Potential Deleterious Effects Following the First Dose of Medroxyprogesterone Acetate as a Contraceptive in Cats

The aim of the present work was to investigate the deleterious effects of the first dose of medroxyprogesterone acetate (MPA) on the female genital system of cats. The study was conducted on 315 cats of different breeds who received their first dose (75 mg) of MPA as a contraceptive. Complete animal identification and stage of estrus were documented at admission. Physical, radiographic and ultrasonographic examinations were done on cats that expressed deleterious manifestations. All of the presented cats received an overdose of MPA during the estrous phase of the estrous cycle. Out of 315 cats who received their first dose of MPA, 27 (8.6 %) demonstrated varied deleterious effects related to the female genital system. Deleterious effects were reported within 15–90 days, including pyometra (n=10, 37.0%), endometritis (n=8, 29.6%), mammary gland hyperplasia (n=4, 14.8 %), cystic endometrial hyperplasia (n=3, 11.2%) and ovarian cyst (n=2, 7.4%). The incidence of these adverse effects increased with age. Persian cats seem to be more susceptible than other cat breeds. Long haired cat breeds seem to be more susceptible to adverse effects following injection of exogenous progestins (MPA) than short haired breeds (Siamese and Egyptian mau). Deleterious effects of MPA occurred following the first overdose. It is advised to use MPA as a contraceptive in the recommended dose during the inter-estrous or anestrous phase. ـــــــــــــــــــــــــــــــــــــــــ


INTRODUCTION
A cat is described as a long-day, seasonally polyestrous animal. During a breeding season, queens undergo repeated estrous cycles unless pregnancy or illness occurs (Little, 2012). The cat litter size ranges from 3.7 to 4.6 kittens (Sparkes et al., 2006), the breeding life is about 10 years, and a queen can give birth to up to 100 kittens in her lifetime (Griffin, 2001). The overpopulation of cats around the world leads to suffering and euthanasia. So, an urgent need for safe and effective contraceptives was developed (Little, 2012).

MATERIALS AND METHODS
An observational study was conducted on 315 female cats of different ages (mean±SD), body weights 3.5±1.2 kg (mean±SD) and breeds (Persian [n = 185], Turkish agora [n = 73], Siamese [n = 83], and Egyptian Mau [n = 14]) in the period between April 2017 and May 2022. Inclusion criteria included cats receiving a single first dose (75mg) of medroxyprogesterone acetate (MPA), which is routinely administered as a contraceptive in veterinary clinics in Egypt. These cats were either initially admitted to the clinic of the Faculty of Veterinary Medicine, Cairo University, or referred by veterinarians.
All cats' owners were aware that their cats would be included for research purposes and signed a consent form indicating their approval. All institutional and international regulations for animal care and use were followed in the present study.
The collected data included the age and phase of the estrous cycle at the time of receiving MPA. All cats were monitored for about 3 months. The onset between receiving the first single dose of MPA and the appearance of adverse clinical signs was documented. The diagnosis of pathological conditions was based on complete physical, radiographic, and ultrasonographic examinations.
Physical examination included body temperature estimation and visual examination of vaginal discharges (colour and amount), mammary gland size and abdominal distention. Lateral abdominal radiographs were taken with exposure factors of 48-50 KVp, 3 mAs, and an 80-90 cm focal film distance.

