Department of Animal Medicine, Production and Health, University of Padova, Agripolis, Legnaro, Italy
Introduction
The progesterone (P4) antagonist Aglepristone has been available in Europe since early in this century. It is an interesting and unique molecule with high affinity for progesterone (P4) receptors in vitro (three times greater than that of P4 in the canine species and nine times in the feline species). Aglepristone binds to uterine progesterone receptors without producing the biological effects of progesterone. Thus it can be used to block the action of P4 during pregnancy (fœtal resorption, abortion, induction of parturition) or non-pregnancy (uterine and mammary conditions) in the bitch, and also in the queen. It is an oily injectable solution for subcutaneous administration at the dose of 10 mg/kg repeated on two consecutive days, 24 hours apart. Aglepristone is currently marketed with the indication to terminate pregnancy in the bitch. However, because of its novel mechanism of action, it has been the object of numerous studies over the last 2 decades and several indications have been proposed both in pregnant as well as non-pregnant females as well as for endocrine, mammary and perineal conditions.
Indications for Pregnant Females
Early and late pregnancy termination - Aglepristone (AGL) is currently marketed with an indication for pregnancy termination in dogs at any time between day 0 (the day of mis/mating) and day 45. Efficacy is very high, 95–100% and side effects are extremely rare and characterized by a short-lasting pain at the injection site1, 2, 3. Treatment causes prevention of implantation if performed prior to day 24 post-ovulation, embryonic resorption if performed between day 25 and 35 post-ovulation, and expulsion of well-developed foetuses after day 35 post-ovulation4. Clinical signs vary from no sign when prevention of implantation or resorption occurs to vulvar discharge, behavioural signs of parturition and occasionally fever, loss of appetite and metritis following fetal expulsion. The leaflet’s indication to be used between day 0 and 45 is somewhat controversial due to the fact that a) bitches may ovulate up to 5–7 days following mating and still conceive, and b) treatment in late pregnancy may take up to 9–10 days to achieve an effect and therefore 45-day old foetuses may occasionally be still alive following a late treatment and either be expelled live around day 53–55 or die and not be expelled from the uterus. Therefore, it is advisable to a) make sure that in early pregnancy corpora lutea are present prior to starting treatment by assaying serum P4, and b) avoid using aglepristone as the only abortifacient drug in bitches who are pregnant beyond day 40. Treatment failures are occasionally observed, therefore it is always advisable to recheck treated females at least twice at weekly intervals following the end of treatment. Treatments with aglepristone can be started after day 40 provided that the issue is thoroughly discussed with the owner and a prostaglandin or antiprolactinic treatment is associated to help evacuating the uterus. There is no effect on subsequent fertility although the first post-treatment estrus may be delayed. AGL is effective to induce abortion in cats. The suggested protocol is the same although most authors use a higher dosage for cats, 15 mg/kg; however, the 10 mg/kg dose seems equally effective at least during the first half of pregnancy5,6. The success rate is similar to the bitch during the first half of pregnancy, while effectiveness may drop to 66% when causing late term abortion7. Haemorrhagic vulvar discharge following abortion has been reported to occur in pregnant queens treated with aglepristone: this is a consequence of damage to maternal uterine venules with endometrial and cervical extravasation and blood loss, a feature which has not been observed in bitches4.
Planning parturition or C-section - When used near term, AGL will induce labor. Parturition should be induced as close to spontaneous parturition as possible, therefore ovulation should have been staged previously. Whelping has been successfully induced in bitches treated on day 58 and 59 day of gestation using AGL alone at the dose of 15 mg/kg or combined with oxytocin or prostaglandin F2alpha. Gestation length is shorter in treated vs control bitches (59 vs 62 days)8. Fontbonne and coworkers9 used a combined AGL+oxytocin treatment: one injection of aglepristone at the dose of 15 mg/kg was administered on day 59–61, and then starting 24 hrs later oxytocin was administered at the dose of 0.15 IU/kg every 2 hr. Parturition began approximately 30 hours after the aglepristone injection (from 9:00 to 12:00–18:00 of the following day) and resulted in the birth of puppies which were alive and viable at 1 month9. Length of parturition, expulsion time and incidence of neonatal mortality are comparable to what happens during normal parturition. However, 2 small-size treated bitches delivered some of their pups before the first administration of oxytocin9; furthermore, 4 Yorkshire terrier pups (treated group) were born premature and died at 19–29 hr after birth9.
AGL can also be used in the planning of an elective caesarean section, particularly if surgery needs to be done prior to physiological termination of pregnancy because of fetal death, or in case of prolonged singleton pregnancy. Levy et al.10 administered one injection of 15 mg/kg AGL 59–60 days post-ovulation to 37 bitches of 15 breeds. C-section was performed 20–24 hours after treatment. There were no post-operative complications and no signs of prematurity in all pups. 5/188 pups died during the first 2 weeks of life (2.6%). Serum P4 remained >2.0 ng/ml at time of surgery, which would justify the use of AGL as a high-serum P4 concentration following a C-section would delay uterine involution10.
