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Hormonal Control of Estrus: Introduction |  |
| The major areas in which administration of hormones may be used to manipulate the estrous cycle are to induce luteolysis, suppress estrus, induce cyclicity in anestrous animals, superovulate cyclic animals, and induce ovulation of a mature follicle. The most effective treatments for these manipulations vary among species. Some of the following treatments currently lack regulatory approval; label instructions should be followed. |
| Horses: |
| Estrous behavior may be undesirable in performance horses and can be suppressed in mares by administration of progestagens, either progesterone in oil (150-300 mg, IM, sid) or altrenogest (0.44 mg/kg, PO, sid). The oral progestagen is preferable because of muscle irritation from the injectable preparation. Progesterone in a biorelease vehicle may be available by prescription from a compounding pharmacy. This preparation (1.5 g, IM) is administered
once every 7-10 days. Treatment with progestagens for 15 days during the late transition season can advance the first ovulation of the year by ~10 days. Although these preparations suppress estrous behavior, they may not effectively suppress follicle growth and ovulation in cyclic mares. |
| Ovulation may be synchronized in mares by administration of progesterone in oil (150 mg) and estradiol 17β in oil (10 mg, IM, sid for 10 days) with prostaglandin (PG) F2α (10 mg, IM) administered on the tenth day. Mares should come into estrus ~3 days after the end of treatment, and 85% of mares ovulate 9-13 days after the end of treatment. |
| Estrus may be induced in diestrous mares (having a corpus luteum that is 5 or more days postovulation) by treatment with PGF2α (10 mg, IM) or cloprostenol (250 µg, IM) to lyse the corpus luteum. Mares should return to estrus in ~3 days and ovulate an average of 9-10 days after PG treatment. The time to ovulation is variable, however, depending on the size of the largest follicle on the ovary at the time of PG administration. PGF2α
causes numerous transient side effects in horses, including sweating, colic, and trembling. PG causes luteolysis of a mature corpus luteum and so is not effective in inducing estrus in anestrous mares. |
| Behavioral estrus may be induced in anestrous or ovariectomized mares by administration of estradiol 17β in oil (1-10 mg, IM) or estradiol cypionate (0.5 mg, IM). Mares should show estrus in 12-24 hr. This estrus is not associated with follicular growth and is not fertile. Treatment with estradiol cypionate is longlasting, but repeated or high doses may cause aggressive or defensive behavior when the mare is approached by a stallion. Treatment with estrogen in the presence of
progesterone (eg, in a cyclic mare in diestrus) will not induce estrous behavior. |
| Ovulation may be induced in mares with mature preovulatory follicles (>33 mm diameter) by administration of human chorionic gonadotropin (hCG), 2,500 IU, IV; by administration of a deslorelin implant, 2.2 mg, SC; or by administration of deslorelin, 1-2 mg, IM, in a biorelease vehicle. Ovulation is seen in 85% of mares within 48 hr, typically 36-42 hr after hCG or injectable deslorelin treatment or 40-44 hr after treatment with a deslorelin implant. Repeated use of hCG over a
long period may be associated with antibody formation and decrease in response to treatment; this should not be seen with deslorelin. Use of deslorelin in implant form has been associated with periods of anestrus in treated mares, especially if the corpus luteum of ovulation is lysed with PG. For this reason, many veterinarians remove the implant after ovulation is seen; this is easily performed if the implant is placed in the vulvar mucosa. |
| Techniques for superovulation have recently shown promise. Mares do not superovulate in response to equine chorionic gonadotropin (eCG), and they do not respond well to follicle-stimulating hormone (FSH) derived from other species, but they may be superovulated (average of 3-4 follicles ovulated) by treatment with equine FSH, which is now commercially available. Administration of 2-20 µg GnRH/hr (by infusion pump) over ~10 days is effective in inducing normal follicular growth
