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Friday, July 20, 2018
AUGUST 2021 - DUE TO COVID-19 LIMITING SPAY/NEUTER SURGERIES, ALLEY CAT ALLIES AND THE ALLIANCE FOR CONTRACEPTION IN CATS AND DOGS NOW ENDORSE THE SHORT TERM USE OF MA TO PREVENT PREGNANCIES IN CATS- SEE THEIR WEBSITES FOR MORE INFORMATION
Edible Birth Control for Cats
It works, is low risk, *LOW COST, and can save millions of cats' lives.
This blog is my opinion based on years of personal experience and dozens of hours of research. I am not a veterinarian. Megestrol Acetate is available by prescription only in the United States but can sometimes be purchased on EBAY under the name "Nonovulin" and through an online retailer named Venivet. Do thorough research and give careful consideration before making your own decision about obtaining or using Megestrol Acetate.
It works -
I have used both Feralstat and Nonovulin with success for over 10 years. A colleague writes about his positive experience on Birthcontrolforcats.com. Fairchild Feral Friends has used it for over a decade to stabilize colonies while T/N/R is being done. A Topix forum (please see archived posts) has caretakers from all over the country discussing their success. And it has been available without a prescription in pharmacies in Europe for more than 20 years.
It's low risk -
The following French study took place after a consumer voiced concerns about side effects of megestrol acetate products for cat birth control. Even though the manufacturer's recommended dosage is much higher than the dose U.S. feral cat caretakers use, risk of side effects was determined to be .074 per 100K pills sold. An English translation as well as the original French study is available through the birthcontrolforcats.com website at http://www.birthcontrolforcats.com/cnpv.pdf
My own research (see archive) showed very little research in the U.S., and all at much higher doses. A European study was more extensive and showed very low risk of adverse reaction. Along with my feral colony, I have used Nonovulin successfully on two indoor cats for which surgery was high risk, with no negative side effects.
It's low cost
July of 2020 I paid $16 for 30 ten mg Nonovulin pills through an EBAY vendor. My colony is currently 7 cats and my weekly birth control cost is 27 cents.
Nonovulin is a megestrol acetate product available in pharmacies in Europe without a prescription. In the U.S. megestrol acetate is prescription only through veterinarians.
My Colony When I began feeding and dosing in September of 2019 there were 17 cats. There are now 7. There have been no births. I've used the chart below to determine dosage. I cut the 10 mg pills with a pill cutter and dissolve the dosage in a little water in a clear container so that I can see that the particles are well dissolved before adding them to one 22 oz can of wet cat food.
Please note that the dosage is PER COLONY NOT PER CAT.
Dosage PER COLONY using Nonovulin 10 mg tablets
Total # of Cats Dosage (dry)per colony < 5 cats 2.5 mg ONCE a week 5-7 cats 5 mg ONCE a week 8-11 cats 7.5 mg ONCE a week 12-15 cats 5 mg TWICE A WEEK 16-19 cats 7.5 mg TWICE A WEEK 20-23 cats 8 mg TWICE A WEEK 24-27 cats 10 mg TWICE A WEEK 28-31 cats 11 mg TWICE A WEEK 32-35 cats 12.5 mg TWICE A WEEKc 2.8 ml TWICE A WEEK 14 mg TWICE A WEEK This information was previously published on my site floridacatnews.com.
Five studies/cases involved high blood sugar/ glucose intolerance and diabetes. One death was reported, but the cat was 18 and had a previous history of diabetes and corticosteroid treatment. Three studies/cases reported that the diabetes reversed after the MA was discontinued, sometimes with insulin therapy and sometimes without. One of the two remaining studies was a survey of insured pet owners in the UK (total number surveyed not given) and reported that the incidence of diabetes among cats in the survey was 1 in 230, but “significantly higher” among cats which had received MA. At less than one half of one percent “significantly higher” could still be a very low number. The last study doesn’t mention if the blood sugar issue resolved after the study.
Mammary swelling and growths were also discussed. One cat, only 1.5 years old, had 121 days of treatment for a skin condition with not just MA, but a host of other drugs. After the MA treatment the cat experienced mammary swelling and although that resolved, when the skin condition returned, the owner elected to euthanize the cat. In another study, nine cats had enlarged mammary glands. Four were spayed and the swelling went away, and in the other five the lesions were excised and did not return during the follow up period. Finally, the tissue of 17 cats treated with MA and with mammary growths was analyzed. Fourteen were benign, three were cancerous.
Two studies involved “adrenocortical function” and even with a medical dictionary much of it was over my head. The first studied 20 cats, 16 of which received MA and 4 of which served as controls, concluded that “the effects of megestrol acetate on glucose tolerance were overshadowed by the unforeseen intolerance caused by chemical restraint with acepromazine maleate and ketamine hydrochloride.” The second study had 7 cats which received MA and 7 cats which received Prednisolone for 16 days and were observed for 30. It stated that on day 8 both groups had suppressed cortisol levels, on day 15 the MA group had more marked changes, and by day 30, 6 of 7 cats receiving prednisolone had recovered their adrenal reserves, but only 3 of 7 receiving MA had. Other side effects were “occasionally noted in both groups”.
Three studies/cases either studied or reported changes in the uterus of cats receiving MA. In 1974 in Oslo, 244 cats were given 2.5mg of MA for 30 weeks by their owners to study its use as a birth control. There were no pregnancies but one cat who received the MA for three years developed Pyometra. Another study dosed spayed kittens for 12 weeks then observed them for another 12 weeks. It doesn’t give the number, but some had uterine horns increase in length and diameter, folds in the endometrium, and one kitten developed pyometra. The third case was of an intact 12 year old Siamese cat that had been on MA for 10 years intermittently as a birth control, and had developed a benign growth in the uterus.
Increased appetite, personality changes, and depression were reported in 21 cats given MA for skin issues.
Theriogenology. 2012 Feb;77(3):662-74. Epub 2011 Oct 19.
PMID:22015158
[PubMed - in process]
Abstract
The aim of the present study was to investigate the safety and efficacy of deslorelin, a GnRH agonist, implants in suppressing estrus behavior and matings in a controlled ambient environment in feline queens in the presence of a tomcat. Local and utero-ovarian side effects of deslorelin implants were also investigated. The queens were housed in groups and assigned to one of three treatments: group 1 received 9.5 mg deslorelin implants (N = 14), group 2 received 5 mg megestrol acetate tablets and 9.5 mg deslorelin implants (N = 7), and group 3 were given placebo implants (N = 7). All implants were placed subcutaneously cranial to the interscapular region under xylazine hydrochloride sedation. Ovarian activity was monitored by fecal estradiol (E(2)) analyses. The animals were observed daily and checked individually at three-day intervals for behavioral signs of estrus. After 18.5 mo of trial, queens were ovariohysterectomized, and ovaries and uteri were weighed and evaluated histologically. E(2) levels were significantly lower in group 1 and 2 than in group 3 with an average of 128.48 ± 19.97 ng/g, 90.44 ± 7.16 ng/g and 283.26 ± 39.21 ng/g, respectively, excepting the first week of treatment. After inserting implants an initial estrus-like increase in fecal E(2) concentrations occurred in all treated queens except one female in group 2. Ovarian and uterine weights were significantly different among the groups (P < 0.01), and were lowest in groups 1 and 2. Primordial and primary follicle numbers were significantly higher in groups 1 and 2 than in group 3 (P < 0.001). Endometrial gland, antral follicle, and corpus luteum (CL) numbers were highest in group 3 (P < 0.01, 0.001, and 0.001, respectively) compared with groups 1 and 2. Deslorelin implants successfully suppressed estrus behavior and E(2) secretion in queens for 18.5 mo of the study period. Further investigations are needed to demonstrate the effects of GnRH agonists on ovarian interstitial tissue.
A 12-year-old, intact female, Siamese cat was presented to the referring veterinarian with a 2-day history of persistent vomiting, inappetence, and abdominal distention. The cat had been seen 2 wk prior for routine vaccinations and was showing estrus behavior at that time. Over the past 10 y, she had been vaccinated yearly and had been treated intermittently with megestrol acetate to suppress estrus. The referring veterinarian performed a complete blood (cell) count (CBC) and serum biochemical profile; results from both test panels showed no significant abnormalities. An in-clinic urinalysis was performed and the urine specific gravity was concentrated beyond the upper limit of the refractometer, and there was 3+ proteinuria. The tentative diagnosis was pyometra; the cat was hospitalized overnight and received lactated Ringer’s solution, IV. The case was then referred to the Small Animal Clinic at the Western College of Veterinary Medicine Teaching Hospital.
On physical examination, a firm, painful mass was detected within the caudoventral part of the abdomen. The cat was afebrile and tachycardic (240 beats/min; normal 160 to 220 beats/min). A superficial mobile mass was present along the ventral aspect of the trachea towards the thoracic inlet. The remaining physical examination revealed no other abnormalities.
Blood samples were submitted for a CBC (Abbott Cell-Dyn 3500R; Abbott Laboratories, St. Laurent, Quebec) and a resting thyroxine hormone level (Immulite; Inter-medico, Markham, Ontario). Results from the CBC were unremarkable, and from her resting T4, they were within the reference interval (45 nmol/L; reference interval, 13 to 50 nmol/L). Radiographs of the abdomen revealed convoluted, fluid-filled tubular structures extending from the pelvis to mid-abdomen; they were interpreted as a distended uterus (Figure 1). Feline uteri are not usually visible on plain radiographs (1). Ultrasonographs of the abdominal cavity further defined the structures as an enlarged uterus, with the left horn measuring approximately 1.5 cm in diameter and the right horn and body measuring approximately 1.0 cm in diameter. The normal uterine outer diameter in a cat varies from 0.39 to 0.70 cm, depending on the stage of the estrus cycle (1). The uterine width is largest in the luteal phase, but it enlarges further with uterine lesions or previous progestin treatment (1). The uterine walls appeared thin, but the lumen was filled with heterogeneous material that did not appear to be fluid. Ultrasonographs also showed 2 cysts (0.9 cm and 0.18 cm) on the left ovary. No other abdominal abnormalities were detected. Urine was collected by cystocentesis and submitted for a complete urinalysis, the results of which were unremarkable. Ultrasonographs showed that the mass in the ventral part of the neck was cystic. Further testing was declined by the owner, and the cyst has since resolved spontaneously.
Ventrodorsal radiograph showing diffusely enlarged and distended uterine horns (arrows).
The cat became markedly depressed throughout the day, so an exploratory laparotomy was scheduled for later that evening. The cat was premedicated with hydromorphone (Hydromorphone hydrocholoride injection USP 2 mg/mL (generic); Sabex, Boucherville, Quebec), 0.1 mg/kg bodyweight (BW), IM, and anesthesia was induced with propofol (Diprivan; Novopharm, Toronto, Ontario), 6 mg/kg BW, IV, and maintained on 1.0 L/min oxygen and 1.5% isoflourane (Isoflo; Abbott Laboratories, St. Laurent, Quebec).
A ventral midline incision was made through the abdominal wall, whereupon enlarged, firm, nodular uterine horns were immediately visible. The entire length of both uterine horns was affected, as was the uterine body. The left ovary had 2 cystic structures, as detected on ultrasonographs. A routine ovariohysterectomy was performed, though ligatures were placed prior to clamping the uterine body, since the tissue was friable. The uterine vessels were ligated separately from the uterine body, which was then singly ligated at the cervix where, grossly, the tissue was normal. Urine was collected via cystocentesis for bacteriological culture. The uterine stump was wrapped in omentum, the peritoneal cavity was lavaged, and the abdominal wall was closed routinely. Cefazolin (Novopharm, Toronto, Ontario), 22 mg/kg BW, IV, was given prior to the surgery and, thereafter, every 90 min throughout the procedure. The uterine horns and body were opened, examined grossly, fixed in formalin, and submitted for light microscopic examination.
Postoperatively, the cat received cefazolin (Novopharm), 22 mg/kg BW, IV, q12h, hydromorphone (Sabex), 0.05 mg/kg BW, IM, q4h, and meloxicam (Metacam; Boerhringer-Ingelheim, Laval, Quebec), 0.1 mg/kg BW, SC, q24h. She became dysphoric after receiving hydromorphone, so the analgesic was changed to buprenorphine (Buprenex; Reckitt and Colman Pharmaceuticals, Richmond, Virginia, USA), 0.01 mg/kg BW, SC, q6h. The buprenorphine treatment was continued at 0.01 mg/kg BW, SC, q8h for 2 d, and meloxicam (Boerhringer-Ingeheim) was given, 0.1 mg/kg BW, PO, q12h for 5 d, after surgery. The antibiotic was changed the following day to amoxicillin-clavulanic acid (Clavamox; Pfizer Animal Health, Kirkland, Quebec), 62.5 mg, PO, q12h for 10 d, and the cat was discharged 4 d postoperatively. No further health concerns were reported in the 6 mo following discharge.
Histopathologic examination of the uterus revealed diffuse adenomyosis of both horns and the body of the uterus. There was endometrial and myometrial hyperplasia, which obliterated the uterine lumen. The walls were at least twice the normal thickness. In areas where the lumen was not obliterated, it was filled with white, adherent material. Endometrial tissue was found within the myometrium, forming glandular structures (Figure 2). The abnormal endometrial tissue appeared to be functional, and no evidence of malignancy was found. Histopathologic examination of the ovaries showed numerous follicles at various stages of development, numerous corpora lutea, and several cystic structures.
Photomicrograph of a uterine horn section showing endometrial proliferation and invasion of the myometrium characteristic of uterine adenomyosis (arrows). Hematoxylin and eosin. Bar = 1000 μm.
Adenomyosis is defined as a benign condition where endometrial glands and stroma occur in a disorganized fashion deep within the myometrium (2,3). There is also characteristic myometrial hyperplasia surrounding the adenomatous tissue. Diffuse disease is known as uterine adenomyosis, while isolated foci are termed uterine adenomyomata (2). Uterine adenomyosis is a rare disorder of domestic animals, though it does occur with variable frequency in humans (2,4). Uterine adenomyosis is thought to occur due to endometrial invagination and invasion of the underlying muscular layers, though it may also occur outside the uterus through aberrant development of the Mullerian ducts (2). The pathogenesis is not well understood, though increased estrogen, abnormal musculature, and increased luminal pressure have been implicated (2,4,5). The immune responses in adenomatous uteri are also abnormal (4,5). Adenomyosis may co-occur with leiomyomata, polyps, and adenocarcinoma (2). Endometriosis shares several characteristics with adenomyosis, but in endometriosis, aberrant endometrium is found only outside the uterus and endometriosis occurs only in menstruating species (primates).
