Recent Advances in Feline Reproduction
World Small Animal Veterinary Association World Congress Proceedings, 2006
Stefano Romagnoli, DVM, MS, PhD, DECAR
Professor, Department of Veterinary Clinical Sciences, University of Padova Agripolis, Legnaro, Italy

The Reproductive Cycle

The cat is a seasonally polyestrous species and a long photoperiod breeder. Anoestrus is induced by decreasing hours of daylight. Artificial light may influence seasonality and in fact cats who live permanently indoor often do not show any seasonal cyclicity. A minimum of 10 hours of light is required for queens to cycle, and using a short photoperiod (8 hrs of light) can be used to suppress oestrus in queens. The feline reproductive cycle is divided into proestrus, oestrus, postoestrus, dioestrus and anoestrus. Proestrus is indicated by continuous rubbing of the head and neck against any object, some vocalizing but refusal of mating, and it is reported to be very short and often not observed. It lasts an average of 1.2+0.8 days. Oestrus behaviour in the queen, as in other mammals, is indicative of receptivity to mating, and is characterized by signs which are similar to those of proestrus but more intense, more frequent vocalizing, crouching with the forequarters pressed to the ground and hyperextension of the back which causes lordosis, so that the vulva is presented for mating. Unlike canine oestrus which begins with decreasing serum estradiol concentrations, oestrus in the queen occurs at peak follicular activity. Vaginal epithelial cornification occurs in the queen as in the bitch, although in felines the sudden decrease in superficial cells at the end of oestrus is not observed. Although useful, vaginal cytology does not have as many clinical applications in the queen as in the bitch.

The term postoestrus has been used to indicate the stage which follows one oestrus and precede the next in queens which did not ovulate. The term metoestrus is sometime used, but may be a source of confusion as it generally refers to a phase of corpus luteum development which does not occur in non-ovulating queens. Queens that ovulate show evidence of corpus luteum development, therefore going through a normal Dioestrus whose length varies depending on occurrence of conception. Dioestrus lasts approximately 40 days in non-pregnant queens. An interoestrus interval of 35-45 days in the queen is generally indicative of occurrence of ovulation, suggesting development of corpora lutea and progesterone secretion whether or not breeding occurred. Following luteolysis, cyclicity resumes with a 7-10 days delay both in pregnant and non-pregnant females, although lactation and suckling may inhibit resumption of cyclicity for 2-3 weeks post-weaning. Queens exposed to natural photoperiod undergo Anoestrus, a phase of reproductive quiescence, during late fall and early winter (October-December).

Breeding Management

Feline ovulation is induced by LH released from the pituitary in response to a neural reflex originating from the vagina stimulated by the Tom's penis. Ovulation may occur spontaneously in approximately 30-35% of queens, even if the female never comes in contact with anybody else (human, animal). This has been demonstrated in studies performed in laboratory queens who live their lives in cages, as well as in household queens in which (thanks to faecal progesterone assay) ovulation has been demonstrated as soon as a tomcat was placed in a room nearby where queens could see him but not interact with him. Occurrence of ovulation does not shorten duration of oestrus which averages 8.5 ± 4.2 days (range 2-19 days) in bred queens (regardless of whether or not follicle/s ovulated). Instead, absence of coitus is associated with a shorter duration of oestrual behaviour (6.2 ± 2.9 days). The number of follicles ovulating has been related to the number of matings, with one mating/oestrus not being sufficient to cause ovulation in up to 50% of bred females, and 4 matings/oestrus being associated with high numbers of follicles ovulating.

Oestrus behaviour may fail to be displayed when a queen is intimidated or taken to a new environment which makes her nervous and anxious. Experienced tomcats can often overcome such situations and the owner can sometime help by carefully holding the queen (although the male may then refuse to mount her). Trying a different male can sometime solve the problem, but occasionally a frightened queen will refuse every male and therefore artificial insemination may be the only choice. Feline follicular maturation is not characterized by a serum progesterone rise, which makes choosing the right day sometimes difficult. Vaginal cytology can help differentiate between heat and non-heat, but will not indicate whether the queen is at the beginning or at the end of heat. Ultrasonography can be very useful to follow follicular maturation in the queen, with follicles progressively growing from 2.0 to 4.2 mm in diameter prior to ovulation.

