrungen bei der Stute. Wien. Tier%rztl. Mschr., 59:13, 1972.
3.
BOWEN, J. M.:
An induced cystic ovarian condition in the mare.
VI. Cong. Intern: Reprod. Anim. Insem. Artif., Paris, Vol. 11:155g, 1968. 4.
HOPPE, R.,
J. Jedruch, W. Karczewski and M. Sajna: Synchronizacja u jalowek przy uzyciu octanu melengestrolu (MGA).
rui
Medycyna Wet., 27=45, 1971. 5.
HOPPE, R.:
6.
HOPPE, R., J. Bienkowski and A. Lipczynski: Treatment of noncycling mares by oral application of chlormadinone acetate. Proc. VII Congr. Anim. Reprod., Munich, 1:769, 1972.
7.
JOCHLE, W. and H. Merkt: Behandlung von Azyklie und Nymphomanie bei Stuten mit einem Depot-Gestagen. Otsch. tier%rztl. Wschr., 7l_(8):201,1964.
8.
JOCHLE, W.:
9.
JOCHLE, W.: Pharmacological aspects of the control of the cycle in domestic animals. Proc. VII Congr. Anim. Reprod., Munich, I_:g7, 1972.
The embryonic mortality in the mare. VI. Cong. Intern. Reprod. Anim. Insem. Artif., Paris, Vol. 11:1573, 1972.
Anwendung der Gestagene in Veterindrmedizin und Zootechnik. Kap. XII, Handbuch d. exp. Pharmakologie, Bd. Xx11/2:606, 1969.
10.
LOY, R. G. and S. M. Swan: Effects of exogenous progestogens on reproductive phenomena in mares. J. Anim. Sci., 25:821, 1966.
11.
MAHLER, R.: Behandlung der Azyklie bei Stuten mit Chlormadinonazetat. Vi. Cong. Intern. Reprod. Anim. Insem. Artif., Paris, Vol. 11:1475, 1968.
12.
VAN NIEKERK, C. H., R. i. Couburgh and H. W. H. Doms: Progesterone treatment of mares with abnormal oestrous cycles early in breeding season. J. S.Afr. Vet. Assoc., 44(1):37, 1973.
13.
ZEROBIN, K.: Ovulation, Ei- und Spermientransport. Tierheilk., 111(6):305, 1969.
6
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1974
Schweiz. Arch.
VOL. 2 NO. 1-2
THERIOGENOLOGY TABLE I - Experimental group:
Breed
No. o*
Mares with anestrus.
Barren, for 1 year or longer
Age, average, in years (range)
Anestrous perfo in days, averag (range)
Half Breed
12 (5)
5
12 (8-21)
127 (23-208)
;;;:; Po1fsh
12 (3)
4
8.5 (3-19)
121 (65-201)
Thoroughbred
16 (8)
4
7.4 (4-16)
35 (17- 61)
40 (16)
13
9.3 (3-21)
64 (17-208)
Total: I
()* number of lactating mares
TABLE11 - Control group:
Breed
No.
()*
Mares with anestrus.
Barren, for 1 year or longer
Age, average, in years (range)
Ane&rous perfo' fn days, averag
(range )
Half Breed
7 (4)
1
7.5 (3-11)
138 (30-244)
;;w;; Polish
7 (2)
2
8.5 (3-14)
121 (43-201)
Thoroughbred
1 (1)
-
15(7)
3
Total:
8 8
(3-14)
89 121 (30-244)
()* number of lactating mares
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THERIOGENOLOGY TABLE III-Effect of CAP* by oral administration on 40 mares in anestrus. 'eriod of CAP adminitration, in days 140 or 60 mg CAP/day)
Number of mares in estrus
conceived
not conceived
6
4
2
7 - 16
13
12
1
7 - 22
6& 12**
4 11
:
1 -3
Total:
37 (92.5%)
31 (77.5%)
no estru
3
6 (15%)
3 (7.5%)
* CAP Polfa, or Jenapharm ** Estrus was observed 1 to 18 days after the end of medication *** Estrus was observed22to 27 days after the end of medication
TABLE IV -Appearance of estrus and conceptions in 15 control mares with anestrus.
