The Feline Estrous Cycle
The pedigreed cat fancy has been growing in North America and around the world over the last one hundred years. The widespread appeal of pedigreed cats means that veterinarians and breeders must be familiar with the unique characteristics of feline reproduction and breeding management to design and carry out successful breeding programs.
Stages of the Estrous Cycle
Proestrus is considerably more difficult to detect in the queen than in the bitch. This part of the estrous cycle may last only one day or so, and the signs may be subtle, so it is often not detected. During proestrus, toms may be attracted to the queen but she will not be receptive. Estrus is defined as behavioral receptivity to mating. This stage may last from as little as one day to as long as 21 days, with the average duration being 7 days.
The period between one estrus and the next in queens who have not ovulated is the interestrus. During this time the serum estrogen level is low (under 15 pg/ml) and no sexual behaviors are seen. The duration of interestrus can range from 2 to 19 days but on average is 7 days.2 Anestrus is the absence of cycling activity that may occur naturally in periods of short daylight. During this time, serum progesterone and estrogen are at baseline levels.
The luteal phase of the queen's estrous cycle is that period after ovulation when the dominant hormone is progesterone. Unlike the bitch, the queen does not experience a pre-ovulatory rise in progesterone. In the queen, mating causes a reflex release of luteinizing hormone (LH) from the anterior pituitary gland in the brain. Sufficient LH release induces ovulation. After ovulation, the granulosa cells of the follicle become corpora lutea and begin to produce progesterone almost immediately.3 If the oocytes are not fertilized after ovulation, a pseudopregnancy will occur that lasts about 40 to 50 days.4 Pseudopregnancy may also result if the queen suffers early embryonic loss. Pseudopregnancy in cats is not usually associated with maternal behaviors or lactation.
Fertilization of the oocytes occurs in the oviducts and the embryos enter a uterine horn by day 4 to 5 after ovulation.5,6 Implantation occurs about 12 to 13 days after breeding and the implantation rate is estimated to be about 84% in the cat.7 Pregnancy length varies from 62 to 74 days in queens, with the average length being 66 days. The average litter size is said to be 4.5 +/- 1.4 kittens7, but there is wide variability, especially among pedigreed cat breeds.
Estrus may resume about 10 days after the end of the luteal phase, but nursing queens often experience a lactational anestrus that can last for up to 8 weeks past weaning. Most queens will return to estrus about 4 weeks after weaning their kittens if it is still the breeding season.4 However, it is entirely possible for a queen to return to estrus while still nursing.1 The first estrus after a pregnancy may be shorter and less fertile.
Hormonal Events of Estrus
Follicle stimulating hormone (FSH), produced by the pituitary gland, initiates the development of ovarian follicles. An average of 3 to 7 follicles develop and start producing estradiol7. As the follicular activity peaks, blood estradiol levels increase and vary widely, but usually are over 20 pg/ml.8 Estradiol levels stay high for 3 or 4 days and then abruptly fall. The high estradiol levels produce two important effects: overt estrous behavior and priming of the gonadotropin surge necessary to cause ovulation.9
Ovulation requires the release of luteinizing hormone (LH) from the anterior pituitary gland. Sufficient stimulus, either copulatory or non-copulatory, is required to stimulate increased release of gonadotropin releasing hormone (GnRH) from the medioventral hypothalamus. GnRH release causes the LH surge. Several days of estradiol priming are required before LH release sufficient to cause ovulation occurs. This is typically reached by the third or fourth day of estrus.9 Queens vary considerably in the number of matings required to induce sufficient LH release and ovulation.10 On average, most queens will ovulate after 4 or more matings.4 All oocytes are ovulated at once, so all kittens in a litter are the same gestational age.
Ovulation occurs 48 hours or more following the LH surge.3 Progesterone levels rise within 24 hours, and may reach highs of 60-90 ng/ml by 15 to 25 days post-ovulation.11 Peak progesterone levels are highly variable from queen to queen. Throughout a pregnancy, progesterone is maintained at high levels until the last few weeks of gestation, when the level falls to under 1-2 ng/ml by term.11 A minimum progesterone level of 1 ng/ml appears to be necessary to sustain pregnancy in the queen.1
Copulatory Ovulation
Traditionally, queens are described as induced ovulators. Ovulation should not occur unless mating or a similar stimulus induces it. During intromission, the penis probably causes distension of the posterior vagina12 and induces release of GnRH from the hypothalamus via neuroendocrine reflexes.1 A surge of LH occurs within minutes of breeding. With multiple breedings, the LH surge is higher in amplitude and lasts longer than when only one breeding occurs.
