section epub:type=”chapter” id=”c0043″ role=”doc-chapter”> Susan E. Little Control of reproduction is necessary to manage owned and unowned cat populations and to prevent specific cats from reproducing, such as in purebred breeding programs or research colonies. Sterilization also provides significant benefits to cats, such as reduced risk of some diseases and improving the human–animal bond by reducing or eliminating sexual behaviors Surgical sterilization remains the most common method for control of reproduction in cats. However, more pharmacologic options have become available and progestins are being re-evaluated. This chapter discusses the increasing array of tools for control of reproduction for feral and community cats as well as breeding and pet cats. Surgical sterilization; castration; neuter; spay; ovariohysterectomy; ovariectomy; vasectomy; nonsurgical sterilization; contraception; deslorelin; melatonin; pregnancy termination; prostaglandins; cabergoline; aglepristone; misoprostol. Control of reproduction is necessary to manage owned and unowned cat populations and to prevent specific cats from reproducing, such as in purebred breeding programs or research colonies. Sterilization also provides significant benefits to cats, such as reduced risk of some diseases and improving the human–animal bond by reducing or eliminating sexual behaviors (Box 43.1).1 The characteristics of an ideal method are safety, reliability, convenience, and affordability. Surgical sterilization (gonadectomy) is the oldest method and is widely available. However, there are various reasons why surgery may not be available, affordable, or appropriate for every cat. Even if a cat is not intended for breeding, owners may have negative attitudes toward surgical sterilization or may find it unaffordable.2 In addition, veterinarians may choose nonsurgical methods for cats that are not good candidates for anesthesia and surgery. For these reasons, safe, effective, and affordable methods of nonsurgical sterilization and contraception (temporary, reversible infertility) are necessary. Nonsurgical methods that cause permanent infertility are an important focus of research for control of feral and community cat populations and have applications for owned cats as well. Contraception is primarily used in certain countries (e.g., European countries) or in certain populations (e.g., purebred cats, research colonies). More information on surgical and nonsurgical approaches to control reproduction in community and feral cat populations is found in Chapter 48: Care and Control of Community Cats. Castration (also known as orchiectomy or orchidectomy) is the most common procedure used to control fertility in male cats. The surgery is easy to perform, requires simple equipment, is effective and irreversible, and eliminates most of the undesirable behavior traits of an intact male (e.g., aggression, roaming, urine marking). The only reported detrimental effect is decreased metabolic rate and obesity, which can be prevented by adjusting caloric intake.3 Castration may be performed as early as 6 to 8 weeks of age (see Chapter 46: Pediatrics). Prepuberal castration is more effective at preventing unwanted sexual behaviors than castration after sexual maturity.4 Cats may be castrated using either an open or closed scrotal approach. The closed approach is preferred as it is difficult to achieve surgical asepsis for castration. Both testicles are removed via a small incision in the scrotum. The spermatic cord may be ligated with suture material, or the cord may be knotted on itself which avoids leaving foreign material in an open surgical site. The scrotal incision is left to heal by second intention. Complications associated with castration in the male cat are few but include scrotal swelling, hemorrhage, bruising, and infection. A newly reported and rare complication is mild, transient hyphema, first noticed by veterinarians providing high-volume spay–neuter services. In one report, post-castration hyphema was documented in 3 of 1399 cats (incidence, 0.2%).5 Hyphema appeared within 1 hour of surgery and resolved within 24 hours. As yet, there is no explanation for this phenomenon. Weight gain following castration is commonly reported and is largely due to increased food intake.6 Proactive nutritional management at the time of castration can help prevent weight gain. Vasectomy involves the bilateral removal or occlusion of a portion of the ductus deferens and causes infertility by preventing ejaculation of sperm during copulation. Vasectomy does not remove or prevent undesirable sexual behaviors, because testosterone is still produced. Therefore, it is infrequently used for control of reproduction in male cats. However, “teaser tom cats” (infertile males with good libido) may be used in catteries to bring queens out of estrus when pregnancy is not desired. Mating with a teaser tom cat induces pseudopregnancy in the queen and delays return to estrus. Vasectomy does not alter libido or mating ability in adult