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THERIOGENOLOGY TABLE V - Course of pregnancy and sex ratio in offsprings in CAP-treated mares. Breed
Embryonic death
Half Breed
Abortion
3 (2)"
Number of foals born
1
Great Polish Breed
1 (1)
Thoroughbred
1 (1)
Total:
4 (3)
2 (1)
males
females
2
1 (l)**
4 (1)
6 (1)
4 (1)
3 (2)
10 (1)
12 (4)
()* number of lactating mares
TABLEVI -Course of pregnancy and sex ratio in offsprings in 5 control mares with anestrus. Breed
Half Breed
Embryonic
1
1 (1)
I
Great Polish Breed Thoroughbred Total:
JULY-AUGUST
1
Abortion
1
Nmw,“f
f~;e~~;;s
I 1
1 (1) 1
-
1
-
2 (2)
1974
VOL. 2 NO. 1.2
I
1 2
I
1
9
THE TREATMENT OF NONCYCLING MARES BY ORAL APPLICATION OF CHLORMADINONE ACETATE (CAP)
BY R. Hoppe, J. Biehkowski and A. Lipczyhski Faculty of Veterinary Medicine Grochowska 272, 03-849 Warsaw, Poland Received for publication July
1, 1974
ABSTRACT During 1970 to 1972, 55 anestrous mares were used to study the therapeutic effect of daily oral applications of 40 to 60 m chlormadinone acetate (CAP). Fourty animals received CAP, up to 18 9or 21) days, while 15 animals served as an untreated control group. During treatment, 19 of 40 animals showed heat and ovulated; CAP was discontinued and all animals bred. Sixteen out of 19 animals conceived. Within 21 days after CAP withdrawal, 12 mares came in heat and 11 conceived. Of 40 treated animals, 37 (92.5 %) came into estrus, and 31 became pregnant (77.5 %); while 8 of 15 control mares started cycling during the season (53.3 %) and only 5 (33.3 X) conceived. This treatment effect is significant (p < 0.01). INTRODUCTION The most common disorders of function of the ovaries in the mare are anestrus and prolonged heats with short irregular intervals, which often pass into continuous estrus. The economical losses, caused by these disorders, are severe since non-fertilized mares remain barren to the next breeding season. Although the literature concerning the influence of progestagens on the activity of the ovaries in mares is scanty, nevertheless the inhibitory effect of exogenous progesterone on estrus has been demonstrated. Loy and Swan (1966) and Van Niekerk, Couburgh and Doms (1973) showed that intramuscular application of progesterone to mares in the luteal phase of the cycle, in daily doses of 100 mg or higher (alternatively 400 mg every second day), blocks the onset of the next estrus and ovulation. Similarly, the onset of the so-called "foal heat" can be delayed by such a treatment. On the other hand, single injections of high doses of progesterone (500 mg) either cause only an insignificant delay of estrus or remain without any effect.
JULY-AUGUST
1974
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1
THERIOGENOLOGY
Thus, the action of progesterone on the process of ovulation in mares seems to be of inhibitory character, as in cows and sheep. However, the effect of synthetic progestogens on this process seem to be different. In-cows and sheep, very low doses of synthetic progestogens inhibit the release of LH and partially FSH, although both these hormones are produced at this time in the pituitary. During the oral application of chlormadinone acetate (CAP),medroxyprogesterone acetate (MAP) or melengestrol acetate (MGA) in cattle and sheep, the corpus luteum becomes atrophic, and in spite of the formation of follicles ovulation does not occur since the ovulatory surge of LH is inhibited. If progestogens are administered in these animals throughout a period as long as the estrus cycle, sufficient quantities of LH and FSH in the pituitary are accumulated to induce ovulation after cessation of progestogen application. Until now, such a distinct action of the progestogens tested in the mare has not been observed. In the experiments of Loy and Swan (1966) the mares showed estrus after daily doses of medroxyprogesterone acetate (MAP) from 425 mg up to 1188 mg, while in the cow a daily oral dose of 180 mg inhibits estrus completely. Oral application of 100 to 200 mg (daily) of MGA, a much more active progestogen than CAP, in the mares did not block estrus and ovulation, while in the cow 0.6 mg per day of this substance is sufficient to inhibit ovulation. Both these progestogens applied in high doses in attempts at regulation of the disorders of the estrous cycle in the mare proved to be completely ineffective. Both the oral and systemic application in cases of continuous estrus did not inhibit estrus; sometimes the intensity was increased. In cases of anestrus, long periods of application of these progestogens did not provoke the expected