In the majority of queens, ovulation occurs following a copulation-induced pituitary LH peak whose magnitude is directly proportional to the number of breedings; ovulation occurs in only 50% of queens bred just once, and in 100% of queens bred > 4 times. More than one day of exposure to increasing estrogen stimulation is necessary before the feline pituitary can release an ovulatory surge of LH in response to a coital stimulus. The threshold of estradiol-17β concentrations indicating active hormonal secretion by growing follicles is generally considered to be 20 pg/ml, with >20 pg/ml indicating oestrus and <20 pg/ml indicating anoestrus or interoestrus. However, significantly higher concentrations of estradiol-17β (approximately 50 pg/ml) are reported on the day of the ovulatory LH surge than on the previous day (approximately 35 pg/ml). Therefore, breeding too early (such as on the 1st day of heat) may not induce ovulation as the pituitary may not be ready to release LH or the follicles may not be mature enough to rupture in the presence of an LH surge. An LH response may not be elicited when queens are bred 2-3 times during the first day only or even the first and second day of oestrus. Therefore, it is always best to wait until the third day of oestrus to take the queen to the tom.

Artificial Insemination

Semen collection in the cat is not as easy as in dogs; it requires the use of a purpose-made artificial vagina (AV) or of electroejaculation. While the latter is a rather complicated and expensive technique which requires anesthesia, the use of an AV is relatively easy and inexpensive, with the only disadvantage being the fact that the tomcat needs to be trained, and training may require up to 2 weeks of attempts using a teaser queen in heat. The AV can be assembled using a 2 ml rubber bulb (from a Pasteur pipette) and a small (2-3 ml) test tube; the device is placed in a polyethylene bottle filled with 52°C water. Semen deposition can be achieved in the cranial vagina or posterior cervix using a 9 cm, 20 G needle with a bulb at the tip. Vaginal dilation is performed with a 1.5 mm nylon probe or a 2.0 mm stainless steel probe. The queen is under general anesthesia or well sedated and placed in dorsal recumbency with the hind quarters elevated and maintained in this position for 15-20 to prevent backflow of semen. Ovulation must be induced with GnRH (50 mcg/queen, IM) or hCG (50-100 UI/queen, IM). Vaginal stimulation with a cotton fioc or a glass rod may occasionally cause ovulation, although this is not a very reliable way and should not be used when performing an artificial insemination.

Oestrus Induction

Oestrus induction in the queen is commonly achieved using PMSG. A variety of different treatments have been used as shown in Table 1, but PMSG at the dose of 100-150 IU a single time followed by 50-100 IU of hCG 5-7 days later is the protocol that consistently has given the best results. Although prolactin does not seem to play a role in determining feline anoestrus, some efficacy of antiprolactinics (cabergoline) has been anecdotally reported.

Table 1. Oestrus induction protocols in the queen.

Protocol

Dosage

Reference

PMSG

100-1000 IU, 5-7 d

Cline et al., Lab An Sci 1003, 1980

PMSG + hCG

100-150 IU on day 1
+ 50-100 IU on day 5-7

Cline et al., Lab An Sci 1003, 1980;
Donoghue et al., Biol Reprod 46:972, 1992;
Swanson et al., Biol Reprod 57:295, 1997

FSH + hCG

2 mg/day 4-5 days
+ 50-250 IU

Dresser et al., Therio 28:915, 1987

FSHp + hCG

2 mg on day 1,
0.5-1.0 mg days 2-5
+ 50-250 IU

Tsutsui et al., Jap J Vet Sci 51:677, 1989

huFSH + hCG

7.5 or 15 IU days 1-4
+ 100 IU on day 4.5

Orosz et al., Therio 37:993,1992

hMG + hCG

15 IU days 1-5,
+ 100 IU on day 6.5

Orosz et al., Therio 37:993,1992

FSHp (ultra pure)