tom cats. However, live sperm may be present for up to 7 weeks after surgery.7 Vasectomy is a relatively simple surgical procedure performed through a 1- to 2-cm incision cranial to the scrotum. After incision of the skin and subcutaneous tissue, the spermatic cords are identified and exteriorized from the tunica vaginalis using blunt and sharp dissection. Gentle manipulation of the testicle is helpful for identification of the spermatic cord. Once the ductus deferens is isolated, a small segment is removed, and the severed ends are ligated. The subcutaneous tissue and skin are closely routinely. Ovariohysterectomy (OVH) is performed through a small ventral midline incision or by a flank approach. The ventral midline incision is centered in the middle one-third of the distance between the umbilicus and the pubis. The incision must be long enough to access the ovaries as well as the junction of the cervix and uterine body. Once the reproductive tract has been exposed, the suspensory ligament is broken by traction. There are several methods for clamping and ligating the ovarian and uterine pedicles. No matter which technique is used, it is important to visualize the ovaries before placement of the clamp. The clamp must not be placed on any part of the ovary itself to prevent leaving ovarian tissue behind that can cause ovarian remnant syndrome. After ligation, each pedicle should be carefully examined for bleeding without tension on the tissue before releasing it into the abdomen. The lateral flank approach may be used by some surgeons or may be used in certain circumstances, such as cats that have normal or abnormal mammary development and for feral cats. The principal advantage for this approach in feral cats is the decreased likelihood of evisceration if body wall dehiscence occurs. Disadvantages include limited exposure of the contralateral side and difficulty in identifying a previous OVH scar. The flank approach is contraindicated in cats that are pregnant, have pyometra, are obese, or are <12 weeks of age.8 More information on the flank approach for OVH is in Chapter 48: Care and Control of Community Cats. Complications of OVH are less common in the cat than in the dog, but include hemorrhage, ovarian remnant syndrome, stump pyometra, and accidental ligation of a ureter. Careful attention to surgical technique will prevent most complications. Although uncommon in the United States and Canada, ovariectomy (OE) without hysterectomy is commonly performed in other countries. There is no scientific evidence that OVH is preferred over OE.9 Benefits of OE over OVH include smaller incisions, decreased abdominal trauma, and shorter surgery and anesthesia times. The development of cystic endometrial hyperplasia–pyometra complex in the intact uterus should only occur if the cat is exposed to an exogenous source of progestins. Ovariohysterectomy and OE may be performed as early as 6 to 8 weeks of age (see Chapter 46: Pediatrics). As for castration of male cats, weight gain is commonly reported after OVH/OE in female cats.6 A proactive nutritional management strategy at the time of surgery can help prevent weight gain. Research has been ongoing for many years to find nonsurgical alternatives that provide permanent sterility to decrease the cost of sterilization and increase availability.10,11 The research has largely been driven by the need for population control of feral and community cats (see Chapter 48: Care and Control of Community Cats). Injection of chemical agents (e.g., zinc gluconate, calcium chloride) into the testis, epididymis, or vas deferens to induce permanent sterility has received some attention.12 This approach is less invasive, can be performed more quickly, and may be less expensive than surgical sterilization. Adequate sedation and analgesia are required. A potential drawback is that while fertility is suppressed, production of testosterone may not be, preserving behaviors associated with intact male cats. A product containing zinc gluconate has been commercially available for dogs in the past but to date, no products have been licensed for cats. One study found that an injection of 1 mL of 70% glycerol into each testis induced azoospermia, a significant decrease in serum testosterone, and a significant decrease in testicular size.13 Immunocontraceptive vaccines that target reproductive antigens (e.g., zona pellucida, gonadotropin-releasing hormone [GnRH]) have also received considerable interest for fertility control in male and female cats, but to date, no product has reached the market. Short- or long-term contraception may be desirable for cats in some circumstances, such as those in breeding programs or cats that are poor candidates for anesthesia and surgery. The most common drugs for contraception in cats include progestins, GnRH agonists, and melatonin (Table 43.1). See Table 43.1 GnRH, Gonadotropin releasing hormone; IM, intramuscular; PO, by mouth; SC, subcutaneous. Progestins are synthetic forms of progesterone and are the oldest class