and ovulation in anestrous mares; the larger dose induces superovulation (average of 3 follicles). Cyclicity has also been induced in anestrous mares by treatment with 200 µg GnRH every 6 hr, or by administration of a GnRH agonist every 12 hr. |
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| Cattle: |
| In cows, ovulation may be synchronized with a progestagen and estrogen combination treatment, a 2-dose PG regimen, or a GnRH and PG combination. An effective progestagen treatment is a commercially available combination of an IM injection of 5 mg estradiol valerate and 3 mg norgestomet, with an ear implant of 6 mg norgestomet that is left in for 9 days. Cows come into estrus 1-2 days after cessation of treatment and may be inseminated one time at 48-54 hr after the implant is
removed for acceptable conception rates. Alternatively, a controlled intravaginal drug-release device may be used. This device contains progesterone and is labeled for estrus synchronization in beef and dairy cattle. It is inserted for 7 days, with an injection of PGF2α on day 6 (or off-label, day 7); most heats are synchronized at ~48 hr after removal. Administration of PGF2a (25 mg, IM) or PG analog (cloprostenol at 500 µg, IM) to
cows with a corpus luteum 7 days after ovulation results in estrus in ~2-5 days. Two PG injections given 14 days apart synchronize estrus and ovulation in most cows. Time to estrus is more variable than with progesterone suppression, so insemination should be based on detection of estrus. Ovulation may also be synchronized by administration of GnRH, 100 µg, IM (day 1), followed by PG treatment on day 8 and a second GnRH treatment on day 10. Cows should be inseminated 0-20 hr
after the second GnRH treatment. This GnRH and PGF2α protocol is termed “ovsynch.” There are many variations on this protocol, using additional steroids, PG, or GnRH treatments, that may increase the degree of synchrony or pregnancy rates after artificial insemination. |
| Ovulation may be induced in cows with mature follicles (10-15 mm diameter) by treatment with GnRH at 100-250 µg, IM; luteinizing hormone (LH) at 25 mg, IM; or hCG at 5,000-10,000 IU, IM. Because the endogenous LH peak develops at the onset of estrus, this administration will not speed the time of ovulation in estrous cows but may be used to ensure luteinization in cows with histories of cystic ovarian disease or to induce ovulation in anestrous postpartum cows. |
| Superovulation may be achieved in the cow by treatment with eCG (not currently commercially available) in mid-diestrus followed by PG-induced luteolysis 2-3 days later, or by treatment with FSH (potencies differ, refer to label instructions), typically IM, bid for 4-5 days, with administration of PG (25-35 mg, IM) usually on day 3 or 4 of treatment. FSH treatment is discontinued at the onset of estrus. |
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| Goats and Sheep: |
| In cycling goats, luteolysis may be induced by administration of PGF2α (2.5-5 mg, IM) as early as day 4. In sheep, PGF2α (5 mg) or cloprostenol (125 µg) is effective after day 5 of the cycle. Estrus may be synchronized by 2 doses of PG, 11 days apart in does or 9 days apart in ewes. Estrus may also be synchronized in cycling or anestrous does and ewes by administration of progestagens; impregnated vaginal pessaries have been the
most widely used agents for control of ovulation but are not currently available for clinical use in the USA. A portion of a bovine norgestomet implant (3 mg/goat) or injection of progesterone in oil (10 mg/day, IM) has also been effective. Progestagen treatment is administered for 10-14 days in sheep and for 14-21 days in goats. Ewes should be joined with rams the day after cessation of treatment; does return to heat on the second or third day after treatment ends. Injection of
eCG (500 IU; not currently commercially available) at the end of treatment increases synchronization of ovulation or ovulation rate, or both, but may result in superovulation and problems with multiple lambs or kids. Alternatively, in does, progestagens may be given for 11 days with eCG and PG administered on day 9, and insemination performed on days 12 and 13. In regimens involving treatments other than PG alone, fertility may be reduced on the first estrus after treatment. |
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| Pigs: |