In women, the most common clinical signs of uterine adenomyosis are dysmenorrhea and menorrhagia, followed by abdominal and pelvic pain and reproductive difficulties (2). Approximately 35% of women are asymptomatic (2). The rare published veterinary cases have been without clinical signs (6), making this cat unusual in that she was presented for vomiting, inappetence, and abdominal pain. In human cases, as in this feline case, definitive diagnosis prior to surgical removal of the uterus is difficult. An enlarged uterus may be noted on ultrasonographs or radiographs, but magnetic resonance imaging is the preferred diagnostic test in women (7). Light microscopy is required to confirm the diagnosis. Hysterectomy or ovariohysterectomy is often the definitive treatment.
The hormonal profile in women with adenomyosis is atypical. Endometrial glands in adenomyosis express more lutenizing hormone, estrogen, and progesterone receptors than in the normal uterus (2). Adenomyotic glands have also been found to secrete excess estrogen and to have higher than normal estrogen sulphatase and aromatase levels, 2 enzymes that increase conversion of androgens to estrogen and also increase estrogen binding (2). These findings, coupled with the success of anti-estrogenic drugs as treatment, support the theory of excess estrogen being a causal factor. The excess estrogen levels in affected women may arise from excess circulating progestins, which elevate aromatase activity, estrogen receptor concentration, and epidermal growth factors (2,6). Initially, progestins oppose estrogenic effects, hence duration of treatment may be important with respect to disease (8). The prevalence of adenomyosis is unexpectedly high in women receiving chemotherapy with the selective estrogen receptor modulator tamoxifen, which has estrogenic effects (4,7). Since this cat received megestrol acetate frequently throughout her life, the exogenous progestins are suspected to have increased her risk for disease. Increased progesterone from corpora lutea, which were numerous in the ovaries of this cat, could also have increased estrogen levels over time through the same mechanisms as exogenous progestins, and thus have contributed to the adenomyosis (6). It is difficult to determine whether the uterine lesions contributed to abnormal ovarian activity or vice versa.
Adenomyosis is correlated with uterine hyperplasia in women and zoo felids (4,6). Endometrial hyperplasia is a reported sequela to progestin therapy in domestic animals; pyometra and other reproductive problems are also potential risks (1). Munson et al (6) found that zoo felids treated with melegestrol acetate were at a 3.6 times higher risk of endometrial hyperplasia and associated reproductive disease than were untreated cats. Progestin treatment significantly increased uterine coiling, curving, and glandular proliferation beyond the changes that normally occur throughout the estrus cycle (1). Synthetic progestins are commonly used for estrus suppression and estrus cycle control in both domestic and zoological animals, the most common being megestrol acetate, melegestrol acetate, and medroxyprogesterone acetate (9). These compounds block gonadotropin releasing hormone (GnRH) production or release. Common side effects in domestic cats and dogs include endometrial hyperplasia, mammary development, and insulin resistance (6,9). Munson et al (6) also found progestin therapy was associated with hydrometra, mucometra, and endometrial mineralization. Cats appear particularly sensitive to adrenocortical suppression and routine doses can cause hypoadrenocorticism (6,8,9). In this cat, there was no evidence of altered steroid profile or insulin resistance, as indicated by normal electrolyte and glucose parameters. The dose and duration of the megestrol acetate treatment previously prescribed for this cat was unknown. Megestrol acetate is not labeled for use in cats, and treatment regimes are variable. Suggested protocols range from 2.5 to 5.0 mg/cat, PO, q24 h for 3 d, if administration is started during estrus, to 2.5 to 5.0 mg/cat, PO, q24 h for 8 to 10 wk, if it is started in diestrus (8). Treatment with 2.5 mg, PO, once weekly for up to 18 mo is suggested for suppression of estrus if it is started in anestrus (8). Varied protocols also exist for its use in treating many feline dermatological problems.
Medical treatment of adenomyosis in women has met with variable success. Oral contraceptives, progestins, antiprogestins, anti-estrogen antibodies, GnRH analogues, and danazol-impregnated intrauterine devices have all been used, with anti-estrogen antibodies, antiprogestins, such as gestrinone or indomethacin, and danazol having the highest success (7). Danazol is a weak androgenic compound that is suspected to act via inhibition of sex steroid production and is a mainstay in endometriosis therapy (8). Severe cases require partial to complete hysterectomy. In veterinary medicine, where reproductive conservation is often less critical, ovariohysterectomy is the most commonly recommended treatment (6).
Both adenomyosis and the prescribed treatments can adversely affect the ability to conceive. This is of concern in rare zoo felids receiving long-term progestin treatment to suppress estrus, as many of these animals will be bred in the future and are genetically valuable. Munson et al (6) caution against the use of exogenous progestins in potential breeding animals; they recommend early breeding or alternating breeding with progestin therapy to maintain reproductive health.
Uterine adenomyosis has been described rarely in the veterinary literature (10). Uterine disease is much less common in the cat than in the dog (6). Pack (3) described a feline case of uterine adenomyosis, with emphasis on the histological appearance and diagnosis of the disease. As in this case, evaluation found a grossly enlarged uterus, endometrial invasion of the myometrium, and purulent debris. Interestingly, the ovaries of both cats had multiple follicles, corpora lutea, and cysts. Tamada et al (10) described a case where adenomyosis and cystic pyometra co-occurred in a Shiba Inu bitch, and a case of adenomyosis diagnosed following uterine torsion has also been described where the dogs showed clinical signs (11). In both these cases, the clinical signs were assumed to be due to the co-occurring lesions, not adenomyosis. In this respect, this case is unusual in that adenomyosis alone caused clinical signs severe enough to warrant exploration and ovariohysterectomy.
Adenomyosis is an important differential diagnosis for uterine disease in both domestic and zoo animals. Uterine adenomyosis may be misdiagnosed clinically, and suggestive lesions merit full light microscopic examination. The potential link of exogenous hormone therapy and adenomyosis deserves further investigation in both veterinary and human medicine.
Acknowledgments
The author thanks Dr. Peter Gilbert for his assistance in attending to this case, and Dr. Trent Bollinger, Dr. Beverly Kidney, and Dr. Bruce Grahn for their assistance formulating the manuscript. CVJ
Footnotes
Dr. Bulman-Fleming will receive 50 free reprints of her article, courtesy of The Canadian Veterinary Journal.
1. Chatdarong K, Rungsipipat A, Axner E, Linde Forsberg C. Hysterographic appearance and uterine histology at different stages of the reproductive cycle and after progestagen treatment in the domestic cat. Theriogenology. 2005;64:12–29. [PubMed]
2. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update: Eur Soc Hum Reprod Embryol. 1998;4:312–322.
3. Pack FD. Feline uterine adenomyosis: A case report. Feline Pract. 1980;10:45–47.
4. Bergholt T, Eriksen L, Jacobsen M, Hertz JB. Prevalence and risk factors of adenomyosis at hysterectomy. Hum Reprod Update: Eur Soc Hum Reprod Embryol. 2001;16:2418–2421.
5. Parrott E, Butterworth M, Green A, White INH, Greaves P. Adenomyosis — A result of disordered stromal differentiation. Am J Pathol. 2001;159:623–630. [PMC free article] [PubMed]
6. Munson L, Gardner IA, Mason RJ, Chassy LM, Seal US. Endometrial hyperplasia and mineralization in zoo felids treated with melegestrol acetate contraceptives. Vet Pathol. 2002;39:419–427. [PubMed]
7. Wood C. Surgical and medical treatment of adenomyosis. Hum Reprod Update: Eur Soc Hum Reprod Embryol. 1998;4:323–336.
8. Plumb DC. Plumb’s Veterinary Drug Handbook. 5. Stockholm, Wisconsin: Blackwell Publ; 2005.
9. Romagnoli S. Clinical use of hormones in the control of reproduction in bitches and queens. World Small Anim Vet Cong Proc 2002. [Last accessed 17/01/07]; Veterinary Information Network [database on the Internet]; Davis: c1991–2007 (Updated 2007)
10. Tamada H, Kawate N, Inaba T, et al. Adenomyosis with severe inflammation in the uterine cervix in a dog. Can Vet J. 2005;46:333–334. [PMC free article] [PubMed]
11. Stocklin-Gautschi NM, Guscetti F, Reichler IM, Geissbuhler U, Brown SA, Arnold S. Identification of focal adenomyosis as a uterine lesion in 2 dogs. J Small Anim Pract. 1001;42:413–416. [PubMed]
Articles from The Canadian Veterinary Journal are provided here courtesy of
Canadian Veterinary Medical Association
Division of Veterinary Clinical Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin, Midlothian EH25 9RG, UK.
Abstract
Prevalence and risk factors for the development of diabetes mellitus (DM) in cats in the United Kingdom have not previously been reported. The prevalence of DM was evaluated in a large insured population and was found to be 1 in 230 cats. In this insured cat population Burmese cats were 3.7 times more likely to develop DM than non-pedigree cats. A convenience-sampling questionnaire-based study was used in order to identify putative risk factors for the development of DM. The univariate risk factor analysis identified being male, neutered, inactive, weighing >or=5 kg and having a history of corticosteroid treatment as significant risk factors for the development of DM in these cats. In addition, male cats treated with megestrol acetate had a significantly increased risk of developing DM compared to females. In contrast, there was no difference in DM occurrence between male and female Burmese cats. A multivariate classification tree-based model on the questionnaire data looking for interactions between risk factors, identified gender as the most important overall risk factor for the development of DM with low physical activity being the next most important risk factor for female cats and breed the next most important for male cats.
Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, 1 Shields Ave., Davis, CA 95616, USA. lmunson@ucdavis.edu
Abstract
Contraceptives are used for reversible reproductive control in genetically valuable wild felids, as permanent reproductive control in generic wild felids, and as an economically practicable means to control feral cats. The progestin contraceptives, megestrol acetate, melengesterol acetate, medroxyprogesterone acetate, and levonorgestrol (administered orally, in implants, or as depot injections), are effective in preventing pregnancy. However, long-term use is associated with endometrial hyperplasia, endometrial cancer, and mammary cancer. Gonadotropin releasing hormone analogs or luteinizing hormone vaccines that achieve contraception by suppressing ovarian or testicular function, do not have the adverse health effects of progestins. However, reliable reversibility has not been demonstrated, and male secondary sex characteristics may be suppressed. Bisdiamines also inhibit spermatogenesis and lower circulating testosterone concentrations in treated male cats. Porcine zona pellucida vaccines are ineffective contraceptives in felids and may cause serious health problems when combined with some adjuvants. Because of the limited availability of non-progestin contraceptives and side effects associated with some agents, widespread application of contraception to felids has been curtailed. More non-steroidal methods of contraception should be tested in the future to provide alternatives for controlling reproduction in felids. Furthermore, all empirical information on contraceptive safety and efficacy should be assembled in a database to provide the knowledge needed by veterinarians and managers to determine benefits/risks of currently available contraceptives in felids, both domestic and wild.
Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4.
This article has been cited by other articles in PMC.
Abstract
A male, neutered cat was presented for lethargy, reluctance to walk, and mammary enlargement after recent treatment with megestrol acetate. Mammary fibroadenomatous hyperplasia was diagnosed on the basis of history, clinical signs, and histopathological findings. Pathogenesis, clinical signs, and treatment options for mammary fibroadenomatous hyperplasia attributed to megestrol acetate treatment are discussed.
A 1.5-year-old, neutered male, domestic shorthair was presented to the Strathmore Veterinary Clinic, Strathmore, Alberta for a pruritic, hemorrhagic dermatopathy of the chin region. A tentative diagnosis of a superficial pyoderma was made and the cat was discharged with the following therapies: topical cleansing; oral orbifloxacin (Orbax; Schering-Plough, Pointe Claire, Quebec), 2.2 mg/kg bodyweight (BW), q24h for 14 d; and oral prednisone (generic), 1 mg/kg BW, q24h for 4 d.
The cat was presented to the clinic again, approximately 1 mo later. The lesion on the chin remained pruritic, and 2 additional similar lesions were on the ventral aspect of the neck and mandible. At this time, the owners declined to have the skin biopsied. Eosinophil-granuloma complex was suspected and methylprednisolone acetate (Depo-Medrol; Upjohn, Mississauga, Ontario), 4 mg/kg BW, SC, was administered. A hypoallergenic food trial was commenced.
The cat was presented to the clinic again, 38 d after initial presentation, with continuing pruritus. The therapeutic regime was modified at this time to include oral megestrol acetate (Ovaban; Schering-Plough), 1 mg/kg BW, q24h for 5 d, and then 0.5 mg/kg BW, PO twice weekly for 21 d. This prescription was refilled 33 d after initiation of the oral megestrol acetate treatment, so that the cat received 1 mg/kg BW, PO, q24h for 2 d, followed by 0.5 mg/kg BW, PO, q24h for 16 d.
A recheck appointment was scheduled for 7 d after the prescription had been completed, that is, 58 d after initiation of megestrol acetate treatment. The cat, at this time, demonstrated acute mammary enlargement and reluctance to walk. Findings on physical examination were unremarkable, except for the chin and mammary glands. All 6 mammary glands were asymmetrically enlarged, with diameters ranging from 1.5 cm to 5 cm. The most severely affected gland was the right inguinal, which was hyperemic, warm, and edematous near the teat. Thoracic radiographs, taken to screen for possible pulmonary metastases, were within normal limits. A complete blood cell (CBC) count and chemistry panel were performed on a blood analysis machine, (IDEXX VetLab; IDEXX Laboratories, Westbrook, Maine USA), and the results were within normal limits. A urinalysis was not performed.
Differential diagnoses included mammary adenocarcinoma or carcinoma, mammary adenoma, or mammary sarcoma. Due to the recent history of progestin administration and the involvement of more than 1 gland, mammary hyperplasia was the most likely diagnosis.
A simple mastectomy of the right inguinal mammary gland and an excisional biopsy of the right inguinal lymph node were performed under general anesthesia. These tissues were submitted to the Western College of Veterinary Medicine for histological examination. The final histological diagnosis of the right inguinal gland was mammary fibroadenomatous hyperplasia (Figure 1). The right inguinal gland also had neutrophilic infiltrates beneath the ulcerated area, suggesting a superficial mastitis. The right inguinal lymph node had no histological lesions.
Figure. 1. Mammary fibroadenomatour hyperplasia in a 1 and 1.5 year old male neutered cat after treatment with standard dosages of megestrol acetate (progesterone analogue). (A) Mammary adenomatous hyperplasia of lobular ducts. (B) Fibrous hyperplasia (more ...)