release of the accumulated gonadotrophins and the onset of estrus. In some cases, estrus occurred during application of these progestogens. On the other hand, Bowen (1968) giving 0.5 mg/day of MGA orally to mares for 8 days, evoked ovarian cysts with continuous estrus lasting up to 80 days. The same effect was obtained by Loy and Swan (19663, giving daily i-m. 50 mg of progesterone. JBchle and Merkt (1964) first obtained favorable results in the treatment of noncycling mares with progestogens by iving f.m. a large single dose of norethfndron enanthat; Mahler (19684 in continuation of these trials and using CAP in a 1 % oily solution observed ovulation in 66 4:of animals between the 6th and 18th day after a single injection of 125 mg CAP to 56 mares; of 42 treated animals, 34 ovulated between Day 2 and 71 after treatment (80 X). Sixty-three percent of all treated animals conceived. In especially resistant mares, the author performed additionally intrauterine infusions of saline solution to stimulate estrus. The majority of animals were treated in April and May. Zerobin (1969) treated 27 anestrous mares by oral administration of 5 mg CAP/day during a period of 14 days; 19 mares exhibited estrus between the 8th and 24th day after medication, and 12 (44 X) became pregnant. Arbeiter (1971) used in 15 noncycling mares CAP in the following doses: single i.m. injection of 80 to 150 mg, and oral administration of 15 mg during a lo-day period. Additionally, he performed intrauterine
2
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1974
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THERIOGENOLOGY infusions of saline to stimulate estrus by direct actions upon the uterus. All mares came into estrus within a period of 4 to 34 days after treatment. Total percentage of pregnancy after mating in three consecutive heats was 60 %. Baier, Bechtold and Brumner (1972) used CAP in 12 anestrous mares, starting the treatment by i.m. injection of 50 mg in 1 4;oil solution, and subsequently giving orally each day 10 mg CAP during a period of 20 days. Seven mares came into estrus within a period of 5 to 25 days after treatment, and four (33 %) became pregnant. All the above-mentioned authors used CAP for the treatment of noncycling mares and in their opinion this progestogen is the most suitable for the mare. The conception rates were rather low, although the authors applied additional treatment (intrauterine fnfusfons) and fncluded also as the posftfve result of treatment, estrus which were exhibited by the mares many weeks after the ending of medication. Unfortunately, none of these authors had a control group of noncycling mares during the period of observations and did not report on examinations of the ovaries of treated animals during and after treatment. Taking into consideration the fact that sterility in the mare due to anestrus causes serious economical losses in Polish horse studs, treatment of these disturbances was undertaken using CAP (mainly of Polish productfon). The main goal of this work was to investigate whether the administration of CAP for a period of time as long as an estrous cycle, would induce development of Graaffan follicles, estrus and ovulation. MATERIAL AND METHODS The animals consisted of 55 anestrous mares from five state horse studs. Fourty animals were treated with CAP while 15 served as the control group. The investigations were performed during a period of three years (1970 to 1972), mostly in the months of March and April and some in May. The breed and age of mares are given in Tables I and II. Fourty mares (16 lactating) in their anestrous period (lasting about 64 days) were given CAP once a day with oat grain. The daily doses were: 26 mares - 40 mg; 4 mares - 50 m ; and 10 mares - 60 mg. The CAP was obtained from VEB Jenapharm (GDR3 and Polfa (Poland). The period of medication lasted 18 to 21 days; in cases of the onset of estrus during administration of CAP, the medication was interrupted and the mares were served, according to the breeding plan of the stud, by stallions. previously examined for fertility. The mares were examined gynecologically and rectally before treatment, during the treatment every 4 to 5 days, and at end of medication as soon as they came into heat and were mated. The cervical mucus of 80 % of the mares was examined bacteriologically to exclude infection of the genital tract. In the 2nd and between the 3rd and 5th month after service, the mares were examfned for pregnancy. The course of pregnancy and parturition as well as the health of the foals were closely observed.