of drug used to control reproduction in cats. They provide negative feedback to the hypothalamus which triggers events that produce contraception: inhibition of GnRH followed by decreases in luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Progestins are not often used for contraception in male cats but may be used for reducing behaviors such as urine-marking although other classes of drugs are more appropriate. Progestins are not approved for use in cats in all countries. Unfortunately, progestins have been misused for years, leading to concerns about adverse effects such as diabetes mellitus, uterine disease and infertility, adrenocortical suppression, mammary hyperplasia, and mammary neoplasia. Although not as well-studied as in female cats, progestins have been associated with mammary hypertrophy and mammary adenocarcinoma in male cats.14,15 Progestins can be safely used provided drug dosages are appropriate and care is taken with patient selection. They should not be used in queens that are prepubertal, pregnant, or in diestrus, or in queens with mammary conditions, uterine discharge, or prolonged estrus. Megestrol acetate is effective for suppressing estrus in queens when given orally and is best started in anestrus. A variety of dosages are reported in the literature and there is some evidence that the risk and severity of adverse effects are dose-dependent. Most adverse effects are associated with high doses given frequently or for a long period of time (0.625 to 1.25 mg/kg/day or 2.5 to 5.0 mg/kg/week for >1 year). A dosage of 2.5 mg/cat/week appears to be safe and is often the recommended dosage for licensed products in Europe.16 Even lower oral dosages may be effective. For example, a megestrol acetate product in Italy (Estrophil, MSD Animal Health) is licensed at 11 µg/kg/day for a maximum of 12 months. Research is needed to determine the optimal duration of administration that is associated with a low risk of adverse effects. Medroxyprogesterone acetate is a long-acting progestin available in oral and injectable formulations that is also effective at suppressing estrus. This progestin does not seem to have diabetogenic effects; the mammary gland seems to be the primary target for adverse effects. Reports of mammary hyperplasia and neoplasia are usually associated with injectable dosages of 25 to 100 mg given every 4 to 6 months. Intramuscular dosages of 2.0 mg/kg every 3 months or 2.5 mg/kg every 5 to 6 months and oral dosages of 0.05 mg/kg/day are still effective and are likely to be safer, although return to estrus may occur more quickly than with higher dosages.16 Injectable doses of 3 to 10 mg/kg or higher may pose serious health risks and should be avoided. Research is needed to determine the lowest effective dosage and the optimal duration of administration that is associated with a low risk of adverse effects. It seems likely that a low-dose protocol can be safely used in young queens for a longer duration than in mature queens due to age-related changes in the uterus and/or mammary glands in mature queens.16 Proligestone is a long-acting injectable progestin with weaker progestational activity than other available drugs.17 It is licensed in some European countries for suppression of estrus in the queen. At the licensed dose of 100 mg/cat (25 to 30 mg/kg) given subcutaneously (SC), the effect of a single dose on estrus suppression lasts about 6.5 months.18 There is limited evidence that proligestone may have a lower risk of adverse effects on glucose and adrenal metabolism and the uterus than other progestins. There is a single case report of a cat developing mammary hyperplasia19 and another case report of a cat developing calcinosis circumscripta.20 Chlormadinone acetate has been reported as safe and effective for prevention of estrus in queens, but the drug is not widely available and is more commonly used in dogs. One study reported that long-term oral dosing (2 mg/cat, once weekly) for up to 4.6 years was not associated with adverse effects other than weight gain.21 However, when treatment is continued for long periods of time, mammary and uterine disorders similar to those seen with other progestins may occur.21 Safe use of progestins in queens involves appropriate patient selection and use of the lowest effective dose for the shortest time. A detailed history should be taken, and a thorough physical examination performed. The examination should especially evaluate the mammary glands for masses and abdominal palpation for increased uterine size. Progestins are best started when the queen is in anestrus or interestrus. Starting when the queen is in estrus will necessitate higher doses and starting during diestrus would mean adding exogenous progesterone when a high endogenous level is present. Vaginal cytology should be performed to rule out estrus and serum progesterone should be evaluated to rule out diestrus. Ideally, mature queens (>2 to 3 years) should have abdominal ultrasound performed to evaluate the uterus for