Recheck examinations were performed 10 d and 15 d after surgery, that is, 68 d and 73 d after initiation of megestrol acetate treatment. Abdominal and thoracic mammary glands had regressed slightly, but the left inguinal mammary gland had enlarged slightly.
The cat was presented to the clinic 7 d later for inappetance (80 d after initiation of megestrol acetate treatment). On physical examination, the cat was mildly febrile (temperature 39.9°C; normal 38.5°C to 39.5°C) and estimated to be 5% dyhydrated. A small, ulcerated skin lesion, similar to previous lesions, was noted on the ventral chin. The left inguinal mammary gland was ulcerated, swollen, warm, painful, and asymmetrically enlarged to 4 cm in diameter. A CBC count showed a mild leukocytosis (18.9 × 109/L; normal, 6.0 to 16.9 × 109/L) and mild neutrophilia (15.5 × 109/L; normal, 2.8 to 10.5 × 109/L). A presumptive diagnosis of superficial mastitis (complicating the underlying mammary hyperplasia) was made. The cat received trimethoprim-sulfadiazine (Tribrissen; Schering Plough), 35 mg/kg BW, SC, q24h for 3 d, meloxicam (Metacam Injectable; Boehringer Ingelheim Vetmedica, Burlington, Ontario), 0.02 mg/kg BW, SC, q24h, and lactated Ringer's solution, 60 to 120 mL, SC, q24 h for the next 3 d. During this time, the cat's temperature returned to normal (38.5°C). The therapeutic plan was to return the cat to the owners once the cat was eating sufficiently on his own, to continue antibiotic treatment for 10 d, and to biopsy the skin lesions after the antibiotic course had been completed.
The owners did not wish to pursue further diagnostic tests. When the cat's skin lesions returned, they elected for euthanasia. A necropsy was not performed.
Feline mammary fibroadenomatous hyperplasia, also known as feline mammary hypertrophy or fibroepithelial hyperplasia, is a nonneoplastic, progesterone-induced condition (1). Typical signalments include young cycling cats, pregnant or pseudopregnant female cats, or older neutered male or female cats given exogenous progestins (2). Cats present with mammary enlargement, involving one or more glands. The enlargement is due to rapid proliferation of mammary duct epithelium and stroma. Hyperplastic mammary tissue may undergo spontaneous regression; may require ovariohysterectomy, if secondary, to elevated estrogen levels; or may regress once progesterone levels decline. Mammary hyperplasia must be distinguished by microscopic examination from mammary neoplasia, as the latter has a poor prognosis. Mammary neoplasms in the cat often grow rapidly, are firm and ulcerated, and metastasize early to local lymph nodes and lungs (3).
Megestrol acetate is a progestagen. In veterinary medicine, it has been used to treat pseudopregnancy in dogs; to suppress or delay estrus in cats and dogs; to treat behavior-related conditions in cats; to treat feline eosinophilic and proliferative keratopathies; and, less commonly, as an appetite stimulant (4,5). However, it has not been approved for use in the cat. Side effects noted in cats are as follows: iatrogenic adrenocortical suppression, transient diabetes mellitus, hepatotoxicity, cystic endometrial hyperplasia, and mammary hypertrophy or neoplasia (6). There is evidence that megestrol acetate has a glucocorticoid-like activity. Its use may result in suppression of the adrenocortical axis for 2 to 4 wk after treatment, 5 mg/kg BW/cat, q24h, 14d, and in hyperinsulinemia (7). Therefore, discontinuing megestrol acetate therapy abruptly is not recommended (7).
Fibroadenomatous mammary hyperplasia is a relatively uncommon sequela to the administration of megestrol acetate (8). This therapy was found to be clearly associated with mammary fibroepithelial hyperplasia in predominantly older (average age 8.1 y) neutered male or female cats (2). In the case reported here, the affected cat was 1.5 y old; however, the youngest cat reported in another study was 11 mo old (5). Secondary mastitis, ulceration, or both may be observed with this condition, as was confirmed in this case on histopathologic examination.
Maximal mammary development seems to require a synergism between pituitary hormones and ovarian steroids (2). Mammary duct epithelium and stromal proliferation (benign) is thought to be progesterone dependent (8). Steroid receptors within mammary tissue recognize progesterone and estrogen, and through these receptors hormonal action is medicated.
Immunohistochemistry techniques have been used to identify and distinguish estrogen and progesterone hormone receptors. In cases that were studies, progesterone receptors were identified in tissues of all cases of mammary hypertrophy, while estrogen receptors were recognized in only 50% of tissues (1). It is hypothesized that “the interaction of progesterone and synthetic progestins with progesterone receptors stimulates the local production of growth hormone, which would act on a potential autocrine/paracrine stimulatory loop to induce proliferation of mammary epithelial and stromal cells” (1).
In this case, one could speculate that the exogenous methylprednisolone acetate given 3 d before initiation of megestrol acetate may have allowed synergistic action between glucocorticoids and progestins, encouraging maximal mammary development. Further studies showing the interaction between these 2 hormones may be indicated.
Typically, the treatment for mammary hyperplasia in cats was ovariohysterectomy (if intact), mastectomy, or cessation of progestin therapy and allowing time for mammary regression. More recently, a progesterone-antagonist has been used successfully to treat hyperplasia in intact or neutered cats by eliminating the source of progestin (5). Seven cats affected with mammary hyperplasia were treated with aglepristone (Alizine; Aventis, Strasbourg, France), 10 mg/kg BW, SC, q24h for 4 to 5 d. Five days after the initial treatment, reduction in the size of the mammary glands, as well as change in consistency of affected glands (from rigid to soft), was observed. Corresponding biopsies taken 7 d after the first treatment showed collapse of the glandular duct lumens and reduction in the number of epithelial cells. It was reported to take 3 to 4 wk for complete involution of the glands. One of the 7 cats studied had recurrence of mammary hyperplasia 13 d after initial reduction in mammary gland size (16 d after initial treatment with aglepristone). No side effects were observed in any of the 7 cats treated with aglepristone.
In this case, progesterone blood levels were not measured, and tests for progesterone receptors on fixed mammary tissue were not performed. Therefore, the diagnosis of mammary hyperplasia due to megestrol acetate therapy is presumptive. However, the “apparent influence of a progestagen, whether present as exogenous therapy in the male or female or as endogenous steroid of ovarian origin, has been demonstrated directly and indirectly in cats with mammary hypertrophy” (6). Aglepristone may have been a viable treatment option for this cat (if commercially available) to reduce the size of all affected mammary glands.
It should be noted that the dose of megestrol acetate used was within the standard dosing regimen (never greater than 0.5 to 1 mg/kg BW, q24h) (10). However, the dose or duration of therapy with exogenous progestins cannot be used as a predictor for mammary hyperplasia (8). Veterinarians should be aware of the potential, yet uncommon, side effects discussed above. CVJ
Footnotes
Acknowledgments
The author thanks Drs. P. Dowling, K. Mealey, M. Johnson, B. Fransson, and E. O'Toole for their advice. CVJ
Dr. MacDougall's current address is Western Veterinary Specialist Centre, 1635–17th Avenue Southwest, Calgary, Alberta T2T 0E5.
Address all correspondence to Dr. MacDougall.
Reprints will not be available from the author.
References
1. de las Mulas JM, Millan Y, Bautista MJ, Perez J, Carrasco L. Oestrogen and progesterone receptors in feline fibroadenomatous change: An immunohistochemical study. Res Vet Pathol 2000; 68:15–21.
2. Hayden DW, Barnes DM, Johnson KH. Morphologic changes in the mammary gland of megestrol acetate-treated and untreated cats: A retrospective study. Vet Pathol 1989;26:104–113. [PubMed]
3. Fossum TW, Hedlund CS, Hulse DA, et al. Small Animal Surgery, 1st ed., St. Louis: Mosby-Year Book, 1997:539–544.
4. Adams R, ed. Veterinary Pharmacology and Therapeutics, 7th ed., Iowa: Iowa State Univ Pr. 1995:594–595,1084,1111.
5. Wehrend A, Hospes R, Gruber AD. Treatment of feline mammary fibroadenomatous hyperplasia with a progesterone-antagonist. Vet Rec 2001;148:346–347. [PubMed]
6. Hayden DW, Johnston SD, Kiang DT, Barnes DM. Feline mammary hypertrophy/fibroadenoma comples: clinical and hormonal aspects. Am J Vet Res 1981;42:1699–1703. [PubMed]
7. Church DB, Watson AD, Emslie DR, Middleton DJ, Tan K, Wong D. Effects of proligestone and megestrol on plasma adrenocorticotrophic hormone, insulin and insulin-like growth factor-1 concentration in cats. Res Vet Sci 1994;56:175–178. [PubMed]
8. Hayden DW, Johnson KH. Feline mammary hypertrophy-fibroadenoma complex. In: Kirk RW, ed. Current Veterinary Therapy IX, Small Animal Practice. Philadelphia: WB Saunders, 1986:477–480.
9. Chisholm H. Massive mammary enlargement in a cat. Can Vet J 1993;34:315.
10. Plumb DC. Veterinary Drug Handbook, 3rd ed. White Bear Lake: Pharma Vet Publ, 1999:398–401.
Department of Veterinary Clinical Sciences, University of Sydney, New South Wales, Australia.
Abstract
This paper reports changes in adrenocorticotrophic hormone (ACTH), insulin and insulin-like growth factor-1 (IGF-1) concentrations in cats from a previously published study. The cats were given oral megestrol acetate (MA, 5 mg once daily for 14 days), subcutaneous proligestone (PRG, 100 mg on two occasions one week apart) or subcutaneous saline (1 ml as for PRG). In the cats given saline (n = 6), basal ACTH, insulin and IGF-1 did not change significantly throughout the following seven weeks. The cats given MA (n = 7) developed significant suppression of plasma ACTH concentrations and hyperinsulinaemia during treatment and for two to four weeks after MA dosage ceased. In the cats given PRG (n = 7), plasma ACTH concentrations were not significantly altered although three cats had markedly suppressed values for some time after PRG treatment had ceased. Serum insulin concentrations were not significantly altered in the PRG-treated cats. The results suggest PRG may be a preferable alternative to MA in some situations.
Department of Physiological Sciences, University of California, Davis 95616.
Abstract
The most frequent type of behavior problem in cats for which veterinary consultation is sought is problem urination. Urine spraying and urine marking have been treated by use of long-acting progestins and diazepam, a benzodiazepine antianxiety drug. Effectiveness of the nonbenzodiazepine antianxiety drug, buspirone, in suppressing urine spraying and marking in 47 male and 15 female cats was evaluated. The effect of the drug in correcting inappropriate urination in 9 cats also was evaluated. Buspirone resulted in a favorable response (> 75% reduction) in 55% of cats treated for urine spraying or marking. There was no sex difference in effectiveness of the treatment, but cats from single-cat households responded favorably significantly (P < 0.001) less frequently than those from multiple-cat households. The 55% response rate was within the range of treatment effectiveness that has been reported for diazepam, and was greater than that reported for progestin. In contrast to diazepam, with which over 90% of treated cats resumed spraying or marking when the drug was gradually discontinued, only half of the cats treated with buspirone resumed spraying when the drug was discontinued after 2 months of treatment (P < 0.001). This difference between diazepam and buspirone in resumption of urine spraying was attributed to diazepam's induction of physiologic and behavioral dependency, not found with buspirone. Cats that resumed spraying were placed on long-term treatment ranging from 6 to 18 months. Buspirone also did not cause the adverse effects of sedation and ataxia, which commonly are seen with diazepam treatment. In cats treated for inappropriate urination, 56% returned to normal litter box usage.(ABSTRACT TRUNCATED AT 250 WORDS)
The regulation of progesterone secretion and release by the corpus luteum and/or by the placenta in cats during pregnancy has been poorly studied and the relative roles of the corpus luteum and the placenta in the release of progesterone into the plasma is not well defined. It is generally assumed that after 40-45 days of pregnancy, circulating progesterone is mainly produced by the placenta and that after 45-50 days the corpus luteum is no longer necessary to maintain pregnancy, even if remnants of corpora lutea are detected in the ovaries during the following interoestrous period. In this study, the relative roles of the placenta and ovary in progesterone production after 30 days of pregnancy have been analysed in an attempt to define the role of progesterone in pregnant cats. Different experiments involved (1) analysis of the effects of an ovariectomy performed at 30 days of pregnancy, and of megestrol acetate supplementation on plasma progesterone during the second half of pregnancy, (2) analysis of the effects of an ovariectomy performed at 45 days on plasma progesterone production and on pregnancy and (3) analysis of the effects of an antiprolactin agent (cabergoline) at days 30 and 40 of pregnancy on progesterone secretion and pregnancy. These results were all compared with the normal plasma progesterone profiles during (a) pseudopregnancy and (b) pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Physiological Sciences, School of Veterinary Medicine, University of California, Davis 95616.
Abstract
The most common treatment for urine spraying and marking in cats has been administration of long-acting progestins. Treatment with diazepam has recently been gaining favor, particularly because of reported adverse effects of progestins. Results of a clinical trial involving 20 cats indicated that diazepam was effective in eliminating or markedly reducing spraying in 11 (55%) of them. However, most cats required continuous treatment, or at least intermittent treatment, when spraying recurred. The physiologic and behavioral dependency of cats on diazepam, which presumably develops over the course of administration, may contribute to the tendency for spraying to recur once diazepam treatment is discontinued. Using data from previously published findings on progestin administration, plus additional cases, it was documented that a significantly (P less than 0.05) higher percentage of males than females responded favorably. Although the number of cases was not sufficient for a statistical comparison of diazepam vs progestin treatment with regard to male vs female, possible gender difference in the effectiveness of diazepam was not indicated.
Veterinär-Chirurgische Klinik, Universität Zürich.
Abstract
A special form of keratitis in the cat is described on the basis of 8 clinical cases. The disease has been known in the United States and the United Kingdom for some time, however, it has, to our knowledge, never been described in Switzerland. This keratitis is characterized by chronicity and infiltration of the cornea by mast cells and eosinophils. It is usually an unilateral and painless condition. We describe the clinical features and diagnostic examinations of the disease. Cytology of a corneal scraping is usually diagnostic. As in the cases described in the literature the cats were successfully treated with oral megestrol acetate. The aetiology of the disease is unknown.
Department of Veterinary Clinical Sciences, University of Sydney, New South Wales, Australia.
