Overview of Systemic Pharmacotherapeutics of the Reproductive System
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 used for treatment of ovarian cysts and for control of ovarian follicular dynamics in cattle, for estrus induction (by pulsatile administration) in mares and bitches, and for stimulation of testicular function (eg, in testing for cryptorchidism). Implants of GnRH analogues (eg, deslorelin) 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 mo) reversible infertility caused by downregulation of GnRH receptors.
Follicle-stimulating hormone (FSH), usually extracted from animal pituitary glands, stimulates follicular growth and estrogen production in females and spermatogenesis in males. It is used for superovulation of several domestic species. It has also found application in induction of fertile estrus in bitches and queens. Prolonged FSH use or 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 for stimulation of gonads (as a test for cryptorchidism and also for treatment of ovarian cysts in cattle or dogs). It is also used to cause ovulation of mature ovarian follicles in cows or mares in controlled-breeding programs. hCG is given parenterally; plasma levels peak in ~6 hr. It is primarily distributed to the ovaries in females and the testes in males, although some is also distributed to the renal proximal tubules.
Equine chorionic gonadotropin (eCG) has FSH activity in most species and is used to induce ovarian follicular growth, both for superovulation and for estrus induction. (Also see Hormonal Control of Estrus and Management of Reproduction: Cattle et seq.)
Estradiol esters (eg, valerate, cypionate, or propionate) have a longer duration of action than the parent compound. These compounds are used in bitches, mares, and cows for induction or enhancement of fertile estrus or for induction of estrous behavior; treatment of urinary incontinence in bitches; and for antitumor activity in prostatic and perianal tumors. Availability of these compounds and restrictions on their use vary by country. Estrogenic therapy may cause bone marrow suppression and potentially fatal aplastic anemia in dogs and cats; its use is also associated with development of cystic endometrial hyperplasia in these species, and it may have teratogenic effects in pregnant animals. Because of these potential complications, estrogens are no longer recommended for termination of pregnancy in cases of mismating.
The nonsteroidal synthetic compound diethylstilbestrol also has estrogenic activity; its use is prohibited in food animals in the USA. Estrogen antagonists, such as tamoxifen, have been proposed for treatment of metastatic mammary carcinoma in dogs.
Progesterone and synthetic progestins are used for suppression or postponement of estrus in bitches and queens. They have also been used in behavior modification and to treat dermatologic disorders. Progesterone supplementation is used to support pregnancies regarded as at risk (eg, in pregnant mares with potentially endotoxemic conditions) and in horses or dogs with demonstrated hypoluteoidism. Adverse effects of progestin administration in small animals include induction of cystic endometrial hyperplasia, adrenocortical suppression, induction or exacerbation of diabetes mellitus, and mammary gland development. Mifepristone (a progesterone-receptor antagonist) has been used experimentally as a canine abortifacient; epostane, a progesterone-synthesis inhibitor, also terminates canine pregnancy.
Testosterone is used for estrus suppression (particularly in racing Greyhounds). Mibolerone, a weak androgenic steroid, is used to prevent estrus in bitches. It should not be used in Bedlington Terriers or cats, and it may exacerbate perianal tumors. After PO administration, mibolerone is absorbed from the intestine, metabolized in the liver, and excreted in the urine and feces. Chronic administration of testosterone may cause testicular degeneration in male animals. Finasteride, a 5α-reductase inhibitor, prevents the conversion of testosterone to 5α-dihydrotestosterone, the active androgen in male accessory sex glands. It is useful in the treatment of benign prostatic hyperplasia of dogs (0.1–0.5 mg/kg/day, PO). Flutamide blocks dihydrotestosterone receptors and is used for the same purpose. Chemical modifications of testosterone potentiate its anabolic actions while minimizing virilizing effects. These compounds (eg, boldenone undecylenate, stanozolol, nandrolone decanoate) are used for their anabolic effects in convalescing or athletic animals. Protracted use may cause at least temporary infertility in both sexes.
Prostaglandin F2α and its analogues are used mainly for their luteolytic effects to induce predictable onset of estrus (or synchronization of estrus) in a variety of species. They may also be used for termination of pregnancy either alone or in combination with corticosteroids (cattle, sheep) or dopaminergic agents (dogs). These compounds also cause marked uterine contractions, which may be useful for expulsion of uterine contents in pathologic conditions (eg, pyometra).
Oxytocin is used to promote milk letdown, to treat agalactia, as an adjunctive treatment of mastitis, and to cause contraction of the uterus either to induce (or supplement) labor or to enhance postpartum uterine contraction and expulsion of uterine fluid or fetal membranes. It is administered parenterally (IV, IM, or SC). Oxytocin may be given intranasally, but absorption can be erratic. Uterine relaxation is caused by β2-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 USA.
Dopaminergic agents, such as bromocryptine or cabergoline, cause decreased serum prolactin concentrations. They are useful in treatment of pseudopregnancy in dogs (bromocryptine at 10 mcg/kg, PO, for 10 days, or at 30 mcg/kg for 16 days) and as an adjunct to PGF2α in terminating pregnancy, although not approved in the USA for this use. Prolactin is luteotrophic in some species, including dogs.
Dopamine antagonists, such as sulpiride, have shown promise in the manipulation of seasonal breeding species—their use hastens the onset of estrous cycles in mares in the spring.
In the UK and New Zealand, melatonin is labeled for use in sheep (and goats in New Zealand) to improve early breeding and ovulation rates. It is available as an 18-mg SC implant; combined with exposure to rams, its use is associated with hastened onset of the breeding season and increased prolificacy.
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 wk of normal term). Their therapeutic administration may inadvertently lead to abortion. Xylazine and other α2-adrenergic agents cause myometrial contraction that may harm the fetus or impede obstetrical manipulations.