Spontaneous Ovulation
Reports of ovulation without breeding in queens may be found in the veterinary literature over the last 100 years. Recent studies have found more evidence that spontaneous ovulation not only occurs in cats but occurs with some frequency.13,14 It appears that non-copulatory ovulation may be possible in response to a variety of visual, auditory or olfactory cues in queens. It is more appropriate to consider the queen to be both an induced and spontaneous ovulator and to keep this in mind when investigating cases of infertility or pyometra in a breeding cattery.
Investigating Infertility in the Queen
Infertility in the queen may mean failure to cycle, failure to breed, failure to conceive or failure to carry a pregnancy to term. The steps important in the investigation of infertility in the queen are outlined in Table 1.
Table 1. Guidelines for Investigation of Infertility in the Queen
Establish stage of estrous cycle with serum progesterone and vaginal cytology
Evaluate diet quality, especially copper and taurine content
Investigate reproductive illnesses, especially cystic endometrial hyperplasia
Investigate non-reproductive illnesses, especially those causing debilitation and chronic ill health
Evaluate cattery conditions: population size, overcrowding, sanitation, lighting, temperature
Identify any stressors such as showing, traveling, conflict in social interactions
Investigate the fertility of the tomcat
Determine if any medications or vaccines have been administered recently, especially anabolic and corticosteroids, progestagens, and modified live vaccines containing feline panleukopenia virus
(from: Little, S. Uncovering the cause of infertility in queens. Vet Med 96(7): 557-568, 201)
Inbreeding and linebreeding are common practices in the pedigreed cat fancy and are necessary for breed development and fixation of desired traits by increasing homozygosity.15 Intensive inbreeding may also fix deleterious traits and contribute to loss of vigor and reproductive capacity.15 Inbreeding should be considered as a cause of subfertility in queens with a normal estrus.16 Queens that are repeatedly difficult to breed may pass on undesirable reproductive traits to the next generation. Breeders should consider removing these individuals from the breeding program.
Infertility in the queen may be due to various causes (see Table 2). A common situation presented to the veterinarian is infertility in a queen with a normal estrous cycle. In this situation, infertility may be due to uterine abnormalities, male infertility, breeding management problems, failure to ovulate, or cystic endometrial hyperplasia (CEH)/pyometra complex. Of these CEH/pyometra complex is an important and common cause of infertility.
Table 2. Common Causes of Infertility in the Queen
True Primary Anestrus:
Abnormalities of sexual differentiation
Persistent Anestrus:
Previous ovariohysterectomy
Inadequate daylight length or intensity
Infrequent Estrus:
Silent heats
Spontaneous ovulation and pseudopregnancy
Intercurrent diseases and stressors
Medications
Prolonged Estrus:
Normal phenomena
Ovarian cysts and tumors
Infertility with Normal Estrus:
Maternal abnormalities
Male infertility
Breeding management issues
Failure to ovulate
Cystic endometrial hyperplasia
(from: Little, S. Uncovering the cause of infertility in queens. Vet Med 96(7): 557-568, 201)
Cystic endometrial hyperplasia (CEH) is a disorder of proliferative and degenerative changes in the endometrium associated with aging and hormonal stimulation. Endometritis and pyometra are forms of CEH associated with bacterial infection. Progesterone induces hyperplasia of the surface or glandular epithelium and cystic dilatation of the uterine glands.17 Fluid in the cystic structures is usually uncontaminated, but if free in the uterus, it easily supports bacterial growth.4 Progesterone also inhibits local leukocyte responses and decreases myometrial contractility.18 In queens, endometrial hyperplasia may also be influenced by chronic estrogenic stimulation from recurrent estrous cycles that do not result in pregnancy.17
Queens with uncomplicated CEH usually have no clinical signs of illness. The results of blood and urine tests are within normal ranges.4 However, CEH is associated with failure of implantation and subsequent small litters or infertility19, as well as early embryonic death.20 CEH may also be associated with spontaneous ovulation in queens.21 Breeding catteries may have high rates of CEH, especially in queens 3 years of age and older. 17
CEH is difficult to diagnose without uterine biopsy. However, it should be suspected in queens that repeatedly ovulate when bred but do not conceive, provided the tom is known to be fertile. There is no effective treatment for CEH and affected queens should be removed from the breeding program.