2.5-10 mg total dose,
in 5 days

Verstegen et al., J Reprod Fert Suppl 47:209, 1993

Antiprolactin drugs

Cabergoline 5 mg/kg,
max 15 days

Verstegen, unpublished;
Zambelli, unpublished

The Feline Pregnancy

Coital stimulation is considered necessary in the queen for LH peak to occur, which is then followed by ovulation 24-27 hours later. Although queens housed in single cages without any physical contact with other cats may ovulate spontaneously without cervical stimulation, ovulation can certainly be timed based on occurrence of mating, and pregnancy length can therefore be accurately calculated. Fertilized ova reach the uterine horn 3-4 days post-ovulation, and implantation occurs around 12-13 days after ovulation. In a large study performed recently in the UK mean length of feline gestation was 65 days with 90% of values occurring between 63 and 67 days and 97% of values occurring between 61 and 69 days. The normal range of feline gestation is 54-74 days timed from the first or last breeding and does not appear to be influenced by age of the queen, parity, number of kittens per litter, mean weight of kittens born, weight gain during pregnancy or genetic background.

Hormones of Pregnancy

Plasma progesterone (P4) concentrations increase above the 2.0 ng/ml threshold level about 4 days after mating, peak at values > 15 ng/ml between day 11 and 30 of pregnancy, and remain above threshold until day 62. Parturition occurs approximately 24-48 hours after luteolysis. Early work from the USA reporting that ovariectomy could be done after day 45 of gestation without causing abortion (because of placental production of P4) was challenged from experiments done in Belgium where queens were showed to abort 7-10 days following ovariectomy performed at day 45 of gestation. As in dogs, prolactin is considered a major luteotrophic factor in the feline pregnancy, and anti-prolactin compounds such as cabergoline have been shown to lyse the feline corpus luteum causing abortion as early as day 30 of gestation, whereas the luteolytic action of prostaglandin F2a in the queen is evident only after day 30 to 40.

Pregnancy Diagnosis

Pregnancy can be diagnosed by abdominal palpation of 2.5 up to 3.5 cm diameter foetal vesicles 21 to 35 days following breeding, respectively. Radiography and ultrasound can be used for pregnancy diagnosis as early as day 17 after breeding, while calcification of the foetal mandible, cranium, scapula, humerus, femur, vertebral bodies and ribs can be observed as early as day 38 after breeding. Radiographic identification and measurement of crown-rump length has been used to estimate foetal age: feline foetuses measure approximately 10.5 cm at 50 days, 12 cm at 55 days and 14.5 cm at parturition.

Cat breeders generally do not have pregnancy diagnosed on their queens on a regular basis. Occasionally queens with a history of infertility may be brought in to the veterinarian for a uterine ultrasound around 20-25 days post-breeding, a time when manual palpation of the abdomen easily allows to detect foetal vesicles of 2.5 cm diameter. Radiography and ultrasound can be used for pregnancy diagnosis as early as day 17 after breeding, while calcification of the foetal mandible, cranium, scapula, humerus, femur, vertebral bodies and ribs can be observed as early as day 38 after breeding. Radiographic identification and measurement of crown-rump length has been used to estimate foetal age: feline foetuses measure approximately 10.5 cm at 50 days, 12 cm at 55 days and 14.5 cm at parturition.

Care of the Pregnant Female

Doing a moderate physical exercise during gestation will help pregnant queens to maintain a good body condition and muscle tone, which will allow for a better and quicker parturition process. Vaccinations should be avoided unless it is specifically requested by the vaccination protocol that the injection be done during pregnancy. Modified live virus feline panleukopenia vaccines are teratogenic in the queen and their use should be avoided. The use of griseofulvin during pregnancy in the queen causes congenital malformations in kittens such cleft palate, exencephaly, hydrocephalus, spina bifida, cyclopia and anophthalmia, atresia ani and atresia coli, and abnormalities of the heart.