Abstract
Five prepubertally ovariectomised kittens served as controls. Ten prepubertally ovariectomised kittens were given megestrol acetate (MA) orally at the rate of either 5 or 15 mg twice weekly for 12 to 13 weeks. The uterine horns of treated cats increased in length and diameter. The endometrium became deeply folded with marked hypertrophy of glandular epithelium and production of glycogen by the glandular cells. One cat developed pyometra. Once weekly administration of 2.5 mg MA for a further 12 weeks maintained the hypertrophic changes. The proliferated endometrium regressed considerably but not completely after 12 weeks without MA administration. In two other kittens 2.5 mg MA once weekly for six weeks was sufficient to induce similar changes. MA is a very potent progestational agent in cats, even if they have been ovariectomised prepubertally.
Department of Veterinary Clinical Sciences, University of Sydney, New South Wales, Australia.
Res Vet Sci. 1989 Nov;47(3):374-6.
PMID:
2556766
[PubMed - indexed for MEDLINE]
Cats were given megestrol acetate (MA, 5 mg once daily for 14 days), subcutaneous proligestone (PRG, 100 mg on two occasions one week apart) or subcutaneous saline (1 ml as for PRG). In cats given saline (n = 6) basal cortical concentrations, cortisol concentrations after adrenocorticotrophic hormone (ACTH) administration and fasting blood glucose concentrations did not change significantly during the following seven weeks. Cats given MA (n = 7) developed suppression of basal and ACTH-stimulated cortisol concentrations and fasting hyperglycaemia during treatment. Effects on cortisol persisted for two weeks after MA dosage ceased. In cats given PRG (n = 7), basal cortisol concentrations were reduced overall, but only three cats had persistently suppressed post-ACTH cortisol concentrations. Adrenal suppression continued for 14 weeks in one of these and for at least 22 weeks in two cats. Fasting blood glucose concentrations were unchanged in PRG-treated cats.
The online version of this article can be found at:
DOI: 10.1177/030098588902600202
Vet Pathol. 1989 Mar;26(2):104-13.
PMID: 2711568
http://vet.sagepub.com/content/26/2/104
The online version of this article can be found at:
DOI: 10.1177/030098588902600202
D. W. HAYDEND, . M. BARNESA, ND K. H. JOHNSON
Department of Veterinary Pathobiology and Department of Veterinary Diagnostic Investigation,
College of Veterinary Medicine, University of Minnesota, St. Paul, MN
Abstract. Abnormal mammary gland growth is a side effect of progestin therapy in some cats. In this
retrospective study, the nature and significance of morphologic changes in the mammary gland of 17 megestrol
acetate (MA)-treated cats were compared to mammary lesions in 97 untreated cats. Fourteen out of 17 MAtreated
cats had non-neoplastic mammary lesions including fibroepithelial hyperplasia (nine cats), lobular hyperplasia
(three cats), and duct ectasia (two cats); whereas three MA-treated cats had mammary neoplasms
including one adenoma and two carcinomas. Although MA has been causally linked to mammary cancer in
cats, only mammary fibroepithelial hyperplasia was clearly associated with MA therapy in this study. Fibroepithelial
hyperplasia occurred in older (average age 8.1 years) neutered male and female cats in the MA-treated
group and in younger (average age 2.1 years) female cats in the untreated group. Morphologically, both intraductal
and solid fibroepithelial growth patterns were seen. Intraductal fibroepithelial hyperplasia was further subdivided
into papillary and circumferential types. An apparent greater association between MA therapy and the intraductal
types of fibroepithelial hyperplasia was noted. Furthermore, it appears likely that mammary lobular hyperplasia
also is linked to MA therapy. Possible mammatrophic effects of MA and other growth-promoting agents in the
cat are discussed.
Megestrol acetate (MA), a 17 alpha-acetoxy-6 methylsynthetic analog of progesterone, was originally developed
as an oral steroid contraceptive agent for use n women.7 This potent anti-ovulatory compound has
progestational activity 25 times greater than that of progesterone.21A although approved for use in dogs to
postpone estrus and alleviate false pregnancy, MA also is given to cats for a multiplicity of clinical problems
including reproductive control, behavioral modification, and certain dermatologic conditions. l 7 The current
popularity of progestins as therapeutic agents for cats increases the possibility of encountering undesirable
side effects of these drugs. Some of the more potentially serious side effects attributed specifically to
MA in the cat are: adrenal cortical suppression, glucose intolerance and overt diabetes mellitus, pyometra, and abnormal mammary growth.
Changes in mammary gland architecture previously reported with MA therapy generally fall into the categories
of either mammary hypertrophy (fibroepithelial hyperplasia), or mammary carcinoma . Mammary hypertrophy is a non-neoplastic, progesterone- responsive condition characterized by rapid proliferation of mammary stroma and duct epithelium in one or more glands. Detailed clinicopathologic information about this condition can be found elsewhere. In comparison, relatively few references to mammary neoplasms or other types of mammary lesions have been documented in cats given synthetic progestins. As part of an ongoing effort to define the role of hormones in the pathogenesis of feline mammary neoplasia, we explored the spectrum of histopathologic lesions encountered in the mammary gland of 17
MA-treated cats. Morphologic effects seen included fibroepithelial hyperplasia, lobular hyperplasia, duct
ectasia, and mammary neoplasia. The nature and significance of these findings are discussed and compared
with similar types of mammary lesions in untreated cats.
Materials and Methods
Case materials compiled for this study included formalinfixed cat mammary tissues submitted to the Veterinary
Diagnostic Laboratory, College of Veterinary Medicine, University of Minnesota (from 1980 to 1986) as well as mastectomy specimens obtained at veterinary hospitals in Minneapolis and St. Paul. Criteria used for selection of the 17
cats included in this study were the diagnosis of mammary lesions concomitant with a history of megestrol acetate (MA)
therapy. Data on breed, age, sex, drug dosage, site of mammary lesion, evolution of lesion in relationship to drug administration, and gross appearance of the lesion were obtained from submission forms and from veterinary hospital case 104 Downloaded from vet.sagepub.com by guest on March 8, 2012 Megestrol Acetate and Mammary Morphology in Cats 105 records. In some instances, veterinarians were queried about the use of MA in cats since this information was not always provided with the history. Mammary lesions were divided into diagnostic categories based on their gross and microscopic appearance. Histologic typing of cat mammary lesions was done on 6-pm-thick hematoxylin and eosin-stained sections, following the World Health Organization publication on classification of animal mammary tumors.14
Data for untreated cats were obtained by reviewing the records of 1 ,O 19 feline cases submitted to the Diagnostic
Laboratory from 1984 to 1986. Ninety-seven untreated cats with mammary lesions similar to those first identified in the
MA-treated group were studied and tabulated for comparison with MA-treated cats.
Results
A summary of the clinicopathologic data for 17 cats with a concomitant history of abnormal mammary
development and megestrol acetate (MA) therapy is given (Table 1). Fourteen of the 17 MA-treated cats
had non-neoplastic alterations of mammary growth including fibroepithelial hyperplasia (nine cats), lobular
hyperplasia (three cats), and duct ectasia (two cats). Three of the 17 MA-treated cats had mammary neoplasms
including one adenoma and two carcinomas. Fibroepithelial hyperplasia
Mammary fibroepithelial hyperplasia was subdivided into two relatively distinct morphologic types, represented
by intraductal and solid growth patterns. Each pattern was about equally distributed among the nine
MA-treated cats in this group. Cats with the solid growth pattern were on the average 1.3 years younger (7.5
versus 8.8 years) than cats with the intraductal growth pattern. A predilection for breed or sex was not apparent
for cats with either growth pattern, but six out of nine cats in this group were neutered. Seven of the
nine cats with fibroepithelial hyperplasia had only one enlarged mammary gland, with the lesions most commonly
(seven out of eight) confined to the two posterior pairs of glands. Although the daily dosage of MA prescribed
for each cat was fairly standard (2.5-5 mg), the temporal relationship between drug dose and diagnosis
was variable. Macroscopically, the intraductal type of fibroepithelial hyperplasia (four cats) projected from
the wall of a fluid-filled space as a polypoid or domeshaped mass, or assumed a more annular growth about
a central cavity. Abundant clear fluid with a viscous appearance usually denoted this type of lesion. Conversely,
the solid type of fibroepithelial hyperplasia (five cats) was characterized by soft, friable, or firm,
smooth-surfaced tissue with scant fluid. Microscopically, there was considerable overlap in
the composition of the intraductal and solid types of fibroepithelial hyperplasia since both types of growth
featured proliferation of mammary stromal fibroblasts and ductular epithelium. In the former instance growth
of new tissue took place within the lumen of a large dilated duct, while in the latter case arborescent tubules
developed within sheets of stromal cells. The intraductal form was further subdivided histologically into
papillary (Fig. 1) and circumferential growth patterns (Fig. 2). The papillary pattern presented as bulbous or
finger-like structures that projected intraluminally from segments of the duct wall, while the circumferential
pattern was more compact and encircled the duct lumen. Differences between the papillary and circumferential
intraductal growth patterns varied mainly in the extent of lesion development. Both of these growths
patterns were seen in one cat (D85-14539) with multiple intraductal mammary lesions. The circumferential
intraductular lesion from this cat consisted of numerous branching tubules lined by regular or dysplastic
epithelium with multifocal areas of squamous metaplasia (Fig. 3). The solid type of fibroepithelial hyperplasia
(Fig. 4) was similar to that previously described.'
Lobular hyperplasia
Lobular hyperplasia occurred in three MA-treated cats. Two were neutered (one male and one female),
and one was an intact female. The first cat, a 7-yearold neutered female (FMT-78), had been given MA
for about 5 weeks. Swollen mammary glands were noted about 1 month after the last treatment, and at the
time of surgery some enlarged glands had already regressed. Milky fluid oozed from the cut surface of the
mastectomy specimen from this cat. The second cat, a 3-year-old neutered male (FMT- 109), had been given
MA for about 13 weeks. Mammary masses composed of firm lobulated tissue were found 2.5 months after
the last treatment. The third cat, a 7.5-year-old female (D85- 13329), developed abnormally firm mammary
tissue 6 months after MA therapy. Microscopically, expanded mammary lobules in various stages of secretory
activity were found in all three cats (Fig. 5). In the male cat, a minor part of some interlobular ducts
were lined by vacuolated secretory-type epithelial cells, whereas elongated basophilic secretory cells with
prominent apical blebs were seen in some alveoli (Fig. 6); these changes were not observed in either female
cat with lobular hyperplasia nor were they seen in prelactational mammary tissue from two normal pregnant
cats studied for comparison.
Mammary duct ectasia
Mammary duct ectasia was found in two neutered female cats 7.5 and 9 years old,
respectively. One of these cats (D84- 18686), with cystic lesions in both mammary chains,
had been on MA for 5.5 years, while the other cat (D86-1761), with only one mammary lesion,
had not been given MA for the last 1.5 years.
Downloaded from vet.sagepub.com by guest on March 8, 2012 106 Hayden, Barnes, and Johnson
These lesions were fluid-filled and fluctuant with some palpable nodular or thickened areas. Microscopically,
the dilated ducts varied in thickness and proliferative activity. Epithelial cells were cuboidal to flattened and
one to two cells thick with fronds or buds of hyperplastic epithelium reaching into the lumen at irregular
intervals. Segments of some duct walls consisted of hyperplastic fibroepithelial tissue. Periductal fibrosis
and small foci of lymphocytes and plasma cells also were seen.
Mammary neoplasms
Three mammary gland neoplasms, one tubular adenoma and two carcinomas (one papillary and one
tubulopapillary), were diagnosed in this study. The tubular adenoma was removed from a 5-year-old neutered
female cat (D84-7386) that had been given MA for 4.5 months. It was well circumscribed and located
near the base of a nipple within a zone of moderately well-developed mammary lobules. Histologically, the
adenoma was characterized by numerous cross-sectional profiles of uniformly sized tubules lined by a
single layer of epithelial cells and an attenuated layer of myoepithelial cells (Fig. 7). There was relatively little
stroma between tubules, although there were patches of quiescent fibrous tissue with no distinct lobulation.
Both cats with mammary gland cancer were neutered adults. An 1 1.5-year-old female (D85-15644) had been
on MA for over 5 years. Most lesions in this cat were cystic, although some were nodular. Microscopically,
a uniform population of neoplastic epithelial cells lined mammary gland ducts with expanded lumina and papillae.
For the adult male cat (D84-6954) information about the dosage of MA was sketchy. Grossly, one
abdominal mammary gland had been converted into firm, white tissue. Microscopically, the tumor was separated
into lobules with a predominately tubular or papillary growth pattern (Fig. 8).
Mammary lesions in MA-treated versus untreated cats
Review of 1,019 routine feline diagnostic cases revealed 97 untreated cats with mammary
lesions analgous to those identified in the MA-treated group. A comparison of the types and incidence of mammary
lesions in MA-treated and untreated cats is given (Table 2). Fibroepithelial hyperplasia in MA-treated cats
and carcinoma in untreated cats were clearly the predominant mammary lesions for each group. Also, the
MA-treated group had a greater incidence (18% versus 3%) of mammary lobular hyperplasia. Both groups had
the same proportion of cats with mammary duct ectasia.
Discussion
Synthetic progestins are derivatives of 1 7a-hydroxyprogesterone
or 19-nortetosterone.Derivatives of 1 7a-hydroxyprogesterone, like megestrol acetate (MA)
and medroxyprogesterone acetate (MPA), are known to elicit a host of possible adverse side
effects in the dog and cat including growth disorders of the mammary gland.3
Although both MA and MPA are effective orally, the repositol form of MPA has the most
prolonged effect and thus the least safety margin. Most information about the adverse effects
of progestins in the cat has been gleaned from clinical data rather than from experimental
studies. In this retrospective study, non-neoplastic lesions (fibroepithelial hyperplasia,
lobular hyperplasia, and duct ectasia) and neoplastic lesions (tubular adenoma and
mammary carcinoma) concomitant with MA therapy were found in 17 cats (Table 1).
A comparison of mammary lesions in MA-treated cats with the incidence of
mammary lesions in untreated cats is given (Table 2). On the basis of this
comparison, only mammary fibroepithelial hyperplasia appears clearly associated
with MA therapy in this study. Fibroepithelial hyperplasia that occurred spontaneously
was seen in young female cats (average age 2.l years), while this condition in
MA-treated cats occurred predominately in older neutered male and female
cats (average age 8.1 years). These observations are entirely consistent with
previous data which link natural and synthetic progestins to the pathogenesis of
feline mammary fibroepithelial hyperplasia.
