1.6: Reproduction Control

Learning Objectives

• Describe basics of normal reproductive physiology in the male and female dog and cat
• Explain the difference between contraception and sterilization and describe medical and surgical techniques for each
• Describe social, behavioral, and medical pros and cons for gonadectomy in male and female dogs and cats

Reproductive Physiology of the Female

The ovaries contain thousands of follicles, each of which contains an egg or ovum. As each estrous cycle begins, a cohort of follicles is selected to begin development. Development is promoted by release of hormones from the hypothalamus (gonadotropin releasing hormone [GnRH]) and pituitary (follicle stimulating hormone [FSH] and luteinizing hormone [LH]). As the follicle develops, it secretes estrogen, which causes the physical and behavioral signs of early heat, or proestrus. Estrogen concentrations fall about 9 days after the onset of proestrus; at this time, the bitch will stand to be bred (standing heat or estrus) and a surge of LH is released, causing ovulation. This is spontaneous ovulation. Queens are induced ovulators. In this species, copulation is the most common trigger for release of GnRH and subsequent ovulation. In either spontaneous or induced ovulators, the eggs are released from the follicles into the uterine tube, where fertilization occurs.

The egg is surrounded by a thick capsule, the zona pellucida, and by a layer of cells from the follicle. Spermatozoa introduced into the reproductive tract of the bitch undergo capacitation, a process involving the acrosome reaction on the head of the spermatozoon and achievement of hypermotility. Capacitated spermatozoa digest the layer of cells surrounding the egg and invade the zona pellucida. As soon as one spermatozoon gets to the inner layer of the zona pellucida, entry of other spermatozoa is blocked by an electrochemical reaction so only one spermatozoon fertilizes each egg. Cell division begins immediately. The developing embryos move into the uterus within days but do not implant in the uterine wall and develop placentas until about 12 days after the LH surge in cats and about 16-18 days after the LH surge in dogs.

Reproductive Physiology of the Male

Testes of male dogs should be descended into the scrotum by 8-14 weeks of age and must be descended by 6 months of age for the dog to be considered normal. Testes usually are descended at birth in male cats but may not be palpable until 6-8 weeks of age. The testes contain spermatogonia, which will divide to form spermatozoa under the influence of the hormone testosterone. Testosterone secretion from testicular Leydig (interstitial) cells is stimulated by GnRH and LH release from the hypothalamus and pituitary, respectively. Spermatozoa are manufactured in the testis but are neither motile nor capable of fertilization until after they pass through the adjoining tissue, the epididymis. Spermatozoa ejaculated at the time of semen collection come from the epididymis.

Reproduction Control

Contraception

Any procedure that prevents reproduction for a time but is reversible such that the individual may be capable of reproduction in the future.

Sterilization

Any procedure that makes an individual permanently incapable of reproduction.

Research into non-surgical methods for sterilization of dogs and cats is ongoing and no products are available at this time.

Surgical Sterilization

Ovariectomy (surgical removal of the ovaries), hysterectomy (surgical removal of the uterus, also called ‘ovary-sparing spay’), ovariohysterectomy (surgical removal of the ovaries and uterus) and tubal ligation (tying off the uterine tubes) are the techniques described in the literature for sterilization of bitches and queens. Tubal ligation is not commonly used for contraception of bitches or queens anywhere in the world.

Ovariectomy is commonly used in Europe and appears to offer the same benefits and concerns as does ovariohysterectomy (OHE or spay). Ovariectomy is reported to be less time-consuming and less invasive then OHE. In one study of 264 dogs, 126 of which had undergone ovariectomy and 138 of which had undergone OHE, no significant differences were reported in incidence of urogenital problems during a follow-up period of 8-11 years after surgery. Urinary incontinence was a reported finding in both groups; difference in incidence between the groups was not statistically significant. Ovary-sparing spay requires complete removal of the uterus to the level of the cervix and is not quicker or less-invasive than OHE. In the United States, OHE still is the most common surgical sterilization method.

In male dogs and cats, castration (surgical removal of both testes) and vasectomy (tying off the spermatic cord) are reported sterilization techniques. Castration is the most common surgical sterilization method.