Feline Parturition

During parturition, the queen alternates pacing with purring behaviour, and when abdominal contractions begin she assumes a semi-squatting position with her calcaneous bones pointed almost straight up and wide apart. In between contractions, she lays on her side and continues purring. Fluids are generally expelled from the vulva before the birth of the 1st kitten. Each kitten is expelled partially through the vulva generally head first, and then the mother seems to pause for a few minutes while keeping contracting her abdomen, while the kitten remains half outside the vulva. Once born, the kitten is licked vigorously to remove the allantois and the amnios, whose remnants are frequently found on newborn kittens. Posterior presentation is common and does not predispose to dystocia. The queen usually ingests most if not all the placentas. Mean duration of stage-1 labour (the preparatory phase) is 0.5-1.0 hr, with >80 of queens taking less than 2 hrs. The duration of stage-2 labour (the expulsion phase) is <6 hrs in the majority of queens, but in a small minority of cases it can be more than 24 hrs, and occasionally intervals of up to 48 hrs have been reported. Parturition of normal, live kittens several days apart is anecdotally reported in the queen (although it has never been documented).

First nursing occur within the first hour of life, with the majority of kittens suckling already by 30 to 40 minutes from birth. Litter size varies from 1 to 10, with a modal litter of 4 kittens. Mortality is higher in one-kitten litters and in low-birth-weight kittens, and lower in adult queen that are not overweight and who deliver litters of 5 kittens.

Using Drugs in Pregnancy

The most delicate period of the feline pregnancy is the first month during which organogenesis takes place. Prior to day 20-22 following ovulation (when implantation occurs and placental development starts) feline embryos are surrounded by "uterine milk", a protein endometrial secretion which is in homeostatic equilibrium with the blood compartment, i.e., any substance that arrives in the bloodstream reaches the endometrium. Therefore, use of any substance during this time carries the potential risk of harming foetal development even though there is no risk associated for the mother. After placental development foetuses become more resistant to toxic insults. Although no real "placental barrier" exist, most substance cannot reach the placental circulation unless they are present in high concentration and for a long time in the bloodstream. However, any drug that reaches the foetal circulation must be metabolised by the foetal kidney (in carnivores the foetal liver is not metabolically active) which in itself might threaten foetal survival. Bromocriptine, estradiol benzoate and cypionate and prostaglandin F2a drugs are cause embryonic/foetal death in the cat. Aspirin, dexamethasone, carbaryl and antiestrogen are described as capable of causing embryonic/foetal death in the bitch, and therefore should be suspected to have the same effect also in the queen. The effect of various drugs on pregnancy in small animals is reported in details by Papich (1989). Table 2 shows a brief summary of drugs which have been either tested in pregnant dogs and cats and proven safe or used in pregnant laboratory animals and pregnant women without any side effect.

Table 2. Drugs which have been either tested in pregnant dogs and cats and proven safe or used in pregnant laboratory animals and pregnant women without any side effect.

Category of drugs

Active principles safe for use in pregnant bitches

Antibiotics

Ampicillin, amoxicillin, carbenicillin, cephalosporins, clindamycin, cloxa- and dicloxacillin, hetacillin, lincomycin, neomycin, oxacillin, penicillin G, ticarcillin

Antimicotics

Miconazole (for topical use only)

Antiparasitics

Diethylcarbamazine, fenbendazole, mebendazole, ivermectin, piperazine, praziquantel, bunamidine, pyrantel, thenium

Anticancer drugs

None

Anesthetics

Lidocaine, naloxone

Gastrointestinal drugs

Antacids, sucralfate

Cardiovascular drugs

Digitalis

Anticonvulsivant drugs

None

Muscle relaxants

None

Endocrine drugs

None

References

1.  Baldwin C. Pregnancy termination in the domestic cat using natural prostaglandins. Proceedings Annual Meeting Society for Theriogenology, S. Antonio, Texas, USA, Sept 13-15, 1995, pp 169-175

