Progestins

Synthetic progestins (Table 2-1) have proven effective in all mammalian species that have been treated. Progestins may prevent ovulation by negative feedback on luteinizing hormone (LH), but they also thicken cervical mucus so that sperm passage is impeded, interrupt sperm and ovum transport, and interfere with implantation.¹² Because higher doses are needed to block ovulation than to affect the other endpoints, ovulation may occur in animals that are adequately contracepted.⁷ Progestins cannot completely suppress follicle development and the resulting estradiol secretion may stimulate physical and behavioral signs of estrus, so those indications cannot be used to judge efficacy.

TABLE 2-1 Currently Available Synthetic Progestin Products Used as Contraceptives

The progestin most commonly used by zoos has been the melengestrol acetate (MGA) implant introduced by Seal in the mid-1970s and now available from Wildlife Pharmaceuticals (Fort Collins, Colo). MGA is also available incorporated into a commercial hoofstock diet (Mazuri, Purina Mills, St. Louis) and as a liquid to be added to food (Wildlife Pharmaceuticals). A disadvantage of this approach is confirming that the animal consumes the dose needed each day. In a herd setting, it is important that the more subordinate animals eat an adequate dosage, which may result in dominant animals consuming more than the recommended dosage. However, data from studies of domestic cows have shown no deleterious effects at as much as three times the minimal effective dose.

Equids are the exception to the species successfully treated with MGA. However, altrenogest (Regu-Mate, Intervet, Boxmeer, The Netherlands), the only synthetic progestin effective in domestic horses for synchronizing estrus, should also be effective as a contraceptive, but at a higher dose. However, cost and the necessity for daily delivery have limited its use.

Depo-Provera (medroxyprogesterone acetate, Pharmacia & Upjohn, Bridgewater, NJ), the second most commonly used progestin in zoos, is often chosen because it is injectable and thus may be delivered by dart. In particular, it has been used for some seasonally breeding species (e.g., prosimians), species in which anesthesia for implant insertion is problematic (e.g., giraffes, hippos), and as an immediately available interim contraceptive. Another synthetic progestin, megestrol acetate, is an option for those that may be administered a daily pill.

The various synthetic progestins differ in degree of binding to receptors of other hormones such as glucocorticoids and androgens, and there are likely also species differences. One concern is possible side effects, such as symptoms of diabetes, as compared with gestational diabetes when endogenous progesterone is elevated. U.S. Seal chose MGA rather than medroxyprogesterone acetate (MPA, the synthetic progestin in Depo-Provera) to use in implants because MPA altered cortisol levels in that study.

A further problem with MPA is androgenic activity, equated in some tests with dihydrotestosterone, a natural androgen with potent morphologic effects, especially during development. For example, Depo-Provera treatment of female black lemurs resulted in male-like pelage darkening.³ Another progestin with androgen effects, levonorgestrel, has the highest binding affinity to androgen receptors of current progestins and is considered a potential health risk because of its effect on lipids and the cardiovascular system.²⁴ Although Norplant implants are no longer available in the United States, some progestin-only birth control pills contain levonorgestrel, its active ingredient.

The major side effect reported for progestins is weight gain, and one product (megestrol acetate, Megace, Par Pharmaceuticals, Woodcliff Lake, NJ) is marketed specifically to increase appetite. Progestin supplementation may help maintain pregnancy in some species, whereas in others, especially early in gestation, they have been associated with embryonic resorption.⁴ Progestins may interfere with parturition via suppression of uterine smooth muscle contractility, as documented in white-tailed deer,²⁰ but primates treated with progestins have given birth without incident.¹ This species difference may be related to the patterns of progesterone near term. In general, species other than primates experience a decline in progesterone before the onset of parturition, which may be necessary to release the myometrium from suppression. In contrast, progestins appear to be safe for lactating females and nursing young. They do not interfere with milk production, and no negative effects on the growth or development of nursing infants have been found.

Although MGA implants have been used since the mid-1970s, proper analyses of reversibility by species have been difficult because of the variables that must be considered. First, there must be a sufficient number of attempts to breed, but other factors include matching contracepted and noncontracepted groups on age and parity prior to MGA use. In addition, although MGA implants are recommended to be replaced every 2 years, this is a conservative estimate and in many cases is effective considerably longer. Thus, reversal may only be reasonably expected if the implant is removed. Such analyses have been performed only on golden lion tamarins and tigers. Wood and colleagues²⁵ have found that 75% of the tamarins conceive within 2 years, a rate comparable to nontreated females, but treated females have higher rates of miscarriage and stillbirths. Chuei and associates⁹ have found that only 62% of tigers give birth 5 years after implant removal compared with 85% of nontreated females after 2.7 years. Possible reasons for poorer recovery in tigers were not tested directly but may be related to the high risk of uterine pathology in felids, which might interfere with pregnancy maintenance.

Estrogens

Estrogens may prevent ovulation by suppressing follicle growth, but at contraceptive doses they have been associated in many species with serious side effects. The estrogens diethylstilbestrol (DES), mestranol, estradiol benzoate, and estradiol cypionate may block implantation following mismating in dogs. However, their tendency to stimulate uterine disease, bone marrow suppression, aplastic anemia, and ovarian tumors makes them inappropriate contraceptive compounds.

Estrogen-Progestin Combinations

Some of the deleterious effects associated with estrogen treatment (e.g., overstimulation of the uterine endometrium in primates) may be mitigated by adding a progestin. However, progestins are synergistic, not inhibitory, to estrogen effects in carnivores, making the combination even more likely to result in uterine and mammary disease. Because this synergy occurs in canids when progestin-only methods are initiated during proestrus, when natural estrogen levels are elevated, treatment should be initiated well in advance of the breeding season if progestins must be used. When treatment is begun during deep anestrus, the side effects of synthetic progestins are minimized, even when continued for several years, a regimen that has been used for domestic dogs in Europe for several decades.

There are numerous orally active contraceptive products containing various combinations of an estrogen and a progestin at various doses that are approved for human use in the United States. Ethinyl estradiol is the most common form of estrogen, although a few products use mestranol. Norethindrone is the most common progestin ingredient; others include levonorgestrel, desogestrel, norgestrel, norgestimate, and ethynodiol diacetate. Oral contraceptive regimes designed for humans were originally intended to simulate the 28-day menstrual cycle, with 21 days of treatment followed by 7 days when either a placebo or no pill is taken, resulting in withdrawal bleeding that resembles menstruation. However, more recently, products have been introduced that only include 1 week of placebo (Seasonale, Duramed Pharmaceuticals, Pomona, NY) every 3 months.

Androgens

Both testosterone and the synthetic androgen mibolerone (Cheque Drops, Pharmacia & Upjohn) are effective contraceptives (gray wolf, Canis lupus; leopard, Panthera pardus; jaguar, P. onca; and lion, P. leo), but masculinizing effects have included clitoral hypertrophy, vulval discharge, mane growth (female lion), mounting, and increased aggression. Mibolerone is approved for use in dogs but not cats, and is contraindicated for females that have impaired liver function or are lactating or pregnant, because female fetuses may be virilized. Mibolerone use in wildlife is inadvisable, especially because of the potential for increased aggression.