Optimal Age for Surgical Sterilization of Dogs and Cats

Optimal age at which to perform OHE or castration of dogs and cats is not defined by the veterinary literature. In the United States, most veterinarians recommend cats and dogs be spayed or neutered when about 6 months of age, prior to puberty, which is defined as acquisition of normal breeding behavior and semen quality in males and first estrus in females. In other countries, veterinarians recommend that dogs and cats be spayed after their first estrus, or do not recommend elective surgical sterilization be performed at any age. Indeed, in some countries, elective gonadectomy is considered unethical and is either strongly discouraged or illegal. For this discussion, it is assumed that the veterinarian is comfortable with the ethics of elective gonadectomy and practices in a country in which such surgery is considered acceptable by professional associations and the society at large.

Dogs and cats can be considered as part of a larger population of animals or as individuals. Recommendation for age at which to perform elective gonadectomy must take this into account. Animals at humane organizations should be evaluated as part of the larger population as those animals are not yet associated with a responsible owner or guardian. Dogs and cats with an owner or guardian may be considered either as part of a larger population or as an individual.

Sterilization of Dogs and Cats With No Owner or Guardian

In the United States, a serious problem with pet overpopulation exists, such that millions of unowned dogs and cats are euthanized yearly. Some of these are feral animals, some are abandoned and brought to the humane association as a stray, and many are relinquished. Intact animals are much more likely to be relinquished than are spayed or neutered animals and animals that are adopted out from the humane association while still intact may either be returned or may repopulate that shelter with their offspring. While most intact animals are adopted out with a spay-neuter contract, compliance with such contracts has been demonstrated to be less than 60%. There is a significant lack of knowledge among pet owners regarding normal reproductive physiology among dog and cats owners; studies have demonstrated that up to 57% of bitch owners were unaware that bitches cycle at least twice yearly, up to 83% of queen owners were unaware that queens are polyestrous from spring to early fall, and up to 61% of dog and cat owners were unsure or believed that their animal would somehow be “better” after having had at least one litter. In one survey of dog- and cat-owning households, 56% of 154 canine litters and 68% of 317 feline litters were unplanned, with the majority of those owners reporting that they did not know the female had been in heat. While everyone would like to believe that better education of pet owners would lead to more responsible pet ownership, and while increasing education is a worthy goal that should be pursued, gonadectomy of dogs and cats prior to adoption is one weapon in the fight against overpopulation that should be employed at this time. Multiple studies have been published demonstrating safety of gonadectomy in puppies and kittens as young as 7 weeks of age. To that end, I recommend that all male and female dogs and cats should be spayed or castrated prior to adoption from humane organizations.

Sterilization of Dogs and Cats With an Owner or Guardian

Pros and cons of spay/castration can include behavioral and medical concerns. Here are some definitions you may find useful:

Incidence = the number of new cases in a population over a period of time

Morbidity = extent of illness among those having the condition

Mortality = death due to the condition

• Male Cats – The normal behavior of most intact male cats is incompatible with their living as house pets. Breeding behavior in cats is aggressive and intact male cats show that behavior readily. Urine from intact male cats is used for territorial marking and has a very distinct, strong odor. Incidence of obesity after castration is high, and is due to decreased metabolic rate in cats after gonadectomy. There are virtually no other health conditions reported to be increased or decreased in association with gonadectomy in male cats. Because of this, I recommend that any male cat not intended for breeding be castrated.

• Female Cats – Benefits of OHE in female cats include decreased incidence of mammary neoplasia, ovarian or uterine tumors, and pyometra. Of these, the most significant is mammary neoplasia. Mammary neoplasia is the third most common tumor of female cats, with a reported incidence of 2.5%. Incidence is increased with number of estrous cycles in the cat’s life and is increased in the Siamese and domestic Japanese breeds. Greater than 90% of cases are malignant adenocarcinoma.

Detriments of OHE in female cats include possible complications of surgery, obesity, increased incidence of feline lower urinary tract disease (FLUTD), and increased incidence of diabetes mellitus. Reported incidence of post-surgical complications in cats is 2.6%, with most reported complications mild and self-resolving. Incidence of obesity after OHE is high, and is due to decreased metabolic rate in cats after gonadectomy. Obesity can be controlled by use of a proper feeding regimen. Finally, increased incidence of FLUTD and diabetes mellitus has been reported after OHE in queens, with the Burmese breed especially prone to development of diabetes mellitus. Incidence of these two conditions is 0.6% and 0.5%, respectively.