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1974
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3
THERIOGENOLOGY RESULTS The effects of treatment with a dose of 40, 50 or 60 mg CAP did not differ; so the results are combined. In mares in which at the beginning of the treatment ovarian follicles of about 3 cm in diameter could > be palpated, or in which the ovaries were larger than normal and of spongy consistence ("shallow anestrus"), the adminfstration of CAP Induced estrus after 2 to 3 days (6 mares - see Table III). In mares in which at the beginning of the treatment no function of the ovaries could be palpated, a gradual enlargement of the ovarfes occurred during the period of 5 to 8 days of CAP application. These changes fnvolved one or both ovaries. Within the next few days, the ovarfes became pear-shaped with formation of Graafian follicles (Table III). Thirteen mares responded fn this way and they exhibited estrus with ovulation between the 7th and 16th day of application and all animals were mated. Out of all treated animals (19). which were mated after an incomplete period of CAP administration, 16 mares conceived. In the mares which did not exhibit estrus during the adminfstratfon of CAP, ovaries which became enlarged before cessation of the treatment either then reduced in size or remained without changes of site and consistency until the end of treatment (+ 20 days). Twelve mares showed estrus with ovulation between the fira and 18th day after the end of treatment without any distinct synchronization effect. Mating of these mares.gave the highest fertilization rate (91.7 %). Incidence of estrus fn mares after the perfod of 21 days from the end of administration of CAP (after one estrous cycle) cannot be attributed to the immediate action of the progestogen. However, since estrus in the control mares after the same period occurred in a consfderably lower percentage as compared to those which received CAP, the results of mating performed later than 21 days after the end of medication was taken into account for the final comparison of the percent of pregnancy in both groups. There were only 4 mares in this class which showed estrus, and 2 of them conceived; 3 mares did not exhibit estrus, while 9 mares (29 %) which did not conceive during the induced estrus, conceived at the 2nd estrus (16 X) or the 3rd (13 %). Out of 40 anestrous mares treated with CAP, 37 (92.5 %) were considered as cured; 31 out of these became regnant (77.5 %). Out of 15 control mares, 8 exhibited estrus (53.3 %P and 5 conceived (33 %) (Table IV). Both the differences in the percentage of estrus observed and the percentage of conceptions between the groups of treated and control mares are statistically highly significant (p < 0.01). The course of pregnancy and sex ratio of foals in both groups of mares are shown in Tables V and VI. In 4 treated mares (3 lactating) embryonic death, and in 2 mares early abortions, were observed. In the control grou , embryonic mortality occurred in 2 lactating mares (40 4 of all pregnant5 . No twin pregnancies occurred; the sex ratio was 10 males to 12 females, which mfght be accepted as normal. The high percentage of embryonic mortality in lactating mares is pointed out by the majority of authors workfng on this problem; the observations of the first author in this paper showed the same phenomenon in Poland (1968).
JULY-AUGUST
1974
VOL. 2 NO. l-2
THERIOGENOLOGY
Since the effect of the treatment with doses of 40, 50 or 60 mg of CAP were the same, the lowest dose, i. e. 40 mg per day, should be accepted as sufficient for the therapeutic effect.
DISCUSSION Our studies revealed that CAP at dose levels of 40 to 60 mg per day either initiated ovarian responses resulting in estrus, ovulation and conception (16 out of 19); or estrus, ovulation and conception during 20 days after drug withdrawal (11 out of 12). Overall, a significantly higher number of mares treated with CAP showed heat and conceived as the untreated control group. Progesterone, at the same dose level supplied systematically to cattle (JHchle, 1969) or horses (Loy & Swan, 1966; Van Niekerk et al., 1973) interrupts cyclic functions; 10 mg CAP, given orally, controls the cycle in cattle (Jdchle, 1969) while in the mare 40 to 60 mg of CAP are only partially active in controlling the cycle. However, our clinical observations clearly.indicate that at these dose levels CAP either caused an immediate gonadotrophin release (positive feedback) or temporarily a negative feedback with an increase in gonadotrophin release after CAP withdrawal (rebound phenomenon). Further discussions about the CAP effects on FSH or LH release are hypothetical and should await data forthcoming in a foreseeable future from blood level determinations of FSH and LH by irmnunoassays. These future studies should also take the effect of CAP on dry or lactating mares and on mares early or late in season into consideration, effects whfch may explain some of the differences in responsiveness seen by us and reported by others in the literature (Arbeiter, 1971; Baier et al., 1972; Zerobin, 1969). In cattle, conceptions at the first heat after cycle synchronization with orally applied progestogens are generally lower than in untreated controls (Jdchle, 1969; 1972). In the mare, our data and some of those published previously (Mahler, 1968; Arbeiter, 1971) do not indicate any fertility reducing effect of CAP when animals are bred at the first heat during the drug administration period or shortly thereafter.
JULY-AUGUST
1974
VOL. 2 NO. 1.2
THERIOGENOLOGY
REFERENCES
1.
ARBEITER, K.: Therapeutische Steroidhormon-Anwendung beim Pferd. Wien. Tierdrztl. Mschr., -58(10):328, 1971.
2.
BAIER, W., M. Bechtold and H. Brusnner: Erfahrungen Uber die Behandlung von ZyklusstBrungen bei der Stute. Wien. Tier%rztl. Mschr., 59:13, 1972.
3.
BOWEN, J. M.:
An induced cystic ovarian condition in the mare.
VI. Cong. Intern: Reprod. Anim. Insem. Artif., Paris, Vol. 11:155g, 1968. 4.
HOPPE, R.,
J. Jedruch, W. Karczewski and M. Sajna: Synchronizacja u jalowek przy uzyciu octanu melengestrolu (MGA).
rui
Medycyna Wet., 27=45, 1971. 5.
HOPPE, R.:
6.