Two major sub-types of fibroepithelial hyperplasia were identified; an intraductal
form and a solid form. Each sub-type was about equally distributed among
the nine MA-treated cats with this condition. The intraductal form was similar
to a condition previously described as either papillary cystic hypertrophy20 or
intraductal papillary fibroepithelial hyperplasia.8 In this report,
intraductal fibroepithelial hyperplasia was further characterized by papillary
and circumferential growth patterns. The former pattern presented as discrete
growths emanating from segments of duct walls, while the latter pattern was
more compact and annular. We believe the papillary and circumferential growth
patterns represent similar pathologic processes that differ only in the degree of
intraductular proliferation. In one cat (D85-14539), however, atypical epithelium and
focal squamous cell metaplasia were noted in the circumferential growth pattern.
In our experience, squamous metaplasia is an unusual finding in fibroepithelial
hyperplasia, while dysplastic epithelial changes may occasionally be seen.
The solid form of fibroepithelial hyperplasia was similar to that previously described
by us and others.'J5J6 Both intraductal and solid forms of fibroepithelial
hyperplasia evolve around the mammary duct system, but each form interfaces
with the ducts in a different manner; small cysts may be found even in the solid
form of this condition.
Table 2 comparison of the incidence of mammary lesions in
megestrol acetate-treated cats and untreated cats.
It is noteworthy that M A therapy was associated with intraductal lesions in four of
nine cats with fibroepithelial hyperplasia in the present study as well as in five of six cats
with intraductal lesions in other studies, whereas only one of the 11 untreated cats
with fibroepithelial hyperplasia in the present study had an intraductal lesion. This observation
suggests that therapy with MA, or perhaps other synthetic progestins,
should be considered, especially when intraductal forms of fibroepithelial hyperplasia
are encountered in cats. The role of MA in the genesis of lobular hyperplasia
is unresolved. However, when the time between drug administration and appearance
of lobular hyperplasia was considered, a cause and effect relationship seemed
possible. This notion is further supported by the fact that lobular hyperplasia
occurred in 18% of MA-treated cats versus 3% of untreated cats.
Lobular hyperplasia was characterized by accentuated development of
mammary lobules with some secretory activity. Elongated secretory epithelial cells
with prominent apical blebs were seen in a MA-treated male cat but not
in either MA-treated female cat; nor were these cells found in three untreated cats
with lobular hyperplasia or in prelactational mammary tissue from two normal
pregnant cats evaluated for comparison. Presumably, these elongated epithelial
cells represent a more advanced stage of secretory activity in the MA-treated
male cat since cells with similar morphology are found in fully developed lactating
adenomas in young women. Such lesions in the cat and humans likely represent
a proliferation of normal mammary lobules or ductules, either as a more diffuse
form of hyperplasia or as a neoplastic process. Although progestins (MA and MPA)
have been implicated in mammary cancer in the cat, results of the present
study neither proved nor disproved this association. Prolonged treatment
with progestins in the dog, however, resulted in development of dysplastic
mammary nodules and malignant This underscores the potential risk associated with progestin
therapy, especially when used on a long-term basis. Also, the unusual occurrence
of mammary cancer in an MA-treated, neutered male cat in this study
lends further support for the judicious use of progestins in cats.
Review of the clinicopathologic data (Table 1) revealed
that 13 of the 17 MA-treated cats in this study were neutered males or females.
Presumably, this ratio reflects the large number of neutered animals in the
general cat population. It was not possible from this study to determine
whether neutered cats have more progesterone-responsive clinical problems
than nonneutered cats. Although the daily dose of MA was fairly standard,
the schedule and length of time the drug was given with respect to detection
of lesions was quite variable. Even the type of histologic lesion did not
necessarily correlate well with the dose of MA or duration of therapy.
This indicates that one cannot accurately predict how an individual cat will respond to
MA therapy. However, it should be noted that MA given for as little as
5 weeks was sufficient to induce lobular hyperplasia in one cat (FMT-78).
Little is known about the specifics of hormonal regulation
of normal mammary growth in the cat. Hormones previously implicated
in mammary growth in general are estrogen, progesterone, growth hormone,
placental lactogen, adrenal corticoids, and possibly thyroid hormone. Synergism
between pituitary hormones and ovarian steroids is essential to achieve maximal
mammary development. Also, hormones may act on mammary growth
indirectly via polypeptide growth factors (e.g., somatomedins). The relative role
that each hormone or hormone combination plays in coordinating mammary growth
varies with the species. For example, estrogen alone has no effect on mammary
tissue in the dog, yet it evokes development of ductal tissue in the cat
and ductular as well as lobulo-alveolar tissue in the goat. There is evidence that
progesterone alone will induce extensive ductal-alveolar proliferation
in neutered dogs. A similar mammogenic response has been demonstrated
in sexually intact beagle dogs given synthetic progestins. How progesterone acts
to effect growth of the mammary gland still is unclear, but recent studies would
indicate several possibilities. Mammary tissue has receptors with high affinity
for progesterone and receptors with low affinity for progesterone which also bind
glucocorticoids. Some investigators believe that progesterone bound to the high
affinity receptor is directly responsible for stimulating mammary gland growth.
Such receptors have been demonstrated in mammary tissue in the cat,
dog, and others. In addition, progesterone may act indirectly by stimulating
release of certain pituitary hormones that effect growth of mammary tissue.
Elevated levels of growth hormone, but not prolactin, have been reported in beagle
dogs with proliferative mammary lesions, established after long-term exposure
to synthetic progestins. The latter mechanism does not appear valid for the
cat since long-term administration of MA to cats failed to induce overproduction
of pituitary growth hormone. Thus we can hypothesize that MA exerts its mammatrophic
effect in the cat by binding directly to progesterone- specific receptors,
by stimulating release of pituitary hormones other than growth hormone (e.g.,
prolactin), or by stimulating synthesis of certain polypeptide growth factors
(e.g., insulin-like growth factor and epidermal growth factor).
In conclusion, this retrospective study revealed a spectrum of mammary gland
lesions in MA-treated cats, but only fibroepithelial hyperplasia was clearly
associated with MA therapy. Although several neoplasms were found in this study,
there was no clear cut evidence that MA therapy is causally linked to
mammary neoplasia. Future studies are needed to more fully explore
the pathobiologic relationships between MA and other growth-promoting agents
in progestin associated changes in the mammary gland of cats.
References
Allen HL: Feline mammary hypertrophy. Vet Pathol
Carroll EJ: Lactation. In: Veterinary Endocrinology and
Reproduction, ed. McDonald LE, 3rd ed., pp. 503-528.
Lea and Febiger, Philadelphia, 1980
Chastain CB, Ganjam VK: Clinical Endocrinology of
Companion Animals, pp. 543-544. Lea and Febiger,
Philadelphia, 1986
Chastain CB, Graham CL, Nichols CE: Adrenocortical
suppression in cats given megestrol acetate. Am J Vet
Res 42:2029-2035, 1981
Chatterton RT: Mammary gland: development and secretion.
Obstet Gynecol Annu 7:303-324, 1978
10:501-508, 1973
6 Concannon PW, Spraker TR, Casey HW, Hansel W:
Gross and histopathologic effects of medroxyprogesterone
Long-term administration of relatively high therapeutic dosages of megestrol acetate to cats produced a progressive deterioration in glucose tolerance, with a significant (P less than 0.05) increase in mean fasting plasma glucose concentrations and decrease in mean plasma glucose clearance rates after six and 12 months of treatment. There appeared to be no relationship, however, between the development of glucose intolerance and circulating growth hormone (GH) concentrations in the cats of this study, since no significant rise in plasma GH concentrations was detected during the 12 month period of megestrol acetate treatment. Administration of megestrol acetate also produced a progressive decrease in both resting plasma cortisol concentrations and cortisol concentrations after ACTH stimulation. Three months after discontinuation of megestrol acetate, the elevated fasting plasma glucose concentrations, decreased glucose clearance rates and subnormal plasma cortisol concentrations all returned to normal pretreatment values, indicating resolution of glucose intolerance and hypoadrenocorticism. The results of this study demonstrate that administration of megestrol acetate to cats can produce a state of moderate to severe glucose intolerance, which is usually reversible after cessation of treatment. Although the exact mechanism of the glucose intolerance and overt diabetes mellitus induced by progestagen treatment of cats remains unclear, it is likely that these alterations in glucose metabolism result primarily from the glucocorticoid activity intrinsic to megestrol acetate.
PMID:
3039622
[PubMed - indexed for MEDLINE]
18)Suppression of cortisol responses to exogenous adrenocorticotrophic
hormone, and the occurrence of side effects attributable to glucocorticoid excess, in cats during therapy with megestrol acetate and prednisolone.
Middleton DJ, Watson AD, Howe CJ, Caterson ID.
Can J Vet Res. 1987 Jan;51(1):60-5.
Suppression of Cortisol Responses to Exogenous Adrenocorticotrophic Hormone, and the Occurrence of
Side Effects Attributable to Glucorticoid Excess, in Cats during Therapy with Megestrol Acetate and Prednisolone
Deborah J. Middleton, A. David J. Watson, Christopher J. Howe and Ian D. Caterson*
ABSTRACT
The major purpose of this investigation was to determine the effect of prednisolone and megestrol acetate in
cats on the adrenal cortisol response to exogenous adrenocorticotrophic hormone during drug administration
at dose rates employed for management of some inflammatory feline dermatoses. Prednisolone (at least
2 mg/kg/day) and megestrol acetate (5 mg/cat/day) were each administered orally to seven cats from days 1
to 16. Three additional cats received no therapy. Basal and stimulated cortisol concentrations, food and water
intake, hematology, blood biochemistry, urinalyses, and hepatic and cutaneous histology were studied in all
cats before, during, and two weeks following the end of treatment. Cats given prednisolone or megestrol acetate
had significant suppression of stimulated cortisol levels on day 8. This change was more marked on day
15, when the suppression in cats given megestrol acetate was also significantly more severe than in those receiving
prednisolone. Recovery of adrenal reserve was considered present on day 30 in six of seven cats given prednisolone,
but in only three of seven receiving megestrol acetate. Eosinopenia, glycosuria and hepatocyte swelling
from glycogen deposition were occasionally recorded in treated cats of both groups, providing additional
circumstantial evidence for glucocorticoid activity of megestrol acetate in cats. It is advised that abrupt withdrawal
of prednisolone or megestrol acetate therapy be avoided in this species to reduce the chance of precipitating
clinical signs of hypoadrenocorticism, even after treatment for as little as one week.
*Department of Veterinary Pathology (Middleton) and Department of Veterinary Clinical Studies (Watson), The University of Sydney, 2006, Australia and Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, 2050, Australia (Howe, Caterson). Present address of Dr. Middleton:
Department of Pathology, Royal Veterinary College, Royal College Street, London NW1 OTU, England.
Reprints are not available.
This work was supported by the Hugh Hughes Bequest, the Departments of Veterinary Pathology and Veterinary Clinical Studies, The University of Sydney and the Department of Endocrinology, Royal Prince Alfred Hospital.
Submitted January 29, 1986.
60 Can J Vet Res 1987; 51: 60-65
INTRODUCTION
The potency of glucocorticoids, as measured by their ability to deposit hepatic glycogen, and their other
properties, including anti-inflammatory activity and suppression of synthesis and secretion of adrenocorticotrophic
hormone (ACTH), tend to parallel one another (1,2). However, cortisol responses to ACTH remained
normal in six cats receiving various oral prednisolone regimes for four weeks (3), including two animals given
doses approximating that recommended for anti-inflammatory activity in cats 4). Veterinary clinicians generally suspect
that the progestin, megestrol acetate, also exhibits glucocorticoid activity in cats, although its mode of
therapeutic action in dermatological conditions such as miliary dermatitis and the eosinophilic granuloma complex
is not precisely known (5,6). Previous work (7) has documented low basal cortisol levels and hypo-responsiveness
to ACTH in three chemically restrained cats one week following completion of two weeks therapy with
megestrol acetate. However, basal and stimulated cortisol concentrations before and during the treatment period,
in both untreated and treated cats, were sufficiently high to suggest interference by chemically induced or
environmental stress. It is therefore possible that these data do not precisely reflect the influence of megestrol acetate on feline cortisol concentrations during therapy. Prednisolone (or prednisone) treatment in dogs, in addition to reducing
the adrenal reserve (8,9), is regularly associated with other changes attributable to glucocorticoid excess, such
as eosinopenia and lymphocytopenia, abnormal hepatic morphology, and increased serum alkaline phosphatase
(ALP), alanine aminotransferase (ALT), and -y-glutamyltranspeptidase (-y-GPT) concentrations (8,10-12).
Development of similar abnormalities has not been studied in cats given prednisolone or megestrol acetate.
The purpose of this study was to reassess effects of prednisolone and megestrol acetate, administered at
dose rates employed clinically for control of inflammatory skin diseases, on basal and ACTH stimulated cortisol
concentrations in cats, and to document the occurrence or otherwise of more overt signs of glucocorticoid
excess.
MATERIALS AND METHODS
Seventeen adult domestic cats (males and females) weighing between 2.6 and 4.6 kg were obtained from The
University of Sydney Animal House. Each cat was clinically normal, immunized against feline panleukopenia
virus infection, treated for nematode and cestode endoparasites, and was well socialized towards people. Cats
were housed individually in cages measuring 1 m x I m x 2 m and containing exercise platforms. They were
given water and a nutritionally complete dry cat food (Go-Cat, Carnation Co, Blacktown, N.S.W., Australia) ad
lib, and acclimatized for at least one month before use. The experiment was conducted in late spring to early summer
with augmentation of natural illumination by fluorescent light during daylight hours. Food (g/ kg of bodyweight) and water (mL/ kg of bodyweight) intake of each cat were measured daily for eight days before treatment commenced, and for the
subsequent month. Bodyweight was recorded weekly. At 6:00 p.m. on days I to 16, seven cats (including two entire males and one desexed male) were given 5 mg megestrol acetate orally (Ovarid, Glaxo, North Ryde, N.S.W., Australia).