RESULTS
Out of 315 cats who received their first and single dose (75 mg) of MPA, 27 cats (8.6 %) demonstrated varied deleterious effects related to the female genital system. These cats were of different breeds (Persian [n = 14], Turkish agora [n = 6], Siamese [n = 5], and Egyptian Mau [n = 2]. The mean age of cats at the time of receiving their first dose of MPA was 5.7-1.9 years. All cats received MPA during the estrous phase of the estrous cycle to overcome the annoying breeding behaviour. The interval between receiving MPA and the appearance of adverse clinical signs ranged from 15 to 90 days. These adverse effects included pyometra (n = 10, 37.0%), endometritis (n = 8, 29.6%), mammary gland hyperplasia (n = 4, 14.8 %), cystic endometrial hyperplasia (CEH, n = 3, 11.2%), and ovarian cyst (n = 2, 7.4%). The distribution of pathological conditions related to the female genital system following the first administration of MPA is demonstrated in Table   The most prevalent clinical signs in cats presented with endometritis were decreased appetite, loud moaning, arched back and turbid vaginal discharges (mixed with blood in 3 cats). Radiographically, a radio-dense mass was detected cranial to the urinary bladder in 4 cats. Ultrasonography was helpful in diagnosing cats with endometritis, where a thick hypoechoic uterine wall with anechoic uterine content was seen.
Cats with CEH were presented with a decreased appetite, polyurea, and polydipsia. One cat had vaginal discharges, while another cat was associated with endometritis. Radiographic diagnoses included the presence of a radio-dense mass cranial to the urinary bladder (one cat). Ultrasonographically, cats with CEH showed a thickened uterine wall with multiple pockets containing anechoic fluid.
Pyometra was manifested clinically by fever (>39.8°C), decreased appetite, polyurea, polydipsia, and lethargy. Seven cats were presented with open pyometra (purulent bloody discharge was drained from the vagina). Three cats were presented with closed pyometra (marked abdominal distension). Radiographically, a radio-dense sac-like structure was seen filling the abdomen, resulting in cranial displacement of the abdominal viscera (Fig. 2a). Ultrasonography revealed a segmentally distended fluid-filled uterus with a thickened hypoechoic uterine wall and characteristic thick hyperechoic bands dividing the uterus into multiple pockets containing hypoechoic pus (Figs. 2b-e).
An ovarian follicular cyst was diagnosed in two cats and they did not express clinical or radiographic abnormalities. It was diagnosed in one cat during routine ovariohysterectomy (Fig. 3a,c) and incidentally during ultrasonographic examination in another cat (1cm anechoic sac). Mammary gland hyperplasia was detected as a painless, doughy, massive enlargement of the mammary gland. These enlargements had a sudden, rapid onset in one cat and progressed slowly over 60 days in three cats (Fig. 3b). Masses were bilaterally symmetrical with sharply circumscribed and clearly delineated borders, including the abdominal and inguinal mammary glands. The skin over the masses was tense, stretched, and erythematous, with marked alopecia.
Radiographically, a homogenous enlargement of the mammary gland was detected with no evidence of lysis or sclerosis. Ultrasonographic examination revealed homogenous enlarged mammary glandular tissue without evidence of malignancy.

DISCUSSION
The present study demonstrated that 27 cats presented with various deleterious effects following the first single dose of medroxyprogesterone acetate (MPA). Fourteen (52%) of the presented cats were Persians, which may be correlated with the overpresentation of this breed in the current study or may be due to the increased sensitivity of Persian cats to progestin. Little, 2012 reported that longhair queens exhibit irregular estrous cycles even during long daylight periods, while shorthair queens, as a Siamese breed, exhibit regular estrous cycles regardless of daylight length. The irregular estrus cycle may lead to changes in the hormonal profile of long-haired breeds such as Persian cats, which predispose them to the rapid deleterious effects of progestin injection.
In the present study, the incidence of adverse effects related to MPA increased with age, while previous studies have reported an increase in the risk of uterine or mammary gland disease at a young age (6-20 months) (Romagnoli and Concannon, 2003;

Loretti et al., 2005). Feldman and Nelson, (2004)
reported that the first estrus of Persians and related breeds may occur at 18 months of age or older, and sexual maturity may occur at 2-3 years of age. Long haired breeds represent 73.6 % of the presented cats and may have an effect on the time of administration of the first dose of MPA. The distribution of deleterious effects following administration of MPA in relation to the age of cats revealed that endometritis and pyometra are closely correlated.
Injection of MPA during the estrus phase of the estrus cycle increased the incidence of its side effects, which could be attributed to the role of oestrogens in priming and stimulating the synthesis of progesterone receptors in the endometrium and mammary glands leading to hypersensitivity of these tissues to endogenous and exogenous progesterone. The follicular cysts reported in this study may be due to the action of synthetic progestins as potent anti-ovulatory compounds where the increase in progestational activity inhibits the luteinizing hormone surge necessary for ovulation, leading to follicular cyst formation (Keskin et al., 2009) In the present study, deleterious effects following MPA administration were reported until 90 days after administration which doesn't rule out the occurrence of their adverse effects after 90 days. It has been reported that MPA can maintain an effective circulating level for 6 months following administration The main limitation of this study was the absence of a hormonal profile in the presented cats before and after MPA administration. Administration of MPA in the recommended dose in an inter-estrus period or in seasonal anestrus is highly recommended. Further studies should be directed to investigate the adverse effects of MPA following administration of the recommended dose.

CONCLUSION
Deleterious effects may occur following the first dose of MPA if taken in overdosage. It is advised to use MPA as a contraceptive in the recommended dose during the inter-estrous or anestrous phase.

Conflicts of interest
The author declares no conflict of interests