2.  Banks DR, Stabenfeldt G. Luteinizing hormone release in the cat in response to coitus on consecutive days of oestrus. Biology of Reproduction 26, 603-611, 1982

3.  Boyd JS: The radiographic identification of the various stages of pregnancy in the domestic cat. J Small An Pract 12: 501-506, 1971

4.  Concannon PW, Hodgson B, Lein DH. Reflex LH release in estrous cats following single and multiple copulations. Biology of Reproduction 23, 111-117, 1980

5.  Gudermuth DF, Newton L, Daels P, Concannon PW. Incidence of spontaneous ovulation in young, group housed cats based on serum and faecal concentrations of progesterone. Journal of Reproduction and Fertility, Suppl 51: 177-184, 1997

6.  Feldman EC and Nelson RW. Feline reproduction. In: Canine and Feline Endocrinology and Reproduction. EC Feldman and RW Nelson editors, WB Saunders, 3rd edition, 2004, pp 1016

7.  Johnston SD, Root-Kustritz MV, Olson PNS. The feline oestrus cyclen. In: SD Johnston, MV Root-Kustritz and Olson PNS (eds), Canine and Feline Theriogenology. Philadelphia: WB Saunders, pp 396-405, 2001

8.  Lawler DF, Johnston SD, Hegstad RL, Keltner DG, Owens SF: Ovulation without cervical stimulation in domestic cats. J Reprod Fert--Suppl 47: 57-61, 1993

9.  Lofstedt RM. The estrous cycle of the domestic cat. Compendium Continuing Education for the Practicing Veterinarian 4: 52-58, 1982

10. Munday HS and Davidson HPB: Normal gestation lengths in the domestic shorthair cat. J Reprod Fert Suppl 47: 559, 1993

11. Papich M. Effects of drugs on pregnancy. In: Current Veterinary Therapy X. Small Animal Practice. Editore RW Kirk, WB Saunders 1989, p 1291

12. Romagnoli S. Clinical Approach to infertility in the queen. Journal of Feline Medicine and Surgery. vol. 5, pp. 143-146, 2003

13. Romagnoli S. Failure to conceive in the queen. Journal of Feline Medicine and Surgery. 7 (1): 59-64, 2005

14. Scott FW, De Lahunta A, Schultz RD et al. Teratogenesis in cats associated with griseofulvin therapy. Teratology 11: 79-86, 1975

15. Smith RN. Appearance of ossification centers in the kitten. J Small Anim Pract 9:497-511, 1968

16. Shille VM, Lundstrom KE, Stabenfeldt GM (1979) Follicular function in the domestic cat as determined by estradiol-17b concentration in plasma: relation to estrous behavior and cornification of exfoliated vaginal epithelium. Biology of Reproduction 6, 953-963,

17. Sparkes AH, Rogers K, Henley WE, Gunn-Moore DA, May JM, Gruffydd-Jones T, Bessant C. A questionnaire-based study of gestation, parturition and neonatal portality in pedigree breeding cats in the UK. J Fel Med Surg 8: 145-157, 2006

18. Verstegen J, Onclin K, Silva LDM, et al. Regulation of progesterone during pregnancy in the cat: studies on the roles of corpora lutea, placenta and prolactin secretion. J Reprod Fertil, Suppl 47: 165-173, 1993

19. Verstegen J, Onclin K, Silva LDM, Donnay I. Abortion induction in the cat using prostaglandin f2alpha and a new antiprolactinic agent, cabergoline. J Reprod Fertil, Suppl 47: 411-417, 1993

20. Wildt DE, Seager SWJ, Chakraborty PK (1980) Effect of copulatory stimuli on incidence of ovulation and on serum luteinizing hormone in the cat. Endocrinology 107, 1212-1217

21. Zambelli D, Cunto M. Artificial insemination in the cat. Proceedings 5th EVSSAR Congress, Budapest, Hungary, 7-9 April 2006, pp 225-231

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Stefano Romagnoli, DVM, MS, PhD, DECAR
Department of Veterinary Clinical Sciences
University of Padova Agripolis
Legnaro, Italy


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