Similarly, seven cats (including two entire males and one desexed male) received prednisolone (Deltacortef,
Upjohn, Rydalmere, N.S.W., Australia; Panafcortelone " ", Protea, Glebe, N.S.W., Australia) at a dose of
2 mg/ kg. The dose of prednisolone was raised to 4 mg/ kg in two cats for the second week. Three animals (including
one entire and one desexed male) were not given megestrol acetate or prednisolone in order to monitor
the effects of sampling procedures on the variables under assessment. Blood samples were collected from
the jugular vein of each cat for hematological and biochemical analyses two days before the start of treatment
(day 1) and on days 4, 7, 14 and 29. Anti-coagulated (EDTA) blood was used for determination of packed cell
volume (PCV), total plasma protein concentration (TPP), and leukocyte count and differentiation by routine
methods. Heparinized plasma was assayed for ALT, ALP and aspartate aminotransferase (AST) activities, and
serum for -y-GTP activity using commercially available reagents (Calbiochem- Behring, La Jolla, California;
Smith Kline Instruments, Sunnyvale, California). Serum protein electrophoresis was also done and plasma
Icteric Index determined (13). Adrenocorticotrophic hormone response tests were performed after a 14
to 16 hour fast and completed between 8:00 a.m. and 10:30 a.m. on days 0, 8, 15 and 30. Venous blood samples were
collected for cortisol estimations immediately before, and one hour after, intramuscular injection of 2.2 units/
was stored at -20°C and cortisol assays were performed within one week. Cortisol was estimated by a solid-phase
radioimmunoassay kit marketed for clinical use in humans (Gammacoat Cortisol, Clinical Assays, Cambridge,
Massachusetts). Validation of the cortisol radioimmunoassay for use in cats was done using methods similar to
those previously described (14). Major cross-reacting steroids with this assay included prednisolone (87.5%), 11-
deoxycortisol (6.3%) cortisone (4.5%), prednisone (3.9%), corticosterone (2.5%), and deoxycorticosterone
(2.1 %). Cross-reaction of megestrol acetate was less than 0.01%. Sensitivity was calculated as 15.5 nmol/ L on 40
cortisol assays; for statistical analysis undetectable levels were assigned the value of 16 nmol/ L. Intra-assay variation
was 8.3% for the low, and 3.1% for the high, control; while the inter-assay variation was 8.6% for both controls.
Standards employed contained cortisol in the following concentrations; 0, 55, 138, 276, 690, and 1655 nmol/L.
After each ACTH response test, general anesthesia was induced with thiopentone and maintained with halothane, nitrous oxide and oxygen. The urinary bladder was catheterized and urine collected for routine urinalysis.
Using aseptic technique a liver biopsy was collected via a small laparotomy and a skin biopsy was taken
from the lumbar area using a 6 mm punch; wound closures were routine. The skin biopsy and a portion of the
61 liver tissues were placed in 10% neutral buffered formalin. Six-micron sections from formalin-fixed paraffin embedded
biopsy tissues were stained with hematoxylin and eosin for light microscopic examination. The remainder
of the liver tissue was cut into 1 mm cubes, fixed in 2.5% glutaraldehyde in sodium cacodylate buffer and
processed for electron microscopy. Statistical methods were employed in evaluation of the following: food
and water intake, lymphocyte and eosinophil counts, and cortisol concentrations. These methods comprised
analyses of variance and, when indicated, unpaired t-tests. Statistical significance was taken at the 5% level.
RESULTS
GENERAL COMMENTS
All cats remained clinically well during the experiment. Results from the two cats whose prednisolone dose
was increased in the second week did not exhibit differences from other cats in the group so the data were
combined.
PLASMA CORTISOL LEVELS
Basal and ACTH-stimulated plasma cortisol concentrations before, during, and after treatment are presented
in Fig. 1.
For statistical analysis resting cortisol levels were studied unchanged while ACTH-stimulated cortisol data
were log-transformed to achieve homogeneity of variance. There were no significant differences between the
three groups of cats for pretreatment resting or stimulated cortisol levels. With regard to resting levels throughout
the experiment, a significant difference between cats was noted and was statistically attributable to the
treatment group, with animals given megestrol acetate having, overall, significantly lower basal cortisol levels
than untreated cats. Within individual cats, there was a significant difference in resting cortisol concentration related
to the stage of the experiment as there was a decrease overall in basal levels as the experiment progressed.
For ACTH-stimulated cortisol concentrations, a significant difference between cats was detected in relation
to treatment group, and within cats in relation to the stage of the experiment, reflecting suppression of the cortisol
response to ACTH after both one and two weeks of prednisolone and megestrol acetate therapy. The degree of
adrenal suppression induced by prednisolone and megestrol acetate after one week of dosage was similar for
the two drugs, but after two weeks the abnormality in megestrol acetate treated animals was significantly more
severe. Individual animal data suggested return of adrenal reserve was present two weeks after drug administration
ceased in six of seven cats given prednisolone, but in only three of seven given megestrol acetate. Additional
ACTH stimulation tests were performed in cats in which recovery was considered incomplete, and normal
responses were documented after a further one or two weeks.
250
200 -
E 150
c
0L-,- 100
o
50
50-
T
T
II
T
II
p
II.
0123
O 1 2 3 4
Weeks
U n=3
It was determined statistically that drug treatments had been randomized between the three groups of cats with
regard to food and water consumption. There were no significant differences for food intake between groups
during or after treatment. However, cats given megestrol acetate drank slightly, but significantly, more than
the other two groups during treatment. Cats given prednisolone drank slightly, but significantly, less than the
untreated and megestrol acetate-treated cats in the post treatment period.
HEMATOLOGY
Packed cell volume and TPP measurements remained within laboratory normal ranges. No significant differences
were detected in lymphocyte numbers for untreated cats over time, or between untreated and treated cats
at any stage of the experiment. One cat given prednisolone was lymphocytopenic (<0.600 x 109 cells/ L) on day 14.
Untreated cats had significantly different eosinophil counts from each other, but within this group eosinophil
numbers did not change significantly T
-I
I
T
-II
0
T
l 0 -r I~~~~~~~~~
O 1 2 3 4v
Weeks
MA n=7
j Pre-ACTH
T Post- ACTH
T
II
T I o
I
I
T II
11 I
I
0134
O 1 2 3 4v
Weeks
P n=7
T
II
during the experiment. There was no significant difference in pretreatment eosinophil counts between the three
groups of cats. Treated cats had significantly lower eosinophil counts than the untreated group on day 4 and also
day 29, although the latter difference was less marked. There was no significant difference in the degree of
62
Fig. 1. Median basal and ACTH-stimulated plasma cortisol concentrations (range indicated by
vertical bars) before (O weeks), during (1 and 2 weeks), and after (4 week’s) treatment with megestrol
acetate (MA), prednisolone (P), or no drug (U).
FOOD AND WATER INTAKE
response for the two drugs. In addition, four cats given prednisolone were eosinopenic on day 14 (<0.040 x
109 cells/L), and on days 7 and 14 single cats in the megestrol acetate group had eosinopenia (Table I).
BLOOD CHEMISTRY
Occasional (five of 340 estimations),u p to threefold, elevations were recorded in enzyme concentrations.
These occurred irrespective of the treatment group or stage of the experiment. No abnormalities developed
in serum protein electrophoresis or Icteric Index.
URINALYSES
Results of analysis were normal in all cats before treatment and remained so in untreated animals. Of cats given
prednisolone, one desexed female had pyuria, bacteriuria and glycosuria (2%) on day 15, and a desexed male
had glycosuria (trace) on day 8 and day 15 (I%). Glycosuria (0.25% and 0.5%) was present on day 8 in two entire
males given megestrol acetate.
HEPATIC AND CUTANEOUS HISTOLOGY
Tissue from all liver biopsies appeared normal before therapy; and remained so in the untreated group.
Diffuse hepatocyte swelling, as judged by sinusoidal compression, and pallor were present on day 8 in two cats given
megestrol acetate (Fig. 2) and in one cat given prednisolone. The distended hepatocyte cytoplasm appeared to
contain a fine reticulum enclosing multiple vacuole-like areas. Two of the three cats with histological liver
lesions were among those developing glycosuria All skin biopsies were histologically normal. In particular, hyperkeratosis,
epidermal and pilosebaceous atrophy, and calcinosis cutis were not detected. Due to an error in processing, resinembedded liver specimens were not suitable for electron microscopic demonstration of glycogen within
hepatocytes. However, hepatocytes appearing abnormal on light microscopy were shown, ultrastructurally,
to have an expanded cytoplasm with reorientation of intracytoplasmic organelles, notably mitochondria, to the
periphery of the cell.
DISCUSSION
Basal cortisol concentrations recorded in all cats before treatment, and in untreated cats throughout the experimental
period, were towards the lower end of baseline values reported for cats by other workers (3,15-17), and, even allowing for different assay methods, were consistent with the blood specimens having been obtained from unstressed cats. Suppression of cortisol responses to ACTH after one and two weeks of megestrol acetate therapy is probably thus an accurate reflection of the influence of this drug on the feline adrenal cortex, and is in contrast to a previous report (7). The
comparative severity of megestrol acetate-induced adrenal suppression relative to that found after prednisolone
in the present study may be due to prednisolone having a shorter half-life, rather than being a reflection of relative
potency. Considering the degree of cross-reaction of prednisolone in the cortisol assay, the low basal levels of
measured cortisol suggested circulating levels of prednisolone in the cats were negligible about 12 hours after
dosage, whereas it is well recognized that megestrol acetate administration may be adequate just once or twice
weekly for remission of medical conditions in cats. This implies a longer biological half-life for megestrol acetate
in cats. Similarly, the more rapid recovery of adrenal responsiveness to ACTH in cats given prednisolone
compared with those given megestrol acetate is consistent with pharmacological concentrations remaining in
the circulation for different times. We have no explanation for the failure of others (3) to document adrenal insufficiency
in cats given prednisolone, except that the higher of their dose rates (5 mg per cat) was slightly lower than 2 mg/ kg. It has also been shown that a normal cortisol response to exogenous ACTH does not exclude the possibility of secondary adrenal insufficiency (18). It may be assumed that prednisolone-induced adrenal cortical suppression in cats is mediated by feedback inhibition of ACTH storage and secretion, but this explanation may not be complete for megestrol
acetate as it has been suggested that medroxyprogesterone acetate in rats 63 exerts a direct toxic effect on the
adrenal cortex as well (19). Measurement of plasma ACTH levels in cats given megestrol acetate would define
the site of drug activity more precisely. Light microscopic changes in the livers of a few cats receiving prednisolone
or megestrol acetate were generally similar to those occurring in glucocorticoid treated dogs (8,11,12,24,25),
and unlike lesions sometimes associated with general anesthesia (26). The appearance of distended hepatocytes
with cytoplasm containing a fine reticulum enclosing large vacuoles is said to be typical of glycogen overload
(24), and redistribution of mitochondria to the cellular periphery has also been observed in cortisone treated rats
(27). It is likely that the duration of treatment, with prednisolone at least, in the present study was too short to
elicit cutaneous atrophy as skin changes consistent with glucocorticoid excess, such as hyperkeratosis, epidermal
atrophy, and alopecia, are recognized in cats with naturally-occurring hyperadrenocorticism (15,28,29), and
prolonged therapy with methylprednisolone (3). Prolonged treatment with methylprednisolone acetate produced a twofold
increase in food intake in two cats (3), and megestrol acetate is frequently employed as an appetite stimulant for
feline patients. However, short term dosage with either prednisolone or megestrol acetate here did not significantly
increase the food intake of normal cats. While it is possible that a modification of ingestive behaviour was reflected by megestrol acetate treated cats drinking more than those given prednisolone, we are not convinced the difference was clinically important. Prednisolone and megestrol acetate appear to reduce circulating numbers of eosinophils in the cat. However, as eosinopenia did not always occur, isolated eosinophil counts may not be useful to assess the presence of pharmacological levels of glucocorticoids in clinical cases. No evidence was found for an influence of either drug on lymphocyte numbers, but it is recognized that the lympholytic action in particular of glucocorticoids varies between species (20). As the number of untreated cats was smaller than either treatment group, interpretation of the findings of glycosuria and changes in hepatic morphology, which were not subjected to analysis, must be cautious. However, glycosuria identified in four treated cats is unlikely to be attributable to an influence of exogenous ACTH on gluconeogenesis, as mediated by stimulated blood cortisol levels, because glycosuria was not found in any pretreatment,
post-ACTH urine specimens, or in any urine specimens from untreated cats. In addition, on the occasions when lycosuria was observed, the post-ACTH cortisol concentrations were abnormally low. Short term therapies with megestrol acetate and prednisolone have been shown to induce impaired elimination of an intravenous glucose load in cats, and fasting hyperglycemia as well in some cats (21). Although urine glucose determinations are not a precise measure of glucose intolerance, glycosuria is not a normal finding in unfed cats. It is probable that glycosuria recorded in a few cats of this study reflected hyperglycemia, and similar effects of glucocorticoids and progestins on carbohydrate metabolism as occur in other species (1,22,23). Glucocorticoid "support" in the form of the prednisolone given to one group of treated cats presumably accounted for their clinical well-being, despite evidence for loss of the adrenals' ability to respond to ACTH
stimulation. This would suggest a similar role for megestrol acetate in the other treated group, where adrenal suppression was even more severe. It must be supposed that signs of adrenal insufficiency did not develop after withdrawal of treatment because return of some adrenal reserve was prompt. However, on present understanding, we advise gradual rather than abrupt withdrawal of prednisolone and megestrol acetate treatment, even after therapies as short as one
week. The occurrence of glycosuria, hepatic glycogen deposition, and a reduction in circulating eosinophil numbers in some cats after short term treatment with prednisolone and megestrol acetate is in agreement with these drugs exerting glucocorticoid activity at dose rates employed for therapy of inflammatory dermatoses. Absence of reduction in lymphocyte counts or enzymological changes is consistent with a feline response to glucocorticoids more similar to people
than to dogs.
REFERENCES
1. HAYNES RC Jr, MURAD F. Adrenocorticotrophic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of adrenocortical steroid biosynthesis. In:
Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. 6th ed. MacMillan Publishing Co, 1980: 1466-1496.
2. LIDDLE GW. The adrenals. In: Williams RH, ed. Textbook of endocrinology. 6th ed. Philadelphia: WB Saunders, 1981: 249-292.
3. SCOTT DW, MANNING TO, REIMERS TJ. latrogenic Cushing's syndrome in the cat. Feline Practice 1982; 12: 30-36
4. MULLER GH, KIRK RW, SCOTT DW. Small animal dermatology. 3rd ed. Philadelphia: WB Saunders, 1983.
5. HALLIWELL RE. Steroid therapy in skin disease. In: Kirk RW, ed. Current veterinary therapy VI. Philadelphia: WB Saunders, 1977: 541-547.