HOPPE, R., J. Bienkowski and A. Lipczynski: Treatment of noncycling mares by oral application of chlormadinone acetate. Proc. VII Congr. Anim. Reprod., Munich, 1:769, 1972.
7.
JOCHLE, W. and H. Merkt: Behandlung von Azyklie und Nymphomanie bei Stuten mit einem Depot-Gestagen. Otsch. tier%rztl. Wschr., 7l_(8):201,1964.
8.
JOCHLE, W.:
9.
JOCHLE, W.: Pharmacological aspects of the control of the cycle in domestic animals. Proc. VII Congr. Anim. Reprod., Munich, I_:g7, 1972.
The embryonic mortality in the mare. VI. Cong. Intern. Reprod. Anim. Insem. Artif., Paris, Vol. 11:1573, 1972.
Anwendung der Gestagene in Veterindrmedizin und Zootechnik. Kap. XII, Handbuch d. exp. Pharmakologie, Bd. Xx11/2:606, 1969.
10.
LOY, R. G. and S. M. Swan: Effects of exogenous progestogens on reproductive phenomena in mares. J. Anim. Sci., 25:821, 1966.
11.
MAHLER, R.: Behandlung der Azyklie bei Stuten mit Chlormadinonazetat. Vi. Cong. Intern. Reprod. Anim. Insem. Artif., Paris, Vol. 11:1475, 1968.
12.
VAN NIEKERK, C. H., R. i. Couburgh and H. W. H. Doms: Progesterone treatment of mares with abnormal oestrous cycles early in breeding season. J. S.Afr. Vet. Assoc., 44(1):37, 1973.
13.
ZEROBIN, K.: Ovulation, Ei- und Spermientransport. Tierheilk., 111(6):305, 1969.
6
JULY-AUGUST
1974
Schweiz. Arch.
VOL. 2 NO. 1-2
THERIOGENOLOGY TABLE I - Experimental group:
Breed
No. o*
Mares with anestrus.
Barren, for 1 year or longer
Age, average, in years (range)
Anestrous perfo in days, averag (range)
Half Breed
12 (5)
5
12 (8-21)
127 (23-208)
;;;:; Po1fsh
12 (3)
4
8.5 (3-19)
121 (65-201)
Thoroughbred
16 (8)
4
7.4 (4-16)
35 (17- 61)
40 (16)
13
9.3 (3-21)
64 (17-208)
Total: I
()* number of lactating mares
TABLE11 - Control group:
Breed
No.
()*
Mares with anestrus.
Barren, for 1 year or longer
Age, average, in years (range)
Ane&rous perfo' fn days, averag
(range )
Half Breed
7 (4)
1
7.5 (3-11)
138 (30-244)
;;w;; Polish
7 (2)
2
8.5 (3-14)
121 (43-201)
Thoroughbred
1 (1)
-
15(7)
3
Total:
8 8
(3-14)
89 121 (30-244)
()* number of lactating mares
JULY-AUGUST
1974
VOL. 2 NO. 1.2
7
THERIOGENOLOGY TABLE III-Effect of CAP* by oral administration on 40 mares in anestrus. 'eriod of CAP adminitration, in days 140 or 60 mg CAP/day)
Number of mares in estrus
conceived
not conceived
6
4
2
7 - 16
13
12
1
7 - 22
6& 12**
4 11
:
1 -3
Total:
37 (92.5%)
31 (77.5%)
no estru
3
6 (15%)
3 (7.5%)
* CAP Polfa, or Jenapharm ** Estrus was observed 1 to 18 days after the end of medication *** Estrus was observed22to 27 days after the end of medication
TABLE IV -Appearance of estrus and conceptions in 15 control mares with anestrus.
JULY-AUGUST
1974
VOL. 2 NO. l-2
THERIOGENOLOGY TABLE V - Course of pregnancy and sex ratio in offsprings in CAP-treated mares. Breed
Embryonic death
Half Breed
Abortion
3 (2)"
Number of foals born
1
Great Polish Breed
1 (1)
Thoroughbred
1 (1)
Total:
4 (3)
2 (1)
males
females
2
1 (l)**
4 (1)
6 (1)
4 (1)
3 (2)
10 (1)
12 (4)
()* number of lactating mares
TABLEVI -Course of pregnancy and sex ratio in offsprings in 5 control mares with anestrus. Breed
Half Breed
Embryonic
1
1 (1)
I
Great Polish Breed Thoroughbred Total:
JULY-AUGUST
1
Abortion
1
Nmw,“f
f~;e~~;;s
I 1
1 (1) 1
-
1
-
2 (2)
1974
VOL. 2 NO. 1.2
I
1 2
I
1
9