abnormalities. Gonadotropin-releasing hormone is the master reproductive hormone, controlling release of LH and FSH from the pituitary gland. The effects of GnRH agonists have two phases: stimulation and downregulation. The initial response is stimulation of reproductive hormones that may last for a few days to a few weeks. However, sustained exposure eventually causes downregulation of GnRH receptors and decreased release of LH and FSH, thereby suppressing fertility in males and females. Deslorelin is the most commonly used GnRH-agonist and is licensed for contraception in some species as a slow-release implant (Suprelorin, Virbac) in some countries, although it may not be licensed for cats. The ease of administration, efficacy, safety, and reversibility make these implants attractive. They are typically placed SC between the shoulder blades or near the umbilicus without the need for sedation or anesthesia.22,23 Most studies in cats have been performed with 4.7-mg implants, but a few have used the 9.4-mg size. During the stimulatory phase after implantation, sexual behaviors (e.g., libido, mounting, attempts to mate) may increase in male cats.22 In the downregulation phase, penile spines disappear, testicular volume decreases, urine marking disappears, and appetite increases.22 In female cats, the stimulatory phase is associated with estrus in some, but not all, cats.23–25 Estrus behavior started by 4 ± 2 days and lasted for 3.5 ± 3 days in one study.24 One small study suggested that treatment of queens with oral megestrol acetate (5 mg/cat) before (14 days before and 12 hours before) and after (14 days later) placing the deslorelin implant may prevent induced estrus during the stimulatory phase.25 For reasons that are not well understood, the time to downregulation is variable. For example, in one study of 10 adult male cats, downregulation of testosterone to basal levels (<0.1 ng/mL) was achieved in 9 cats after 3 months (including 5 cats that reached basal levels within 20 days).22 One study found a significant decrease in sperm counts by week 16,26 while another found complete azoospermia did not occur until 6 months.27 This delay between the initial effect on sperm numbers and complete suppression of sperm production is expected as the sperm production cycle in male cats takes about 47 days.28 The duration of effect is also variable. A survey of cat breeders in France reported that sexual behaviors were suppressed in males for a mean of 13 months (range, 8 to 21 months) in 37 of 57 cats.29 In the same survey, estrus was reportedly inhibited in 26 of 41 females for a mean of 16 ± 5.7 months (range, 8 to 38 months). Interestingly, two of the females had persistent estrus, necessitating removal of the deslorelin implant. In one study of 20 female cats, the time to return of estrus was 680 ± 62 days (range, 16 to 37 months) for 19 of the cats.23 The remaining cat’s implant was still active at 37 months. In one placebo-controlled study of 10 queens, the duration of suppression varied from 5 to 14 months or longer.30 In a study of seven male cats using a testosterone concentration of >0.5 ng/mL as the threshold for resumption of gonadal activity, the mean duration of action for deslorelin was 79 weeks (range, 62 to 100 weeks).31 In the same study, libido returned in about 22 months but an additional 1 to 3 months elapsed before normal mating behavior returned. A study of 16 adult male cats treated with a 9.4 mg deslorelin implant found that duration of effect was 750 to 850 days, up to two times longer than that achieved with 4.7 mg implants.32 The unexpectedly long duration of effect in some cats may lead a breeder to request removal of an implant to restore fertility. In one study of 18 male cats that received a 4.7 mg deslorelin implant, resumption of serum testosterone production occurred about 3 weeks after implant removal, independent of age and season.33 The ability of deslorelin implants to postpone puberty has also been investigated. In a trial of 30 prepubertal female cats, 15 were given a deslorelin implant and 15 were untreated controls.34 In the treatment group, 14 cats reached puberty at a mean age of 281 ± 22 days (range, 180 to 428 days) while the untreated cats reached puberty at a mean age of 178 ± 11 days (range, 134 to 286 days). One cat in the treatment group had induced estrus and one had pyometra. In another study of nine prepubertal queens, one queen showed signs of estrus at 7 days. Five queens were lost to follow-up; puberty was postponed for 21 to 36 months in the four remaining cats.35 In a study of six prepubertal male cats, sexual behaviors and sperm production were suppressed for at least 48 weeks.36 No adverse effects on the health of cats have been noted with deslorelin implants. Male and female cats have demonstrated normal fertility and have produced healthy kittens after treatment.23,29,31 One case report describes a cat that was inadvertently mated 9 days before treatment with a 4.7-mg implant.37 The cat delivered four healthy kittens 66 