6. SCOTT DW. Feline dermatology 1900- 1978: A monograph. J Am Anim Hosp Assoc 1980; 16: 331-459.
7. CHASTAIN CB, GRAHAM CL, NICHOLS CE. Adrenocortical suppression in cats given megestrol acetate. Am J Vet Res 1981; 42: 2029-2035.
8. CHASTAIN CB, GRAHAM CL. Adrenocortical suppression in dogs on daily and alternate-day prednisone administration. Am J Vet Res 1979; 40: 936-941.
9. KEMPPAINEN RF, THOMPSON FN, LORENZ MD. Use of a low dose synthetic ACTH challenge test in normal and prednisone- treated dogs. Res Vet Sci 1983; 35: 240-242.
10. JASPER DE, JAIN NC. The influence of adrenocorticotrophic hormone and prednisolone upon marrow and circulating leukocytes in the dog. Am J Vet Res 1965; 26: 844-850
11. DILLON AR, SPANO JS, POWERS RD. Prednisolone induced hematologic, biochemical, and histologic changes in the dog. J Am Anim Hosp Assoc 1980; 16: 831-837.
12. BADYLAK SF, VAN VLEET JF. Sequential morphologic and clinicopathologic alterations in dogs with experimentally induced glucocorticoid hepatopathy. Am J Vet Res 1981; 42: 1310-1318
13. LEPHERD EE. Technical procedures - haematology. Post Graduate Committee Course Notes, The University of Sydney, 1972: 326.
14. REIMERS TJ, COWAN RG, DAVIDSON HP, COLBY ED. Validation for radioimmunoassay for triiodothyronine, thyroxine, and hydrocortisone (cortisol) in canine, feline, and equine sera. Am J Vet Res 1981; 42: 2016-2021.
15. FOX JG, BEATTY JO. A case report of complicated diabetes mellitus in a cat. J Am Anim Hosp Assoc 1975; 11: 129-134. 64
16. JOHNSTON SD, MATHER EC. Feline plasma cortisol (hydrocortisone) measured by radioimmunoassay. Am J Vet Res 1979; 40: 190-192.
17. SCOTT DW, KIRK RW, BENTINCKSMITH J. Some effects of short-term methylprednisolone therapy in normal cats. Cornell Vet 1979; 69: 104-115.
18. CUNNINGHAM SK, MOORE A. Mc- KENNA TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276-2279.
19. HOLUB DA, KATZ FH, JAILER JW. Inhibition by 6-methyl- 17-acetoxyprogesterone of ACTH synthesis and release in the rat. Endocrinology 1961; 38: 173-177.
21. MIDDLETON DJ, WATSON ADJ. Glucose intolerance in cats given short-term therapies of prednisolone and megestrol acetate. Am J Vet Res 1985; 46: 2623-2625.
22. ALTSZULER N, MORRISON A, GOTTLIEB B, BJERKNES C, RATHGEB 1, STEELE R. Alteration by fasting of the effects of methyl-prednisolone on carbohydrate
metabolism in the normal dog. Metabolism 1974; 23: 369-374.
23. WEIKEL JH Jr. NELSON LW, RENO FE. A four-year evaluation of the chronic toxicity of megestrol acetate in dogs. Toxicol Appl Pharmacol 1975; 33: 414-426.
24. FIELDER FG, HOFF EJ, THOMAS GB, TOLKSDORF S, PERLMAN PL CRONIN MTI. A study of the subacute toxicity of prednisolone, methylprednisolone,
and triamcinolone in dogs. Toxicol Appi Pharmacol 1959; 1: 305-314.
25. ROGERS WA, RUEBNER BH. A retrospective study of probable glucocorticoidinduced hepatopathy in dogs. J Am Vet Med Assoc 1977; 170: 603-606.
26. CHRISTOFFERSEN P, POULSEN H,SKEIE E. Focal cell necroses accompanied by infiltration of granulocytes arising during operation. Acta Hepatosplenol 1970; 17:240-245.
27. WIENER J, LOUD AV, KIMBERG DV, SPIRO D. A quantitative description of cortisone-induced alterations in the ultrastructure of rat liver parenchymal cells.
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28. SWIFT GA, BROWN RH. Surgical treatment of Cushing's syndrome in the cat. Vet Rec 1976; 99: 374-375.
29. MEIJER JC, LUBBERINK AAME, GRUYS E. Cushing's syndrome due to adrenocortical adenoma in a cat. Tijdschr Diergeneeskd 1978; 103: 1048-1051. 65
Six cats were each given prednisolone (2 mg/kg of body weight/day) and megestrol acetate (5 mg/cat/day) on separate occasions for 8 days. The drugs induced similar increases in fasting blood glucose concentrations and decreases in glucose excretion rates in the cats. Usually, each cat developed reduced tolerance of an IV glucose load; concomitant fasting hyperglycemia occurred in 3 cats after prednisolone therapy, and in 1 of these 3 cats after megestrol acetate
J Am Vet Med Assoc. 1984 Dec 1;185(11):1383-6. No abstract available.
PMID:
6511591
[PubMed - indexed for MEDLINE]
21) Feline miliary eczema: megestrol acetate does not suppress immune responses.
Browning MJ, Herbert WJ, White RG.
Res Vet Sci. 1983 Sep;35(2):245-6.
PMID: 415771 [PubMed - indexed for MEDLINE]
Abstract
Megestrol acetate was found to have no influence on immunological skin and corneal reactivity nor on antibody responses in guinea pigs. Its curative effect in feline miliary eczema is probably not, therefore, the result of interference with the immune response.
Thirteen cats with diabetes mellitus were evaluated. Clinical signs included polydipsia, polyuria, polyphagia, lethargy, and weight loss. Results of physical examination included obesity, hepatomegaly, mild seborrhea sicca, muscle wasting, and dehydration. One cat walked plantigrade and was suspected of having a diabetic neuropathy. Persistent hyperglycemia, glucosuria, high liver enzyme activities, hypercholesterolemia, hyperproteinemia, and low electrolyte concentrations were the common laboratory findings. In 3 cats diabetes mellitus developed after megestrol acetate therapy; 2 of these cats required only temporary insulin treatment. In a 3rd cat, which had no history of receiving diabetogenic drug therapy, remission of diabetes mellitus also was observed. Serum insulin and plasma glucose concentrations were determined in 6 cats after administration of an intermediate-acting insulin (isophane insulin) and in 3 cats after administration of a long-acting insulin (protamine zinc insulin). The insulin concentration peaked 2 to 6 hours after the injection of intermediate-acting insulin and 6 to 12 hours after the injection of long-acting insulin. The lowest glucose concentration was recorded 4 to 8 hours after injection of intermediate-acting insulin, and 6 to 12 hours after injection of long-acting insulin. It was concluded that, although insulin therapy must be adjusted to the individual, the diabetic cat usually requires twice-daily administration of isophane insulin; however, the protamine zinc insulin can be given once daily for satisfactory control.
Department of Medicine, School of Veterinary Medicine, University of
Montreal, P.O. Box 5000, St. Hyacinthe, Qu6bec, Canada J2S 7C6
SUMMARY
Twenty-one cats were treated with megestrol acetate because they were showing clinical signs associated with
one of the following problems: eosinophilic ulcer, eosinophilic plaque, neurodermatitis, endocrine alopecia
and miliary dermatitis. The dosage schedule was 5 mg orally per day per cat for seven days, then 5 mg every
three days for 21 days. In all cats, we noted a good improvement of the lesions as soon as treatment was started. In 25% of the patients, one treatment schedule was sufficient to control the skin disease for at least 18 months. In the remaining
75%, two treatment schedules and/ or a maintenance dosage had to be established. Side effects encountered were
increased appetite, personality changes and depression.
I NTRODUCTION
Megestrol acetate is an oral progestational agent with generally antigonadotrophic properties and without any estrogenic, androgenic and anabolic effects (11,14,25). The drug was introduced to suppress or delay estrus (5,6,8,9), and to arrest pseudopregnancy in the bitch (9). It has also been used in the queen (9,13,21,23). A literature search revealed that
megestrol acetate is being used for feline dermatological problems (1,3,7, 14,16,20,26,27,28,29). It has been used to control eosinophilic granuloma (1,7,16,20,27,28), feline neurodermatitis (7), miliary dermatits (3,7,14) and feline endocrine alopecia (7). This article is a clinical study of a megestrol acetate regimen used to control the signs of feline ermatological
problems.
MATERIALS AND METHODS
In this study, 21 cats were treated with megestrol acetate' to control or suppress the clinical signs of dermatological diseases cited above. Nine cats were purebreds (Siamese, Himalayan, Persian), male and female were equally represented and their age varied between seven months and 11 years, with an average of 3.5 years. The disease processes, already present from two weeks to 3.5 years (average 1.75 years), had been medicated with different drugs without success before therapy was first started with megestrol acetate. The therapeutic regimen used was as follows: 5 mg per day given orally for the first seven days, then the dosage was reduced to 5 mg every three days for 21 days. At the end of treatment, the cats were reexamined and medication was then adjusted according to the response (lesions still present or absent) and physical state of the patients (treatment was discontinued when side effects were severe). In some
cases, a dosage of 5 mg every three days was maintained until the lesions regressed. In other cats, the dosage was increased or decreased to find the amount of drug needed to maintain the animal in an asymptomatic state. Whenever the animal was presented again after the initial treatment because of a relapse, then the initial therapeutic regimen was resumed.
RESULTS
Eosinophilic Ulcer (Rodent Ulcer) Two cats were treated for well demarcated lesions of upper lip, characteristic of this skin disease. In one cat, the lesions disappeared completely after the first treatment, while it took two treatments, one month part, to eliminate the lesions from the second cat. No relapse of the lip lesions has occurred 18 months after treatment. It
is important to note that the second cat had to be put on a maintenance dosage of 5 mg weekly or biweekly to control the clinical signs of eosinophilic plaque. This latter condition worsened when medication was discontinued, while the lip ulcer never reappeared
(Table I).
'
Eosinophilic Plaque In six cats a diagnosis of eosinophilic plaque was established after finding circular, raised, Erythematous and exudative lesions associated with alopecia and pruritus. The distribution pattern varied from one subject to the other, but most lesions were found on the abdominal wall. All cats responded well to megestrol acetate,
but one cat did not develop any more skin lesions after the initial treatment was stopped. In the remaining five
cats, the prescription had to be repeated two to seven months after the first visit and four cats are presently on
a maintenance dosage of 5 mg once or twice a week (Table I).
Feline Neurodermatitis
Seven cats were examined and showed skin lesions that could be associated with this disease; of these four were purebreds. Single, erythematous lesions with complete or partial alopecia were associated with pruritus and excessive licking. In all cats a good response was noticed with the megestrol acetate regimen. In two cats, no relapse was noted six to 18 months after treatment. In the five other animals a maintenance dosage of 5 mg once or twice a week had to be established (Table I).
Feline Endocrine Alopecia
Two cats with symmetrical and bilateral lesions of partial to complete m = male (c) = castrated or spayed
alopecia of the abdominal and inner thigh area were treated with megestrol acetate. No noticeable inflammation of the skin was seen and the owners did not report excessive pruritus. The two cats showed a marked improvement while on medication, but the skin lesions reappeared two to four weeks after therapy was discontinued. These cats had to be put on a maintenance dosage of 5 mg once or twice weekly (Table I).
Miliary Dermatitis In three of four cats with clinical signs of this skin disease, i.e. partial alopecia, erythema, hemorrhagic
crusts, and small papules associated with pruritus; lesions reappeared one or two months after discontinuing the drug. In these cats a maintenance dosage of 5 mg had to be established to control the skin lesions. In one cat, relapse occurred 18 months after the initial treatment (Table I). In two of those cases, before a megestrol acetate treatment was started, a flea control therapy program had been established without any good results.
D I S C U S S IO N
Many types of therapy have been advocated to control these skin diseases in the cat. For eosinophilic ulcer and/ or plaque, some authors recommend: surgical excision (26) or cryosurgery (10,15,17,18,30) when dealing with single lesions. Others suggest the use of: radiation therapy (4,24,26), levamisole or thiabendazole (12,19), lincomycin (10), glucocorticoids (10,24,26) and progestational compounds , like megestrol acetate (26,27,28,29) and medroxyprogesterone acetate (26). Progestational compounds seem to be the drugs of choice for the treatment
of miliary dermatitis (2,3,14,22,26). Many therapeutic regimens have been used for the treatment of feline neurodermatitis. Glucocorticoids, tranquilizers, vitamin-mineral supplements, radiation therapy, foul tasting ointments and Elizabethan collars have been used (27). Phenobarbital and diazepam have also been advocated and are effective in certain cases
(27). Progestational drugs, like megestrol acetate, given in large doses seem to control the skin lesions associated with this condition (26). Combined androgen-estrogen injections or progestational drugs have been used for the treatment of feline endocrine alopecia (26). Initially a dosage of 2.5 mg per day per cat was randomly chosen. However, it became clear that this therapeutic regimen was insufficient and the initial dosage was doubled to 5 mg. A literature review had shown a wide range in the dose and dosage schedules used by various authors (14,16,20,22, 26). A good improvement of the lesions was noted in all cats, after the initial treatment. In 25% of the patients one treatment regimen was sufficient to control the skin disease for at least 18 months. In the remaining 75%, two treatment regimens and/or a maintenance
dosage had to be established. Some of the side effects reported with the use of megestrol acetate are: increased appetite, personality changes, pyometra, mammary hyperplasia, transient diabetes mellitus, poor reproductive performance in the male, local alopecia and/ or cutaneous atrophy (I 1,14,21,26). The most frequently seen side effects in our study were: increased appetite, personality changes and depression. In one case, iatrogenic transient diabetes mellitus was diagnosed. Finally, it must be emphasized that megestrol acetate is not licensed for use in the cat in Canada.
2. ASPINAL, K.W. and J.M. EVANS. The use of megestrol acetate in the treatment of military eczema in the cat. Vet. Rec. 88: 374. 1971.
3. ASPINAL, K.W. and W.T. TURNER. Feline military dermatitis. J. small Anim. Pract. 13: 709-710. 1972.
4. BIERY, D.N. Radiation therapy in dermatology. In Current Veterinary Therapy VI. Small Animal Practice. pp. 527-528. Philadelphia: W.B. Saunders. 1977.
5. BURKE, T.J. and H.A. REYNOLDS. Megestrol acetate for estrus postponement in the bitch. J. Am. vet. med. Ass. 167: 285-287.1975.
6. CHAINEY, D., A.M. McCONBREY and J.M. EVANS. The excretion of megestrol acetate by beagle bitches. Vet. Rec. 86: 287-288.1970.