Because the incidence and morbidity of mammary neoplasia are much higher than are the incidences of FLUTD and diabetes mellitus, and because morbidity associated with obesity can be controlled by the owner or guardian of the cat, I believe that female cats not intended for breeding should be spayed as early in their life as possible.

• Male Dogs – Benefits of castration in male dogs include decreased incidence of testicular neoplasia and non-neoplastic prostate disease, and possible increased lifespan. Testicular neoplasia is a common tumor of aged, intact male dogs, with a reported incidence of 0.9%. Morbidity generally is low. Benign prostatic hypertrophy (BPH) is a very common disorder of male dogs, with reported incidence of 75-80% in dogs aged 6 years or more. Again, morbidity generally is low. Finally, several studies have documented increased lifespan in castrated male dogs compared to intact males. This may be due to greater care by owners after the “investment” of surgery has been made in that animal, or may be due to a decrease in sexually dimorphic behaviors that put the animal at increased risk, such as roaming.

Detriments of castration in male dogs include complications of surgery; increased incidence of prostatic neoplasia, transitional cell carcinoma, osteosarcoma, lymphosarcoma, and hemangiosarcoma; increased incidence of anterior cruciate ligament (ACL) injury and hip dysplasia; obesity; and possible increased incidence of diabetes mellitus. Some reports also suggests increased incidence of behavioral disorders, such as fear of storms. Reported incidence of post-surgical complications in dogs is 6.1%, with most reported complications mild and self-resolving. Prostatic neoplasia, transitional cell carcinoma, osteosarcoma, and hemangiosarcoma generally are low in incidence but high in morbidity and mortality. No breed predisposition has been identified for prostatic neoplasia, but does exist for the other cancers noted. Incidence of ACL injury in dogs is relatively high, at 1.8%, and morbidity may be high, although this is generally considered to be a curable condition with surgery. Again, some breeds, most notably large and giant breeds, are predisposed to ACL injury. Obesity is high in incidence but morbidity can be controlled by the owner or guardian.

Appropriate recommendation for castration of male dogs is less readily evident than is that for male cats. While a given male dog can produce many more offspring than can a given bitch, suggesting that castration is necessary for population control, the significant morbidity associated with castration as a possible predisposing cause of the conditions described above suggests that castration is not recommended when considering the animal as an individual. I believe this recommendation must be made on a case-by-case basis, evaluating the breed of the dog, his intended working life or activity level, and the owner’s wishes regarding use of that animal for breeding. Many owners choose castration for male dogs to control normal male reproductive behaviors that we have deemed to be inappropriate, such as mounting.

• Female Dogs – Benefits of OHE in bitches include decreased incidence of mammary neoplasia, with greatest benefit if spayed before the first heat; decreased incidence of ovarian or uterine neoplasia and pyometra; and possible increased lifespan. Mammary neoplasia is the most common tumor of female dogs,with reported incidence of 3.4%. It is the most common malignant tumor in female dogs, with 50.9% of mammary tumors reported to be malignant; metastases are found in about 75% of cases of mammary carcinoma with the lung the most common site of metastasis. Exact cause-and-effect relationship has not been defined, although a hormonal basis for malignant transformation of mammary cells and progression of neoplasia is hypothesized based on the decreasing benefit of OHE with increasing number of estrous cycles in the dog’s life prior to surgery. The other very common disorder in female dogs when aged is pyometra, reported to occur in 15.2% of dogs by 4 years of age and in 23-24% of dogs by 10 years of age. Morbidity is high, although OHE at the time of clinical presentation is curative; reported mortality ranges from 0-17% in dogs.

Detriments of OHE in female dogs include complications of surgery; increased incidence of transitional cell carcinoma, osteosarcoma, lymphosarcoma, cutaneous mast cell tumors, and hemangiosarcoma; increased incidence of ACL injury and hip dysplasia; obesity and diabetes mellitus; a possible increase in aggression in at least one breed and reactivity in one breed; and increased incidence of urethral sphincter mechanism incompetence (estrogen-responsive urinary incontinence). Reported incidence of post-surgical complications in dogs is 6.1%, with most reported complications mild and self-resolving. As in male dogs, incidence of tumors reportedly associated with gonadectomy is low but morbidity with these tumor types is high. Breed predispositions exist for many tumor types. Incidence of obesity is high after OHE but morbidity can be controlled by the owner. Incidence of ACL injury in dogs is relatively high, at 1.8%, and morbidity may be high, although this is generally considered to be a curable condition with surgery. Again, some breeds, most notably large and giant breeds, are predisposed to ACL injury. Aggression after OHE has been reported in English Springer Spaniels; there is some suggestion that this effect may be more likely in bitches that demonstrated aggressive tendencies prior to surgery. Urethral sphincter mechanism incompetence is a problem of spayed female dogs, especially those weighing more than 20 kg. Morbidity is low and this is a disease easily controlled with medical therapy in most female dogs. Evidence exists suggesting incidence can be decreased by spaying bitches when greater than 3-5 months of age.