Endometritis is characterized by inflammation of the endometrium. Most queens with endometritis have bacterial infections. Ascending infections from the vagina may occur during estrus, when estrogens dilate the cervix.4 The only sign associated with endometritis may be infertility.19 Thickening of the uterine wall or fluid retention may be demonstrated with ultrasonography.
Endometritis often progresses to pyometra19 and so most affected queens should be removed from the breeding program. If the diagnosis is suspected or confirmed with uterine biopsy and culture, an attempt may be made to breed valuable queens concurrent with the administration of a broad-spectrum antibiotic,16 such as amoxicillin/clavulanate (Clavamox®-Pfizer; 62.5 mg, PO, every 12 hours.).
Pyometra represents a severe endometrial infection with an accumulation of purulent exudate in the uterus. E. coli is reported to be the most common bacterial species involved in feline pyometra.22 An intact queen with a vaginal discharge should be presumed to have pyometra until proven otherwise. Common signs associated with pyometra in the queen include vaginal discharge, lethargy, anorexia, abdominal distension, dehydration, polyuria/polydipsia and pyrexia.19,22 Queens with a closed cervix pyometra have abdominal enlargement with no vaginal discharge and may be severely ill with septicemia.4,19 A variety of abnormalities may be found on routine blood tests (hematology and serum chemistries) in queens with pyometra.17,22 Uterine enlargement may be demonstrated with abdominal radiographs or abdominal ultrasound.
Initial management of queens with pyometra revolves around patient stabilization. Antibiotic therapy should be started with a broad-spectrum product such as enrofloxacin (Baytril®-Bayer; 5 mg/kg, PO, once daily) or amoxicillin/clavulanate. Choice of antibiotic may also be based on results of culture and sensitivity testing of vaginal discharge. However, antibiotic treatment as sole therapy is not usually successful in preservation of fertility.4,18 Ovariohysterectomy is the treatment of choice for queens not valuable to a breeding program, and is the only choice for those queens with closed cervix pyometra or critically ill queens.
Valuable breedings queens with open cervix pyometra may be treated with prostaglandin F2α (Lutalyse®-Pharmacia & Upjohn) and antibiotics. Prostaglandin treatment causes evacuation of the uterus via smooth muscle contraction. Patients suitable for prostaglandin treatment are young queens that are not seriously ill and have no evidence of retained fetal tissue or viable fetuses on abdominal ultrasound.4,18,19,22 Protocols in the literature include doses ranging from 0.1 to 0.25 mg/kg Lutalyse® subcutaneously once or twice daily for up to 5 days.2,4,18,22 Serious risks associated with prostaglandin therapy in cats are uncommon.22
Newer drugs showing potential as adjunctive treatment in feline pyometra include aglepristone and cabergoline. Aglepristone (Alizin®-Virbac Corp.) is an antiprogestin that may be useful for reducing serum progesterone levels via lysis of corpora lutea on the ovary. Cabergoline (Galastop®-CEVA), a dopaminergic agonist, may also be useful for lysing corpora lutea by reducing levels of prolactin, a known luteotrophic factor. Neither aglepristone nor cabergoline are available for small animal use in the United States at this time.
Results of a complete blood cell count should be normal by two weeks after treatment.4 A clear vaginal discharge may be present for up to 10 days after treatment and is a good prognostic sign. A second series of prostaglandin injections can be given to queens that still have mucopurulent vaginal discharge at the two-week point.Treated queens should be bred on the next estrus.4,18,22 Antibiotic therapy may be continued until the queen is at least part way through any resulting pregnancy. Most queens are able to conceive and deliver litters after prostaglandin therapy,4,18,22 however pyometra is likely to recur in up to 15% of treated queens.22
References
1. Verstegen, J.P.: Physiology and endocrinology of reproduction in female cats. Manual of Small Animal Reproduction and Neonatology (Simpson, G.; England, G; Harvey, M. eds). British Small Animal Veterinary Assoc., Cheltenham, U.K., 1998; pp 11-16.
2. Shille, V.M.; Sojka, N.J.: Feline reproduction. Textbook of Veterinary Internal Medicine, 4th ed. (Ettinger, S.J.; Feldman, e.C., eds). W.b. Saunders, Philadelphia, P.A., 1995; pp 1690-1698.