7. CHESNEY, c.i. The response to progestagen treatment of some diseases of cats. J. small Anim. Pract. 17: 3544. 1976.
8. cox, J.E. Progestogens in bitches: a review. J. small Anim. Pract. 11: 759-778. 1970.
9. GERBER, H.A. and F.G. SULMAN. The effects of methyloestrenalone on oestrus, pseudopregnancy, vagrancy, satyriasis and squirt-Nord VetMed. 29: 287-291. 1977 1092. 1964.
10. GRIFFITHS, B.C.R. Eosinophilic granuloma (rodent ulcer) in the cat. Vet. Rec. 100: 159. 1977.
11. HART, B.L. Behavioral effects of long-acting progestins. Feline Practice 4: 8-11. 1974.
12. HESS, P.W. and E.G. MacEWEN. Feline eosinophilic granuloma. In Current Veterinary Therapy VI. Small Animal Practice. pp. 534-537. Philadelphia: W.B. Saunders. 1977.
13. HOUDESHELL, J.W. and P.N. HENNESSEY. Megestrol acetate for the control of estrus in the cat. Vet. Med. small Anim. Clin. 72: 1013-1017. 1977.
14. HOUDESHELL, J.E., P.W. HENNESSEY and H.B. BIGBEE. Treatment of feline miliary dermatitis with megestrol acetate. Vet. Med. Small Anim. Clin. 72: 573-575. 1977.
15. KRAHWINKEL, JR., D.J., D.L. MERKLEY and D.R. HOWARD. Cryosurgical treatment of cancerous and non-cancerous diseases of dogs, horses and cats. J. Am. vet. med. Ass. 169: 201-207. 1976.
16. KRISTENSEN, s. and A. FLAGSTAD. Behandling of eosinofilt granulom type II has kat med megestrol acetat. Dansk Veterinaertidsskrift 63: 665-669. 1979.
17. LANE, J.G. Practical cryosurgery: an introduction for small animal clinicians. J. small Anim. Pract. 15: 715-725. 1974.
18. LANE, J.G. and T.J. GRUFFYDD-JONES. Eosinophilic granulomas in cats. Vet. Rec. 100: 251. 1977.
19. MacEWEN, E.G. General concepts of immunotherapy of tumors. J. Am. anim. hosp. Ass. 12: 363-373. 1976.
20. McDOUGAL, B.J. Eosinophilic granuloma complex in the cat. Feline Practice 7: 27-30. 1977.
21. OEN, E.O. The oral administration of megestrol acetate to postpone oestrus in cats. Nord VetMed. 29: 287-291. 1977.
Megestrol acetate was given orally to 8 cats at a dose of 2.5 mg every other day for 2 weeks and to 8 cats at a dose of 5.0 mg every day for 2 weeks. Four cats were designated nontreated controls. Pre-ACTH-stimulated plasma concentrations of cortisol (hydrocortisone) and ACTH-stimulated cortisol and tolerance to large-dose glucose infusion (IV) were determined on each of the 20 cats given megestrol acetate. Cats were restrained with acepromazine maleate and ketamine hydrochloride during blood sample collection and large-dose glucose infusion. Adrenocortical function and tolerance to large-dose glucose infusion were reevaluated for 4 weeks--after 1st and 2nd weeks of megestrol acetate treatment of the treated groups, and after 1st and 2nd weeks when treatment was stopped (i.e., experiment weeks 3 and 4). Each week a cat from the control group and 2 cats from the 2 treated groups were selected to determine the changes occurring during the experiment for that week; after collection of plasma samples, each week's 5 selected cats were euthanatized and necropsied. Significant impairment of adrenocortical function and alteration of adrenocortical morphology occurred with both treated groups. The most severe adrenocortical alterations occurred in the cats 1 week after megestrol acetate was no longer given (i.e., experiment week 3). Megestrol acetate-induced adrenocortical suppression contributed to the death of 1 cat. It was concluded that if stress occurs to cats on treatment or soon after treatment with megestrol acetate, glucocorticoids should be supplemented. The effects of megestrol acetate on glucose tolerance were overshadowed by the unforeseen intolerance caused by chemical restraint with acepromazine maleate and ketamine hydrochloride.
PMID: 6280517 [PubMed - indexed for MEDLINE]
25) [The use of megestrol acetate to stop urine spraying in castrated male cats (author's transl)].
Chalifoux A, Gosselin Y.
Can Vet J. 1981 Jul;22(7):211-2. French.
PMID: 7340918 [PubMed - indexed for MEDLINE]
Abstract
The use of megestrol acetate to stop urine spraying in castrated male cats Four castrated male cats were treated with megestrol acetate because they were showing signs of urine spraying. The dosage used was 5 mg a day for seven days followed by 5 mg every three days for 21 days. The treatment did not exceed one month. Treatment was successful in three of the four animals with this therapeutic regime. A relapse was noticed one year after the initial treatment in two of these cats. Treatment was resumed in one case, while in the other case spontaneous regression of urine spraying occurred. No relapse have been reported after six months. Other methods of treatment used to suppress this undesirable behavior are also discussed. ( full text available, in French.)
The increasing use of long-acting progestins to treat objectionable urine spraying and urine marking in gonadectomized cats prompted a survey of the comparative effectiveness of the injectable medroxyprogesterone acetate (MPA) and the orally administered megestrol acetate (MA). Both drugs were successful, overall, in about 1/3 of the patients. However, the proportion with favorable response was higher for males (48%) than for females (13%) and was higher for cats from single-cat homes (50%) than for cats from multi-cat homes (18%). Because of the reportedly higher frequency of depression and increased appetite following MA treatment, when compared with MPA treatment, it is recommended that MPA be used initially for routine treatment of these behavioral problems. The survey revealed that if MPA proves ineffective, subsequent treatment with MA can be expected to yield favorable results in some of these patients.
Can Vet J. 1979 Apr;20(4):117. No abstract available.
PMID: 427709 [PubMed - indexed for MEDLINE]
A Hyperglycemia-Glucosuria Syndrome in Cats Following Megestrol Acetate Therapy
DEAR SIR:
Recently, megestrol acetate has been associated with the appearance of clinical signs of transitory diabetes mellitus in the cat (2,5). We would like to expand on Dr. Hutclison's letter (Can. vet. J. 19: 324. 1978) and describe in greater detail the three cases in which hyperglycemia and glucosuria appeared after megestrol acetate therapy for various skin conditions was instituted.
Case I - An 18 year old male, neutered, domestic long-haired cat with miliary dermatitis was treated with an alternate day dosage of 5 mg megestrol acetate.' There was a history of prolonged corticosteroid therapy as well as diabetes mellitus which had regressed spontaneously one year previously. After two weeks of treatment, polydipsia and polyuria was reported and urine reacted positively to a test for glucosuria.2 A blood test for hyperglycemia was also positive.3 The cat died within three days, in spite of insulin and supportive therapy.
Case 2 - A ten year old, male, neutered, domestic short-haired cat with miliary dermatitis was treated initially with 30 mg methlylprednisolone acetate4 intramuscularly. Two months later he was treated with 5 mg megestrol acetate on alternate days. Polydipsia, polyuria, polyphagia and weight loss appeared within ten days. The cat was stabilized on insulin and megestrol acetate therapy was continued. Within a month, signs of hypoglycemia appeared and therapy was stopped. The cat has remained normal since.
Case 3 - A three year old, male, neutered cat was treated for an eosinophilic granuloma with an intralesional injection of 20 mg methylprednisolone acetate. When healing failed to occur, surgical excision was performed. When the granuloma recurred, the cat was placed on 2.5 mg prednisone5 daily and 100 mg chloramphenicol ' daily. One week later, surgical
excision was again attempted and, when this failed, the cat was then treated with 5 mg megestrol acetate on alternate day dosage. The lesion was also injected with 0.4 cc triamcinolone. The treatment was repeated again two weeks later and the megestrol acetate continued. The cat was admitted again after two weeks for polyuria, polydipsia and an elevated temperature of 40.30C. The cat was stabilized with insulin and megestrol acetate therapy was discontinued. The insulin dose was gradually reduced over ten days and the cat is doing well. Whether or not megestrol acetate can precipitate
signs of transitory diabetes mellitus remains unproven. In all these cases blood and urine tests were positive for glucose. Unfortunately, no glucose tolerance tests were done. Megestrol acetate is contraindicated in cats with diabetes (I ) and side effects of the drug include polydipsia, polyuria, weight increase, thickened hair coat, personality changes and endometritus (1,3,4). We have successfully used megestrol acetate in the treatment of selected dermatological cases in
cats, particularly those with miliary dermatitis, eosinoplilic lick granulomas, including rodent ulcers, and hormonal alopecias. It has also been used with some success in behavioural (territorial) urine marking in neutered and unneutered cats. If megestrol acetate therapy is to be used, we would suggest that the owner be made aware of the possible side effects and, if polydipsia and/or polyuria occur, a routine urinalysis, including a test for glucosuria, should be performed. If
positive, therapy should be discontinued or the dosage levels reduced.
Yours truly,
B.P. PUKAY, B.A., D.V.M.
1814 Bank Street Ottawa, Ontario K! V 7 Y6
References
1. HALLIWELL, R.E. Steroidal therapy in skin disease. In Current Veterinary Therapy VI. W.E. Kirk, Editor.
pp. 541-547. Toronto: W.B. Saunders. 1977.
2. HUTCHISON, J.A. Progestogen therapy for certain skin diseases of cats. Can. vet. J. 19: 324. 1978.
3. OEN, E.O. Megestrol acetate for estrus suppression in cats. Nord. Vet. Med. 29: 287-291. 1977.
4. SCOTT. D.W. Miliary eczema in the cat: a review. Proc. Am. anim. hosp. Ass. 43: 145-152. 1976.
5. WERNER, R. Letter to the editor. Feline Pract. 8: 4. 1978.
During 1974, megestrol acetate tablets were distributed to 397 cat owners in the Oslo district for use as an oestrus suppressing agent in cats. A weekly dose of 2.5 mg megestrol acetate was given for at least 30 weeks. Treatment was carried out according to plan in 244 cats. Results are shown in Table I. The course of birth was abnormal in two cats which were pregnant before the trial began. Pregnancy was not registered in any of the remainder. Heat was observed during the period of treatment in 21 of the 244 cats treated according to plan without pregnancy being registered. As regards side effects of the preparation, increased appetite, weight increase and changes of temperament were the most pronounced. One cat developed pyometra after three years of treatment with the preparation.
Vet Med Small Anim Clin. 1977 Jun;72(6):1013-7. No abstract available.
PMID: 586070 [PubMed - indexed for MEDLINE]
NO ABSTRACT GIVEN
33)Non-neoplastic memmary hypertrophy in the cat associated either with pregnancy or with oral progestagen therapy.
Hinton M, Gaskell CJ.
Vet Rec. 1977 Apr 2;100(14):277-80.
PMID: 871052 [PubMed - indexed for MEDLINE]
Abstract
Nine cases of mammary glandular hypertrophy in the cat are described. Three cases occurred in pregnant queens aged between six and eight months and one in an aged non-pregnant queen. The other cases were in neutered animals which had been treated with megestrol acetate for periods of between 14 months and five years. The pregnant queens were spayed and their mammae returned to normal; in the other cats the affected mammary glands were removed surgically. No recurrence occurred in seven cats in which adequate follow-up information was available. The importance of differentiating this benign lesion from mammary neoplasia is discussed.
PIP:
This report is based on data from 9 cats: 4 were queens, of which 3 were pregnant, 5 were neutered cats, 2 male and 3 female, which had been receiving megestrol acetate (MA) for the treatment of miliary eczema for periods of 14 months to 5 years. In all cats the condition was painless. There was gross enlargement of the mammary glands. In 2 cases the skin over the glands was ulcerated. Ovaro-hysterectomy was done on the 3 pregnant queens. The other 6 cases were diagnosed from biopsy specimens. The lesions were then excised. Following ovaro-hysterectomy, the lesions softened and gradually regressed. In the neutered cats no recurrence occurred during the follow-up period. Histological studies showed only benign changes with fibroglandular hyperactivity. An excess of progesterone has been suggested as a cause. The MA therapy cannot be excluded as a cause in some cases. Differentiation of this condition from adenocarcinoma is important. The distinction may be made by histological study of biopsy specimens.
Problems associated with the use of the Beagle dog in chronic toxicological studies of contraceptive steroids are described. A short review is presented on the occurrence of spontaneous tumours in dogs and in bitches of various breeds. The current status of knowledge of canine reproductive hormones and endocrinology is outlined, together with effects of contraceptive steroids. The pathology and histological classification of spontaneous and induced mammary neoplasia in the dog is discussed and compared with breast cancer in women. A series of recommendations are included for future research in this field which it is hoped may resolve some of the outstanding issues and lead to a more suitable toxicological model for contraceptive steroids.
PIP:
Many scientists have criticized the mandatory use of dogs for studies of the chronic toxicity of synthetic steroidal contraceptive hormones. The estimated annual incidence rates for cancer of all sites in dogs is 381.2/100,000 dogs. The estimated relative risk (R) value for the occurrence of tumors in the Beagle breed is 0.9; for malignant tumors, the R value in the Beagle is 0.8. A review of the hormonal potency of various contraceptive steroids in the Beagles indicates that progestogenic compounds generally produce a much lower progestational activity in dogs than in women, and the predominant hormonal action of norethisterone in dogs is estrogenicity rather than progestogenicity. This weak activity for the canine species may account for some of the toxicological findings for norethisterone and related compounds in the Beagle. It is also possible that there are species differences in the relative affinities of estrogen and progesterone receptors for contraceptive steroids. Studies on long-term administration to female Beagle dogs suggest that the nodules found in the mammary gland are not histologically comparable to mammary tumors found in the human female although there is a superficial morphological resemblance to some forms of human mammary dysplasia. Several authors suggest that the results of testing progestational compounds in Beagles are unlikely to be indicative of a potential hazard to the human female. In testing megestrol acetate, it is suggested that the unique sensitivity of the canine females to megestrol acetate is exemplified by intense mammary development at dose levels 10 times the human oral contraceptive level. In contrast, daily dose levels of 500 mg/day in women as a palliative for endometrial cancer have been used with no serious side effects or mammary enlargement. Also the canine mammary gland produces certain pathological changes following administration of natural or synthetic progesterones in a way not readily seen in other species. Possible alternative models (cat, pig) for contraceptive steroid toxicological studies and recommendations for future research are discussed.