Appropriate recommendation for OHE of female dogs is less readily evident than is that for female cats. Certainly mammary neoplasia and pyometra are of high incidence and high morbidity, and are greatly decreased in incidence by OHE. However, possible predisposition to very high morbidity tumor types or ACL injury must be evaluated. As with male dogs, I believe this recommendation must be made on a case-by-case basis, evaluating the breed of the dog, her intended working life or activity level, and the owner’s wishes regarding use of that animal for breeding.

Much information and misinformation about this topic is available to the owners, guardians, and breeders of dogs and cats. It behooves us, as veterinarians, to be familiar with the current veterinary literature and to base our recommendations on science, rather than on anecdote or tradition.

Benefits and Detriments of Spay / Castration Surgery in Dogs and Cats

Bold indicates high incidence, Italic indicates high morbidity or mortality

	MALE CAT	FEMALE CAT	MALE DOG	FEMALE DOG
Undesirable physical or behavioral manifestations of reproduction
Ovarian / Uterine disease (pyometra)
Mammary cancer
Benign prostatic hypertrophy
Testicular cancer
Risks of anesthesia / surgery
Bone cancer
Genitourinary cancer
Anterior cruciate ligament injury
Urinary incontinence
Obesity

Non-Surgical Reproductive Control

What about non-surgical sterilants? Are there contraceptives available for dogs that would control reproduction without completely removing the possibility of fertility in that animal later in life?

Pharmacologic Reproductive Control

Drug therapy affects normal hormone secretion, decreasing estrous cycling. Examples include:

• Progesterone – Megestrol acetate (Ovaban™). This is the only drug that was ever FDA-approved for estrus suppression for breeding dogs in the United States. It is not available as a veterinary product but can be dispensed through human pharmacies. Ovaban can be given either during anestrus (0.25 mg/lb once daily per os x 30 days) to prolong time until the next proestrus begins, or within the first 3 days of proestrus (1.0 mg/lb once daily per os x 8 days) at which point the bitch will go out of heat in 5-6 days and will not ovulate at that cycle. If used properly, megestrol acetate should not cause uterine disease or impact fertility in bitches. Possible side-effects of treatment with any form of progesterone in dogs include weight gain, predisposition to mammary neoplasia and uterine disease, and induction of diabetes mellitus. These same side-effects are seen in queens with administration of progesterone, as is mammary hypertrophy. Current research describes use of progesterone within silastic implants, reported to suppress estrus for up to 2 years in bitches with no side-effects.
• Androgens – The only androgen that was FDA-approved for use in female dogs (Cheque™) was never approved for use in breeding animals and is no longer available from the manufacturer. The active ingredient, mibolerone, is available through compounding pharmacies. Other androgens described for estrus suppression are forms of testosterone, which are effective in a dose-dependent manner and have been reported to be only 66% effective at suppressing estrus in Beagle bitches. Possible side-effects include vaginitis, hypertrophy of the clitoris, and liver disease. Androgens cannot safely be used for estrus suppression in queens, in which they are hepatotoxic and thyrotoxic.
• GnRH agonists – These drugs mimic the action of GnRH, causing release of FSH and LH. Initially this will cause estrus but continued treatment with the drug will shut down the system, with no further estrous cycling. These drugs have been demonstrated to prevent estrus in bitches for up to 27 months and have not been associated with decreased fertility. Similarly, in males initially administration of these drugs will cause increased release of LH and testosterone but will eventually shut down the system, decreasing testosterone secretion and spermatogenesis. GnRH agonists have been demonstrated to suppress fertility for up to 27 months in dogs with subsequent return to normal fertility. These drugs are not approved for use in dogs or cats in the United States. In queens, GnRH can be used to induce ovulation (GnRH; 25 mcg/cat IM). Luteinized follicles will be maintained an average of 40 to 50 days, giving the owner a respite from estrous cycling in the queen. Ovulation induction by physical means also has been described but in the author’s experience is less effective than is pharmacologic induction of ovulation.
• Estrogen – Estrogen compounds can be used to induce azoospermia (lack of spermatozoa in the ejaculate) in dogs. However, toxic effects of estrogen include induction of squamous metaplasia in the prostate and pancytopenia. I do not recommend the use of estrogens in male dogs.

