Overview of Systemic Pharmacotherapeutics of the Reproductive System in Animals

Also see Principles of Therapy 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 for control of 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, buserelin acetate) and intramuscular use in mares (deslorelin acetate). Implants of GnRH analogues (eg, deslorelin acetate) are effective for induction of estrus and ovulation in mares and bitches and, in higher doses over a prolonged period, are useful for contraception in male and female animals (such as dogs) by mediating longterm (≥12 months) reversible infertility caused by downregulation of GnRH receptors. Deslorelin acetate, the only approved implant formulation in the US, is currently licensed for treatment of adrenal disease in ferrets. Additional formulations, as implants, are licensed in Canada, Europe, Australia, and New Zealand for use in dogs and horses.

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 used for induction of a fertile estrus in anestral bitches and queens. 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 exerts mainly luteinizing hormone–like effects in domestic animals, is used to cause ovulation of mature ovarian follicles in cows or mares in controlled-breeding programs. It is also used for the stimulation of gonads as a test for cryptorchidism and in treatment of ovarian cysts in cattle or dogs. hCG is administered parenterally, with plasma levels peaking in ~6 hours. It is primarily distributed to the ovaries in females or the testes in males, with a small amount distributed to the proximal renal tubules. Although it is used extensively in equine breeding management in the US, chorionic gonadotropin is currently officially licensed only for the treatment of nymphomania and cystic ovarian 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 also may be used in superovulation protocols in ruminants. In the US, a commercially available swine formulation comprised of 400 IU of eCG and 200 IU of hCG for administration IM, is indicated per labeling for induction of estrus in gilts and sows experiencing delayed return to estrus after weaning. Treatment to induce estrus in small animals experiencing anestrus has also been described. (Also see Hormonal Control of Estrus and )

Estradiol esters (eg, valerate, cypionate, or propionate) have a longer duration of action than the parent compound. The availability of these compounds and restrictions on their use by species vary by country. In mares, estradiol esters may be used to induce estrous behavior (eg, in ovariectomized teaser mares) or may be used to synchronize ovulation when used in combination with progesterone and prostaglandins. In mares, treatment with estradiol cypionate has recently been proposed for management of compromised pregnancies, such as cases of placentitis.

Progesterone and synthetic progestins are used commonly to assist in the control of 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 may be useful for breeding or artificial reproductive techniques (eg, embryo transfer). They have also been used in behavior modification in horses, suppression of male libido in horses and dogs, and in the treatment of dermatologic disorders in dogs.

Androgens and androgen derivatives have previously been used to suppress estrus (particularly in racing Greyhounds) and to stimulate libido in young or senescent males. Because of potential adverse effects such as testicular degeneration from chronic administration, as well as concerns with 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 pathologic accumulation of uterine fluid (eg, pyometra). It should not be used in Bedlington Terriers, cats, or animals with hepatic disease, and it may exacerbate androgen-responsive neoplasms such as perianal adenomas or perianal adenocarcinomas. Additional adverse effects include hyperexcitability or aggressiveness, increased appetite, clitoral hyperplasia, vaginal discharge, changes in hair coat quality, and an objectionable musky odor. After oral administration, mibolerone is absorbed from the intestine, metabolized in the liver, and excreted in the urine and feces.

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 treatment of benign prostatic hyperplasia of dogs (0.1–0.5 mg/kg per day, PO).

Flutamide, although not approved for veterinary use in many countries, blocks dihydrotestosterone receptors and may be used for the same purpose (5 mg/kg per day, PO).

Prostaglandins such as prostaglandinF2_alpha (PGF2_alpha) and PGE2 and their analogues are used in veterinary medicine for various purposes.

PGF2 and its analogs are used mainly for their luteolytic effects to induce a predictable onset of estrus or to synchronize estrus in a variety of species. They may also be used for termination of pregnancy, either alone (in horses or pigs) or in combination with corticosteroids (in cattle or sheep) or dopaminergic agents (in dogs). These compounds also cause marked uterine contractions, which may be useful for expulsion of uterine contents in pathologic conditions (eg, pyometra) in horses, pigs, ruminants, and small animals. The most common compounds used include dinoprost, a naturally occurring PGF2_alpha, and cloprostenol, a synthetic prostaglandin analog.

In horses and cattle, PGF2_alpha may be administered during diestrus in the presence of a mature corpus luteum (CL). Antiluteogenic protocols have also been reported in which serial PGF2_alpha administered during the first 5 days of diestrus can be used to prevent the formation of a new CL in horses and to induce a new estrus. Common transient adverse effects in horses include sweating and abdominal discomfort (colic); increased salivation may occur in cattle. Small animals treated with prostaglandins may have increased salivation, vomiting, or diarrhea. The extent of the adverse effects may vary by patient and by the formulation used.

PGE2 (misoprostol) 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 pathologic 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. It is administered parenterally (intravenously, intramuscularly, or subcutaneously). Oxytocin may also be administered intranasally; however, absorption can be erratic.

In small animals, intranasal oxytocin (2 IU every 2 hours or before nursing) can be administered to stimulate maternal bonding and behavior in the immediate postpartum period.

In mares, oxytocin (60 IU, IM, every 24 hours for 30 days; or 60 IU, IM, every 24 hours, for 7–14 days when initiated after ovulation detection) has been administered to prevent estrus by prolonging the period of diestrus and CL function.

Uterine relaxation is caused by beta-2-mimetic agents, such as clenbuterol. Such agents have been used to postpone parturition (to reduce obstetrical complications in heifers) and to facilitate obstetric manipulations in large domestic animals. Clenbuterol use in food-producing animals is illegal in the US.

Dopaminergic agonists, such as bromocryptine, metergoline, or cabergoline, cause decreased serum prolactin concentrations. They are useful in treatment of pseudopregnancy in dogs (eg, bromocryptine at 10 mcg/kg per day, PO, for 10 days, or at 30 mcg/kg per day, PO, for 16 days) and as an adjunct to PGF2_alpha in terminating pregnancy or in treating pathologic accumulation of uterine fluid. Dopaminergic agonists can also be used to induce estrus in dogs because they are luteotrophic in this species (eg, cabergoline at 5 mcg/kg per day, PO, until 2 days after onset of proestrus).

Dopamine antagonists, such as sulpiride or domperidone, have shown promise in the manipulation of seasonal breeding species. In mares, sulpiride (1.1 mg/kg per day, IM) can shorten the interval to the onset of the ovulatory season, particularly when used in combination with artificial lighting programs or photostimulation. Domperidone (1.1 mg/kg per day, PO) has also been proposed. Although the exact mechanism of action is not completely understood, dopamine antagonists increase endogenous prolactin levels and may 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 (eg, domperidone at 1.1 mg/kg per day, PO) and dogs (eg, metoclopramide 0.1–0.3 mg/kg, PO or SC, every 6–8 hours).

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. 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 cats, subcutaneous implants labeled for sheep (18 mg) or oral formulations (4 mg/cat, PO, every 24 hours) may be used to suppress estrus. Duration of efficacy in cats may 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.

Glucocorticoids, especially the C-16 substituted steroids dexamethasone, betamethasone, and flumethasone, are used for induction of parturition in ruminants (eg, dexamethasone 20–30 mg, IM, given within 2 weeks of expected calving date). Their therapeutic administration may inadvertently lead to abortion.