Also see Principles of Treatment for Reproductive Disorders in Animals.
Drugs used to regulate or control the reproductive system are often naturally occurring hormones or chemical modifications of hormones.
Gonadotropin-releasing hormone (GnRH) and its analogues are commonly used to control ovarian follicular dynamics and ovulation induction in cattle, ovulation induction of mature follicles in horses, treatment of follicular cysts in cattle or in dogs, and stimulation of libido or testicular function (eg, in testing for cryptorchidism) in horses, dogs, cats, and camelids.
In the US, multiple formulations are approved for intramuscular or intravenous use in cattle (eg, gonadorelin acetate) and intramuscular use in mares (deslorelin acetate and histrelin acetate). Currently, no FDA-approved long-acting release formulations are available for horses in the US; compounded extralabel products are available.
Implants of GnRH analogues (eg, deslorelin acetate) are effective for induction of estrus and ovulation in mares and bitches. In higher doses over a prolonged period, these analogues are useful for contraception in male and female animals (such as dogs) by mediating long-term (≥ 12 months) reversible infertility caused by downregulation of GnRH receptors.
Deslorelin acetate, the only FDA-indexed implant formulation in the US, is currently licensed for treatment of adrenal disease in ferrets. Because this formulation is an indexed drug, extralabel drug use is not permitted in other species. Additional formulations, as implants, are licensed in Canada, Europe, Australia, and New Zealand for use in dogs and horses.
Extralabel drug use (ELDU) for reproductive management in food animals with associated implants is not compliant with the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA).
Follicle-stimulating hormone (FSH) is usually extracted from animal pituitary glands and stimulates follicular growth and estrogen production in females and spermatogenesis in males. It is used for superovulation of several domestic species. It has also been described for induction of fertile estrus in anestrous bitches and queens, with varied success (1, 2, 3, 4). Prolonged FSH use or use of higher doses can cause adverse effects such as cystic endometrial hyperplasia and follicular cysts.
Human chorionic gonadotropin (hCG), which in domestic animals exerts mainly effects similar to those of luteinizing hormone (LH), is used to induce ovulation of mature ovarian follicles in cows or mares in controlled breeding programs. hCG is also used to stimulate gonads as a test for cryptorchidism or ovarian remnant syndrome and to treat ovarian cysts in cattle or dogs.
hCG is administered parenterally, and plasma concentrations peak in approximately 6 hours. It is distributed primarily to the ovaries in females or to the testes in males; a small amount is distributed to the proximal renal tubules. Although used extensively in equine breeding management in the US, hCG is currently officially licensed only to treat nymphomania in horses and cystic ovary disease in cattle and to assist spawning behavior of finfish species.
Equine chorionic gonadotropin (eCG) has FSH activity in most species and is used to induce ovarian follicular growth and to induce estrus. It can also be used in superovulation protocols in ruminants. In the US, a commercially available eCG-hCG swine formulation is indicated, per labeling, to induce estrus in gilts and sows experiencing delayed return to estrus after weaning (see Hormonal Control of the Estrous Cycle in Pigs).
Treatment to induce estrus in small animals experiencing anestrus has also been described (5, 6, 7); see Hormonal Control of Estrus in Dogs and Cats). (Also see species-specific "Management of Reproduction" chapters.)
Steroid Hormones for the Reproductive System
Estradiol esters (eg, valerate, cypionate, propionate) have a longer duration of action than the parent compound has. The availability of these compounds and restrictions on their use in different species vary by country.
In mares, estradiol esters may be used to induce estrous behavior (eg, in ovariectomized teaser mares), or they may be used in combination with progesterone and prostaglandins to synchronize ovulation. Treatment of mares with estradiol cypionate has been proposed for management of compromised pregnancies, such as cases of placentitis (8).
Progesterone and synthetic progestins are commonly used to help control follicular dynamics in ruminants as part of many synchronization protocols. In combination with estradiol esters and prostaglandins, progestins are used to synchronize estrus and ovulation in mares, which can be useful for breeding or artificial reproductive techniques (eg, embryo transfer). Progestins have also been used for behavior modification in horses (9), for suppression of male libido in horses (10) and dogs, and for treatment of dermatological disorders in dogs (11).
Historically, androgens and androgen derivatives were used to suppress estrus (particularly in racing Greyhounds) and to stimulate libido in young or senescent males of all species. Because of potential adverse effects of androgens, such as testicular degeneration from chronic administration, as well as concerns about their misuse and abuse in humans, the use of androgens in veterinary medicine is limited.