3. Schmidt, P.M. et al: Ovarian activity, circulating hormones and sexual behavior in the cat. II. Relationships during pregnancy, parturition, lactation and the postpartum estrus. Biol. Reprod. 28:657-671; 1983.
4. Feldman, E.C.; Nelson, R.W.: Feline reproduction. Canine and Feline Endocrinology and Reproduction, 2nd ed. W.B. Saunders, Philadelphia, P.A., 1996; pp 741-768.
5. Tsutsui, T.; Stabenfeldt, G.H.: Biology of ovarian cycles, pregnancy, and pseudopregnancy in the domestic cat. J. Reprod. Fertil., Suppl. 47:29-35; 1993.
6. Swanson, W.f. et al: In vivo embryogenesis, embryo migration, and embryonic mortality in the domestic cat. Biol. Reprod. 51:452-464; 1994.
7. Tsutsui, T. et al.: Evidence for transuterine migration of embryos in the domestic cat. Nippon Juigaku Zasshi 51(3):613-617; 1989.
8. Goodrowe, K.L. et al.: Reproductive biology of the domestic cat with special reference to endocrinology, sperm function and in-vitro fertilization. J. Reprod. Fert., Suppl. 39:73-90; 1989.
9. Banks, D.H.; Stabenfeldt, G.H.: Luteinizing hormone release in the cat in response to coitus on consecutive days of estrus. Biol. Reprod. 26:603-611; 1982.
10. Schmidt, P.M.: Feline breeding management. Vet. Clin. North Am. (small Anim. Pract.) 16(3):435-451; 1986.
11. Verstegen, J.P. et al.: Regulation of progesterone during pregnancy in the cat: studies on the roles of corpora lutea, placenta and prolactin secretion. J. Reprod. Fert., Supp. 47:165-173; 1993.
12. Watson, P.F.; Glover, T.E.: Vaginal anatomy of the domestic cat (Felis catus) in relation to copulation and artificial insemination. J. Reprod. Fert., Suppl. 47:355-359; 1993.
13. Lawler, D.F. et al.: Ovulation without cervical stimulation in domestic cats. J. Reprod. Fert., Suppl 47:57-61; 1993.
14. Gudermuth, D.F. et al.: Incidence of spontaneous ovulation in young, group-housed cats based on serum and faecal concentrations of progesterone. J. Reprod. Fert, Suppl 51:177-184; 1997.
15. Robinson, R.; Pedersen, N.C.: Normal genetics, genetic disorders, developmental anomalies and breeding programs. Feline Husbandry: Disease and Management in the Multiple Cat Environment (P.W. Pratt, ed.). American Veterinary publications, Goleta, C.A.; 1991; pp 61-128.
16. Johnston, S.D. et al.: Clinical approach to the complaint of infertility in the queen. Canine and Feline Theriogenology. W.B. Saunders, Philadelphia, P.A., 2001; pp 486-495.
17. Potter, K. et al.: Clinical and pathologic features of endometrial hyperplasia, pyometra, and endometritis in cats: 79 cases (1980-1985). JAVMA 198(8):1427-1431; 1991.
18. Davidson, A.P.: Medical management of pyometra with prostaglandin F2 alpha in the dog and cat. Kirk's Current Veterinary Therapy XII Small Animal Practice (J.D. Bonagura, ed.). W.B. Saunders, Philadelphia, P.A., 1995; pp 1081-1083.
19. Wolf, A.M.: Infertility in the queen. Current Veterinary Therapy XI Small Animal Practice (R.W. Kirk; J.D. bonagura, eds.). W.B. Saunders, Philadelphia, P.A., 1992; pp 947-954.
20. Stabenfeldt, g.H.; Pedersen, N.C.: Reproduction and reproductive disorders. Feline Husbandry: Diseases and Management in the Multiple Cat Environment (P.W. Pratt, ed.). American Veterinary Publications, Goleta, A.A., 1991; pp 129-162.
21. Lawler, D.F. et al.: Histopathologic features, environmental factors, and serum estrogen, progesterone, and prolactin values associated with ovarian phase and inflammatory uterine disease in cats. AJVR 52(10):1747-1753; 1991.
22. Davidson, A.P. et al.: Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990). JAVMA 200(6):825-828;1992.