| In pigs, estrus synchronization may be easily achieved by synchronized weaning of lactating sows; estrus is seen 4-10 days later. Administration IM of a commercially available combination of eCG (400 IU) and hCG (200 IU), given as a single injection within 12 hr after weaning, tightens the synchronization, and estrus is seen 4-5 days after weaning. This eCG and hCG combination also induces estrus in gilts with delayed puberty and in sows with postweaning anestrus. Exogenous PG
induces luteolysis of the porcine corpus luteum only after day 12 of the estrous cycle and, therefore, is not a practical agent for estrous cycle control; however, estrus may be synchronized by induction of abortion in sows pregnant >15 days by administration of PGF2α (15 mg, IM, then 10 mg, IM, 12 hr later) or cloprostenol (1 mg, followed 24 hr later by 0.5 mg); sows return to estrus 4-10 days after treatment. Estrus may also be synchronized by feeding
altrenogest (15-20 mg, PO, sid for 14-18 days) or by using bovine norgestomet implants (one implant followed by addition of a second implant 9 days later) removed 19 days after initiation of treatment; neither treatment is currently approved in the USA for swine. Combination eCG and hCG may be given on the day of progestagen withdrawal to better synchronize estrus. |
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| Dogs: |
| In bitches, estrus may be suppressed by administration of mibolerone (an androgen, 30-180 µg, PO, sid, depending on the dog’s weight) for no more than 24 mo. Treatment must be started at least 30 days before estrus. Estrus is variable but typically develops soon after cessation of treatment; fertility should be normal by the second estrus after treatment. The progestagen megestrol acetate (2.2 mg/kg, PO, sid for 8 days) may be used to stop a cycle
when the bitch has already entered proestrus. Administration must start in the first 3 days of proestrus (vulvar bleeding). The next estrus usually develops 4-6 wk earlier than expected. To delay estrus, megestrol acetate treatment is begun in late anestrus (up to a few weeks before estrus is expected); the bitch is treated with 0.55 mg/kg, PO, sid for 32 days. Estrus is seen in 2-9 mo (typically 5-6 mo); fertility is not affected. Neither drug is recommended for
use in bitches on their first estrus or in bitches primarily used for breeding. Side effects of megestrol acetate treatment are uncommon but include cystic endometrial hyperplasia and pyometra; longterm treatment may result in obesity, diabetes mellitus, and neoplasia of the uterus and mammary glands. Mibolerone may cause skin, vaginal, and clitoral changes. Extended-release implants of deslorelin have suppressed estrus for >1 yr in bitches without apparent side effects and
with full return to fertility; clinical use of deslorelin for estrus suppression is currently under investigation. |
| Estrus induction in bitches is problematic; many methods have been proposed but repeatability is low. Recently, use of the dopamine agonists cabergoline (5 µg/kg, PO, sid until 2 days after onset of proestrus) and bromocryptine (0.3 mg/bitch for 3 days followed by 0.6-2.5 mg per bitch for 3-6 days after onset of proestrus) has been reported to induce fertile estrus. Average length of treatment was 16-19 days. Use of deslorelin implants may also be effective for
induction of estrus but has been associated with low progesterone values during diestrus. Removal of the implant 10 days after insertion may overcome this problem. Induction of estrus with GnRH analogs is currently under investigation. |
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| Cats: |
| Megestrol acetate may be used to suppress estrus in queens by treating with 5 mg/cat daily for 3 days, then 2.5-5 mg once weekly for a maximum of 10 wk. The queen should be allowed an estrus before resuming therapy. Mibolerone is not approved for use in queens due to hepatotoxicity but is effective at 50 µg/cat, PO, sid. Longterm deslorelin implants have also suppressed estrus in cats, but the length of suppression is variable. Estrus may be induced in queens
with FSH, 2 mg, IM, the first day, then 0.5-1 mg, IM, daily for 4 additional days. For queens with anovulation or for queens undergoing artificial insemination, ovulation of mature follicles (present on day 2 of estrus) may be induced by treatment with hCG at 250 mg, IM, or GnRH at 25 µg, IM. |
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