Mibolerone, a weak androgenic steroid, is used to prolong the interestrus interval to suppress estrus in bitches or to allow for extended periods of anestrus and uterine remodeling in females with cystic endometrial hyperplasia or after medical management of pathological accumulation of uterine fluid (eg, pyometra).
Mibolerone should not be used in Bedlington Terriers, cats, or animals with hepatic disease, and it can exacerbate androgen-responsive tumors such as perianal adenomas or perianal adenocarcinomas. Additional adverse effects include hyperexcitability or aggressiveness, increased appetite, clitoral hyperplasia, vaginal discharge, changes in coat quality, and an objectionable musky odor. After oral administration, mibolerone is absorbed from the intestine, metabolized in the liver, and excreted in urine and feces.
Pearls & Pitfalls
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Finasteride, a 5-alpha-reductase inhibitor, prevents the conversion of testosterone to 5-alpha-dihydrotestosterone, the active androgen in male accessory sex glands. It is useful in the treatment of benign prostatic hyperplasia in dogs. Flutamide, although not approved for veterinary use in many countries, blocks dihydrotestosterone receptors and may be used for the same purpose.
Luteolytic and Ecbolic Agents for the Reproductive System
Prostaglandins, such as prostaglandin F2alpha (PGF2alpha) and misoprostol (PGE2), and their analogues are used in veterinary medicine for various purposes.
PGF2alpha and its analogues are used in a variety of species mainly for their luteolytic effects to induce a predictable onset of estrus or to synchronize estrus. They may also be used for termination of pregnancy, either alone (in horses or pigs) or in combination with either corticosteroids (in cattle or sheep) or dopaminergic agents (in dogs).
These compounds also cause marked uterine contractions, which can be useful for expulsion of uterine contents in pathological conditions of horses, pigs, ruminants, and small animals, such as pyometra (see Pyometra in Production Animals and Cystic Endometrial Hyperplasia-Pyometra Complex in Small Animals). The compounds used most commonly include dinoprost (a naturally occurring PGF2alpha) and cloprostenol (a synthetic prostaglandin analogue).
In horses and cattle, PGF2alpha may be administered during diestrus in the presence of a mature corpus luteum. There are also antiluteogenic protocols, in which serial PGF2alpha administered during the first 5 days of diestrus can be used to prevent the formation of a new corpus luteum in horses and to induce estrus (12). Common transient adverse effects in horses include sweating and abdominal discomfort (colic); increased salivation can occur in cattle.
Small animals treated with prostaglandins might have increased salivation, vomiting, or diarrhea. Bronchospasm can occur in severe cases, especially in brachycephalic small animal breeds. The extent of the adverse effects can vary by patient and by the formulation used.
PGE2 may be applied topically to the cervical lumen or external cervical os in mares before induction of parturition or abortion or to assist in cervical dilation to facilitate the expulsion of intrauterine fluid. In addition, PGE2 may be applied topically to the serosal surface of the oviduct in mares to facilitate the passage of in vivo embryos by dilating the oviduct to resolve oviductal blockages.
In dogs, PGE2 may be used intravaginally to assist with cervical relaxation in medical management of cases with pathological accumulation of intrauterine fluid.
Oxytocin is used in a variety of species to promote milk letdown, as an adjunctive treatment of mastitis or agalactia, and to cause uterine contraction either to induce (or supplement) labor or to enhance uterine contraction for expulsion of uterine fluid or fetal membranes.
Oxytocin is usually administered intravenously, intramuscularly, or subcutaneously; it may also be administered intranasally.
In small animals, oxytocin may be administered to stimulate maternal bonding and behavior in the immediate postpartum period (see Periparturient Problems in Bitches and Queens).
In mares, oxytocin has been administered to prevent estrus by prolonging the period of diestrus and corpus luteum function (13); see Hormonal Control of Estrus in Horses.
Tocolytics for the Reproductive System
Uterine relaxation is caused by beta-2-mimetic agents, such as clenbuterol. Such agents have been used to postpone parturition (to decrease obstetrical complications in heifers) and to facilitate obstetric manipulations in large domestic animals.
The use of clenbuterol in food-producing animals is prohibited in the US.
Other Drug Classes for the Reproductive System
Dopaminergic agonists, such as bromocriptine, metergoline, or cabergoline, cause decreased serum prolactin concentrations. They are useful in the treatment of pseudopregnancy in dogs and as an adjunct to PGF2alpha in terminating pregnancy or in treating pathological accumulation of uterine fluid.