Immunologic Reproductive Control

Immunologic approaches to contraception work by vaccinating the animal against one of the tissues or hormones described above. When an animal is vaccinated against a tissue, for example, it will create antibodies against that tissue that will either destroy the tissue or prevent its normal function. There is no commercially available contraceptive vaccine for dogs or cats at this time. Compounds that are being investigated include:

• Zona pellucida – Vaccinated bitches and queens may or may not continue to cycle and time until re-vaccination is required varies much between individuals. This technique may or may not be reversible; ovarian pathology described after immunization of bitches against porcine zona pellucida proteins include ovarian atrophy and polycystic disease.
• GnRH – This is a compound against which animals do not develop antibodies readily. Immune response in tested animals has been variable, however, this vaccine may be the best candidate for commercial availability in the near future.

The search for the elusive “spay vaccine” has been ongoing for decades. Recently, a concerted effort has been made to gather like-minded scientists and to ensure sharing of ideas and materials. These collaborative efforts by the Alliance for Contraception in Cats and Dogs and the Found Animals Foundation have served to increase the number of research studies performed in field of dog and cat contraception and sterilization. Current concepts under investigation include immunocontraception, targeted cytotoxins, and gene silencing. No such products are commercially available as of this writing. Products approved for use in other species show great promise in dogs and cats and it is hoped that some sort of injectable reproductive control agent will be available within the next 5-10 years.

Sclerosing Agents for Reproductive Control

Sclerosing agents are drugs or compounds that are injected into the testes or epididymes to cause localized inflammation and destroy or scar testicular or epididymal tissue, preventing formation and movement of spermatozoa. Testicular tissue does not regenerate so if that tissue and the spermatogonia within it are destroyed, sterility may be achieved. Many compounds have been investigated.

In 2002, the FDA approved one compound, Neutersol™, for use in puppies aged 3-10 months with testicular width between 10 and 27 mm. This compound was most recently available under the brand name Zeuterin™; as of this writing, no product is commercially available in the United States. The compound (zinc gluconate with arginine) is injected directly into each testis, with dose dependent on testicular width. Sedation may be required but most dogs are reported to tolerate the injection well. Immediate side-effects include transient swelling of the testes or scrotum, and vomiting. Zeuterin™ cannot be used in cryptorchid dogs and should not be used in dogs with scrotal irritation or malformation of the testes or epididymes. In a field study of 224 dogs treated with Neutersol™, 223 were considered to be completely sterilized by 6-12 months after injection, based on inability to collect normal semen from these males. Testosterone secretion was decreased but not to as great an extent as with castration. Studies are ongoing for evaluation of safety of the product, efficacy as a contraceptive or sterilant, and effect of decreased testosterone concentrations on prostate disease and on behavior.

Non-Surgical Sterilization Techniques Currently Under Investigation

	DEFINITION	EXAMPLE
Immunocontraception	Induction of humoral (antibody) and cellular immunity to destroy proteins or tissues specific to reproduction	“Vaccination” against zona pellucida (outer layer of ova) to prevent conception by inducing antibodies that block sperm-binding sites
Targeted Cytotoxins	Attachment of toxins to carriers that will bind to and destroy cells specific to reproductive function ; analogous to chemotherapy for cancer treatment	Exotoxin A from Pseudomonas aeruginosa bound to a ligand that binds to the receptor for FSH, selectively destroying cells that require FSH to function, such as granulosa cells lining ovarian follicles
Gene Silencing	Introduction of short strands of RNA that block transcription of homologous segments of DNA and effectively abolish expression of that gene	Use of interfering RNA to block production of kisspeptin in neurons, subsequently altering section of GnRH and FSH

Extra Resources

• Non-Surgical Reproductive Control: Dr Bob Weedon – pdf presentation
• Alliance for Contraception in Cats and Dogs: (www.acc-d.org)
• Found Animals Foundation: (http://www.michelsonprizeandgrants.org/)