days after mating but had inadequate milk production and poor maternal behavior. At the next mating 498 days after treatment, a healthy litter was born and successfully raised by the queen. This case report raises the possibility that deslorelin may affect maternal care if the implant is placed during pregnancy. Mild, temporary reactions (e.g., swelling, erosions due to scratching, pyodermatitis) at implant sites have been reported.23–25 No changes in health status based on physical examination, complete blood counts, and serum biochemistries have been detected in limited studies.22 These studies show that deslorelin is an effective means of contraception in cats, but time to suppression of fertility and duration of action are somewhat unpredictable. Another drawback is the lack of information on repeated use of deslorelin implants in cats. Melatonin is a hormone produced by the pineal gland with secretion controlled by photoperiod. Higher concentrations are produced during times of shorter photoperiod and will suppress ovarian activity. Daily oral melatonin was found to be effective at estrus suppression in cats but only after 30 days of treatment.38 The effect was reversible, with normal ovarian activity returning 21 to 40 days after melatonin was withdrawn. However, melatonin can induce estrus, ovulation, and pseudopregnancy A subcutaneous implant containing 18 mg melatonin licensed for use in sheep (Melovine, Ceva) has been investigated off-label in the queen. In one study, the implant effectively and reversibly suppressed estrus in nine queens for 2 months without adverse effects when placed in estrus and 4 months when placed in interestrus.39 Although OVH and histopathology were not performed on these queens, six of eight treated queens that were bred after return to estrus had normal pregnancies. In another study, the same implant inhibited estrus in 33 of 42 queens for a mean of 86 ± 50 days (range, 21 to 277 days).29 Other studies using the sheep implant have confirmed the variable duration of effect and the lack of effect in some cats, as well as cats with a potentially fertile estrus within 10 days of implantation.40 To date, only one study has evaluated melatonin implants in prepubertal female cats. In this study, 22 cats received an 18-mg implant, and 10 cats were untreated controls.41 The cats were observed daily for signs of estrus and vaginal cytology was assessed three times per week. There was no significant difference between the groups for age at puberty. The main drawbacks for the use of melatonin implants in cats are the highly variable duration of effect and the lack of effect in some cats. It is possible that performance may be improved with higher dosages or slow-release formulations. The most predictable effect of the implant seems to occur when it is implanted during interestrus. As for GnRH agonists, there is little information on repeated use. Termination of an unwanted pregnancy can be achieved with surgery (OVH) or drug therapy. If the queen is not valuable to a breeding program and is otherwise healthy, the surgical approach is often elected. Pharmacologic pregnancy termination is uncommonly requested for the queen, but several options are available (Table 43.2). The traditional mismating treatment has been estrogen (diethylstilbestrol or estradiol cypionate) given 2 to 3 days after breeding. The mechanism of action is thought to be interference with tubal transport of fertilized eggs. However, estrogens will prolong estrus in the queen and are associated with potentially serious adverse effects, such as pyometra and aplastic anemia, and so cannot be recommended. A single oral dose of megestrol acetate (5 mg) is also reported to prevent implantation of fertilized eggs and may be safer than estrogen.42 Table 43.2
Control of Reproduction
Abstract
Keywords
INTRODUCTION
SURGICAL STERILIZATION
Castration
Vasectomy
Ovariohysterectomy and Ovariectomy
NONSURGICAL STERILIZATION
CONTRACEPTION
e-Box 43.1 for further reading.
Drug
Dosage
Effect
Comments
Progestins
Chlormadinone
2 mg/cat, PO, once weekly21
Estrus suppression
Not widely available
Medroxyprogesterone acetate
Estrus suppression
Significant dose-dependent adverse effects; use of lowest effective dose is highly recommended
Megestrol acetate
Significant dose-dependent adverse effects; use of lowest effective dose is highly recommended
Proligestone
100 mg/cat (25 to 30 mg/kg), SC18
Estrus suppression
Duration of effect is about 6.5 months
Other drugs
Deslorelin
4.7 mg, SC implant52
Suppression of fertility and reproductive behaviors; postpone puberty
GnRH agonist; stimulatory phase before downregulation; duration of effect is variable; scant information on long-term use of multiple implants
Melatonin
Estrus suppression, takes >30 days to reach effect with oral dosing
Duration of effect is variable and short; single implant will not work in all cats; scant information on long-term use of multiple implants
Progestins
Gonadotropin-Releasing Hormone Agonists
Melatonin
PREGNANCY TERMINATION