Dopaminergic agonists such as cabergoline can also be used to induce estrus in dogs, because these drugs are luteotrophic in this species. For bromocriptine and cabergoline dosing information, see Pseudopregnancy in Small Animals.
Dopamine antagonists, such as sulpiride or domperidone, have shown promise in the manipulation of seasonal breeding species. In mares, sulpiride can shorten the interval to onset of the ovulatory season, particularly when used in combination with artificial lighting programs or photostimulation. Domperidone has also been proposed for this purpose (see Hormonal Control of Estrus in Horses).
Although their exact mechanism of action is not completely understood, dopamine antagonists increase endogenous prolactin concentrations and might have an effect at the level of the hypothalamus to increase FSH or LH secretion.
Dopamine antagonists are also commonly used to stimulate lactogenesis and supplement milk production in horses and in dogs.
Melatonin may also be used to regulate reproduction in species that are seasonal breeders (small ruminants, cats, and horses). Species with breeding seasons respond to increases in melatonin by either increasing endogenous GnRH secretion (short-day breeders such as sheep or goats) or decreasing GnRH secretion (long-day breeders such as horses or cats).
Melatonin is labeled for use in sheep in the UK and New Zealand (and for use in goats in New Zealand) to improve early breeding and ovulation rates. In those locations it is available as an 18-mg subcutaneous implant; combined with exposure to rams, its use is associated with hastened onset of the breeding season and increased prolificacy.
In the US, melatonin is not approved for use in food animals, and extralabel use for reproductive management is not compliant with AMDUCA.
In cats, subcutaneous implants labeled for sheep or oral formulations may be used to suppress estrus (see Hormonal Control of Estrus in Cats). The efficacy duration of subcutaneous implants in cats can be affected by the stage of the estrous cycle at the time of implantation, with prolonged interestrus intervals reported in cats treated during interestrus compared with cats treated during estrus (14).
Glucocorticoids, especially the C-16 substituted steroids dexamethasone, betamethasone, and flumethasone, are used to induce parturition in ruminants and occasionally in horses and small animals. Their therapeutic administration can inadvertently lead to abortion.
For More Information
Also see pet owner content regarding drugs used to treat urinary tract and reproductive tract disorders.
References
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Concannon PW. Biology of gonadotropin secretion in adult and prepubertal female dogs. J Reprod Fertil Suppl. 1993;47:3-27. https://pubmed.ncbi.nlm.nih.gov/8229941
Shille VM, Thatcher MJ, Simmons KJ. Efforts to induce estrus in the bitch, using pituitary gonadotropins. J Am Vet Med Assoc. 1984;184(12):1469-1473. https://pubmed.ncbi.nlm.nih.gov/6429111
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Nickson D, Renton JP, Harvey MJA, Boyd JS, Ferguson JM, Eckersall PD. Oestrus induction in the bitch. In: Proceedings of the 12th International Congress on Animal Reproduction, the Hague, the Netherlands, August 23rd–August 27th, 1992. Vol 4:1799-1801.
Scrogie NJ. The treatment of sterility in the bitch by use of gonadotrophic hormones. Vet Rec. 1939;51:265-268.
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Curcio BR, Canisso IF, Pazinato FM, et al. Estradiol cypionate aided treatment for experimentally induced ascending placentitis in mares. Theriogenology. 2017;102:98-107. doi:10.1016/j.theriogenology.2017.03.010
Crabtree JR. A review of oestrus suppression techniques in mares. Equine Vet Educ. 2022;34:141-151. doi:10.1111/eve.13405
Miller C, Varner D, Blanchard TL, Thompson JA, Johnson L. Effects of altrenogest on behavior and reproductive function of stallions. In: Proceedings of the 43rd AAEP Annual Convention, Phoenix, Arizona, USA, December 7–10, 1997. American Association of Equine Practitioners; 1997. Vol 43:195-196.
Frank LA, Watson JB. Treatment of alopecia X with medroxyprogesterone acetate. Vet Dermatol. 2013;24(6):624-e154. doi:10.1111/vde.12073
Coffman EA, Pinto CR, Snyder HK, Leisinger CA, Cole K, Whisnant CS. Antiluteogenic effects of serial prostaglandin F2α administration in cycling mares. Theriogenology. 2014;82(9):1241-1245. doi:10.1016/j.theriogenology.2014.07.038
Vanderwall DK, Parkinson KC, Rigas J. How to use oxytocin treatment to prolong corpus luteum function for suppressing estrus in mares. J Equine Vet Sci. 2016;36:1-4. doi:10.1016/j.jevs.2015.09.007
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