Contraception


Chapter 81

Contraception



Cheryl Asa, Mary Agnew


Contraception has become integral to the reproductive management of mammals. Contraception recommendations are incorporated into animal care manuals and master plans, and almost all zoos and aquariums in North America use contraception to control reproduction. We use the term contraception to refer to methods that are designed to be reversible so that animals may return to reproduction at a later date if recommended to breed. In contrast, we use the term sterilization for methods that are considered permanent. For more extensive discussions of the issues surrounding contraceptive use and available methods, as well as complete citations, see Wildlife Contraception: Issues, Methods and Application3 and Wild Mammals in Captivity.4



Female Methods


Permanent Sterilization


Permanent sterilization may be the best choice for those not likely to receive breeding recommendations in the future or that may have clinical conditions that make reproduction inadvisable. Ovariectomy removes the source of gametes as well as reproductive hormones, eliminating estrous behavior and secondary sex characteristics such as perineal swelling. Although removal of the uterus in addition to the ovaries is common for domestic dogs and cats in the United States, a comparative study of the two procedures in dogs has found no differences in prevalence of any of the anticipated side effects.23 Information on potential side effects of ovariectomy is available primarily for dogs, cats, and humans. No data, however, are available on the potential for decreased bone density following removal of the ovaries in long-lived animals such as the great apes, but it may be assumed equivalent to the results for humans.


Tubal ligation or blocking the oviducts by other means may be an option for species in which gonadal hormones are not associated with pathology (e.g., primates). However, it should not be used in female carnivores because the repeated cycles of elevated estrogen and progesterone levels increase the risk of mammary tumors and uterine infection and tumors.



Reversible Contraception


Steroid Hormones


Progestins.

Synthetic progestins (Table 81-1) 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.15 Because higher doses are needed to block ovulation than to affect the other endpoints, ovulation may occur in animals that are adequately contracepted.9 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.



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, CO). MGA is also available incorporated into a commercial hoofstock diet (Mazuri, Purina Mills, St. Louis, MO) 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 species differences may also exist. One concern is possible side effects such as symptoms of diabetes compared with gestational diabetes when endogenous progesterone is elevated. The 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.5 Another progestin with androgen effects, levonorgestrel, has the highest binding affinity to androgen receptors of more recent generation progestins and is considered a potential health risk because of its effect on lipids and the cardiovascular system.30 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, it has been associated with embryonic resorption.6 Progestins may interfere with parturition via suppression of uterine smooth muscle contractility, as documented in white-tailed deer,26 but primates treated with progestins have given birth without incident.3 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, a sufficient number of attempts to breed must have been made, 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 they are 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 colleagues31 have found that 75% of the tamarins conceive within 2 years, a rate comparable with that in nontreated females, but treated females have higher rates of miscarriage and stillbirths. Chuei and associates11 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.


Numerous orally active contraceptive products containing various combinations of an estrogen and a progestin at various doses have been 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. Mounting evidence indicates that continuous daily treatment without interruption may be safe, and in fact may be preferable in some species to prevent estrous behavior.



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.



Gonadotropin-Releasing Hormone Analogues


Synthetic analogues of gonadotropin-releasing hormone (GnRH) may be antagonists that block the action, or agonists, that have the same effects as the natural hormone on target tissue. Although antagonists would be the more logical selection for contraception, they are considerably more expensive and shorter acting, which limits their application. In contrast to antagonists, GnRH agonist administration is followed first by an acute stimulatory phase, when pituitary LH and follicle-stimulating hormone (FSH) levels are elevated, which may result in estrus and ovulation. Continued treatment using long-acting preparations such as implants or microspheres causes failure of stimulation of FSH and pulsatile LH secretion because of downregulation of GnRH receptors on pituitary gonadotrophs.19 The observed effects in the animal are similar to those following ovariectomy but are reversed after the hormone content of the implant or microspheres is depleted.


The stimulatory phase may be prevented by treatment with the synthetic oral progestin megestrol acetate given for 1 week before and 1 week following implant insertion. This method has successfully prevented proestrus and estrus32 when tested in domestic dogs and has been successful in many carnivores in zoos.3


Numerous GnRH agonist products are available, but most are expensive because they were approved for treatment of prostate cancer in humans. Leuprolide acetate, as Lupron Depot injection (TAP Pharmaceuticals, Deerfield, IL), has been used in zoos and aquariums for a variety of species, but results are not available except for some marine mammals.10 Deslorelin implants (Suprelorin, Peptech Animal Health, Macquarie Park, Australia), available in the United States by arrangement with the AZA Wildlife Contraception Center (St. Louis), have been effective in many mammalian species7,8 (Table 81-2). They have been used primarily in carnivores as an alternative to progestins that were associated with uterine and mammary pathology in that taxon.


Related posts:

  1. Sphenisciformes (Penguins)
  2. Tubulidentata (Aardvark)
  3. Lacertilia (Lizards, Skinks, Geckos) and Amphisbaenids (Worm Lizards)
  4. Trogoniformes

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Aug 27, 2016 | Posted by in EXOTIC, WILD, ZOO | Comments Off on Contraception

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