Indications for Non-pregnant Females
Open and closed-cervix pyometra - Pyometra is a uterine condition characterized by accumulation of pus within the uterus and very often fever, leukocytosis, depression11. It is potentially a life-threatening disease which has been treated for a long time mostly through surgical removal of the reproductive tract12. Medical treatment used to be possible only for open cervix cases while closed cervix ones could only be treated with (sometimes elaborate and dangerous) surgery13, as the only way to open the cervix was using prostaglandins with the inevitable risk of causing uterine rupture14,15. AGL has solved this problem as cervical opening occurs without any appreciable uterine contraction within the first 48 hrs post-treatment16,17. AGL treatment of pyometra requires often a longer protocol than what is used for pregnancy termination; the usual dosage of 10 mg/kg aglepristone is administered on days 1, 2, and then at weekly intervals counting from day 1 for as long as necessary. Therefore, injections are typically given on days 1, 2, 8 and then also 15 and 28 or even longer depending on the clinical situation18,19. The use of aglepristone should be associated with antibiotics if necessary, and may also be associated with PGF/PGE1 provided that cervical opening has occurred. Aglepristone is as effective for the treatment of pyometra also in the queen6,20.
Mammary Indications
Feline mammary hyperplasia - Benign mammary hyperplasia is a benign fibroglandular proliferation of one or more mammary glands which typically occurs in young queens at their first luteal phase. The proliferation of the mammary gland is due to an excessive response to the action of progesterone which is present in presumably normal concentrations in affected animals. Mammary glands will start swelling rapidly and within 2–3 days all glands become very swollen, firm and nodular. If left untreated, the problem may disappear on its own without any complication in most cases. Treatment with prostaglandins or antiprolactinic is not effective, while removal of ovaries or administration of aglepristone is often (but not in 100% of cases) curative. When mammary hyperplasia occurs following progestogen administration, signs typically do not subside immediately following neutering or withdrawal of progestin therapy21. In such cases, surgical removal of persisting nodules should be considered in order to perform histology and rule out presence of neoplasia. Feline mammary hyperplasia may be treated successfully with aglepristone21,22,23, which may be an option also for cats treated with long-acting progestogens. Dosages for mammary hypertrophy may need to be prolonged in time depending on whether it is a spontaneous disease or if it is due to progestogen administration4. Muphung et al .24 studied the effect of AGL in a group of queens treated with a high dose of medroxyprogesterone acetate (MPA - 50 mg) followed by 2 injections of 10 mg/kg AGL 3 weeks later. Based on histology and immunohistochemistry, no evidence of an effect of AGL on the mammary gland of treated queens was present24. Lack of effect might be due to the very high dose of MPA used, to the rather low dose of aglepristone (10 mg/kg instead of 15 mg/kg), to the short treatment with AGL (only 2 injections) or to the long interval between MPA and AGL treatments.
Endocrine Indications
Diabetes - Diabetes mellitus is a condition characterized by an altered carbohydrate metabolism due to an absolute deficiency of insulin, which is fairly common in the canine, particularly in dogs of >5 years of age25. Neutered male and female dogs as well as intact (also pregnant) bitches are at a higher risk of developing this condition. In diabetic dogs, insulin deficiency is typically paralleled by an increase in glucagon which, coupled with the decrease in peripheral use, causes hyperglycemia25. The action of insulin is modulated by a number of so called counter regulatory hormones (glucagon, glucocorticoids, catecholamine and growth hormone) responsible for reducing the effect of insulin at the cellular level26. Whenever a higher than normal concentration of these hormones is present in the general circulation for a prolonged period of time a normal amount of insulin will produce a lower biologic response26. Such decreased response to insulin is referred to as insulin resistance, and it is generally suspected whenever hyperglycemia is present despite administration of single insulin doses higher than 1.0–1.5 IU/kg.
An increase in the concentration of the above counter regulatory (or diabetogenic) hormones occurs whenever there is a) an inflammatory condition, b) an endocrine disorder or c) following exogenous administration of one of the counter-regulatory hormones (i.e., glucocorticoids) or of other compounds which may raise their concentration, such as P426,27. In the bitch, endogenous or exogenous P4 can cause insulin resistance by stimulating the release of growth hormone (GH) from the mammary gland thus raising GH concentrations in the general circulation27,28,29. While pituitary GH secretion is normally pulsatile, mammary GH secretion is not characterized by a pulse pattern and is not sensitive to stimulation and inhibition tests30, the only exception being the capacity of being inhibited by the P4 antagonist AGL31. AGL binds to P4 receptors displacing P4 as well as progestogens from their binding sites, therefore it can be used to decrease clinical effects of high P4 concentrations directly as well as indirectly by causing a decrease in serum GH levels. A decrease in serum GH levels can be very important in an intact diabetic bitch as soon as diestrus starts, because of the high production of ovarian progesterone characterizing the first 2-3 weeks of the canine luteal phase. The effectiveness of AGL in helping in the clinical management of diabetes in intact bitches was assessed in a group of 8 diabetic intact bitches of 9–15 yrs of age diagnosed as having a P4-induced insulin resistance complicating the management of their glycemia, with blood glucose levels remaining persistently higher than 200 mg/dl over 12 hour periods regardless of being treated with doses higher than 1.5 IU/kg BID of insulin32. These animals, whose serum P4 was higher than 5.0 ng/ ml at the beginning of the study, were treated with a 10 mg/kg dose of AGL on days 1, 2, 9 and 17, and compared to a control group of 6 diabetic intact bitches in which an equivalent amount of saline solution was administered on the same days of the treated bitches 32. Both groups of dogs received a porcine insulin zinc suspension treatment as appropriate in relation to their serum glucose concentrations. Glycemia was controlled on the day of treatment (day 0) and on days 5, 12 and 20 post- treatment. While no significant variation was observed in serum glucose levels at day 5, glycemia was significantly reduced at day 12 (when the average dose of insulin could be reduced to 0.8 IU/kg) and further on at day 20. Progesterone did not change between day 0 and 20, while GH showed a significant decrease in AGL treated bitches32. The use of AGL should always be considered when dealing with diabetic intact bitches in diestrus.
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