Progestogens

Synthetic analogues of progesterone, also termed progestins or progestogens (PG), are pharmaceutical compounds commonly used to control the reproductive cycle of domestic animals. The following PGs are commonly used in dogs and cats for temporary (starting the treatment shortly before proestrus onset) or prolonged (starting in anestrus) postponement of estrus, or for suppression of estrus (starting the treatment after proestrus onset) : medroxyprogesterone acetate (MPA), megestrol acetate (MA), proligestone (PR), chlormadinone acetate (CMA), delmadinone acetate (DMA), norethisterone acetate (NTA) and melengestrol acetate (MGA). From the clinical point of view all these product act in the same way through a block of the production and/or release of GnRH from the hypothalamus. If used at suprapharmacologic doses or for excessively long periods, these compounds show a variety of action on the reproductive and endocrine system (such as hyperplasia of the endometrium, hyperplasia of the mammary parenchyma, decreased production of adrenocorticosteroids, increased secretion of prolactin and growth hormone, insulin resistance) as well as some local skin reactions at the injection site and behavioral modification (increased appetite and weight, polydipsia, slight depression, decreased libido in males). In pregnant bitches and queens use of PGs may cause masculinization of female fetuses if administered early in pregnancy (during organogenesis) or delayed parturition if administered in the last decade of pregnancy.

Clinical Considerations for a Safe Use of Progestogens

All the above cited effects may occur also after normal dosing but are generally subclinical, fully reversible and do not cause problems in healthy young to adult animals. In general, a treatment period of 6-12 months is considered safe in healthy individuals, although longer treatments can also be as safe provided that the female is given a rest of 1-2 months every year or so. While most bitches and queens may tolerate treatment periods of more than 12 months, animals with a pre-existing disease such as subclinical diabetes, microscopic mammary lesion/tumor or cystic endometrial hyperplasia may see their condition worsen rapidly as a result of the PG treatment. The following is a series of considerations on patient selection and type of presenting complaint for which a PG treatment should or should not be used.

 Do not use long acting compounds (such as MPA or PR or any other compound marketed for long term use) prior to puberty in felines, as this may cause the queen to develop a long-lasting mammary hypertrophy which could become a life-threatening situation. In prepuberal animals it is best to use initially a short acting compound (such as MA) per os for 1-2 weeks and then change to a long acting PG once potential side effects have been ruled out.

 Do not treat pregnant females, as this may cause fetal developmental defects as well as delayed parturition, thereby causing fetal death in utero due to placental ageing and detachment.

 Do not treat pseudopregnant bitches. During a PG treatment clinical signs of pseudopregnancy will disappear but will recur once treatment is discontinued, and the problem may worsen.

 Do not treat a female during diestrus. The stage of the reproductive cycle should always be identified using vaginal cytology and/or serum progesterone assay, and the bitch or queen should best be treated during anestrus. Diestrus should be ruled out in felines too, as approximately 30% of queens ovulate spontaneously, maintaining thereafter a 30-45 day-long diestrus.

 Do not treat females with uterine haemorrhage. Prolonged sanguineous vulvar discharge following parturition in the bitch can be a critical problem which should either be treated with a uterine contractant (i.e., as ergonovine) or sent to surgery. Milder bloody vulvar discharge can be caused by uterine neoplasia, cystic endometrial hyperplasia with superimposed endometrial inflammation, pyometra, metritis. None of these conditions will benefit from administration of a progestogen.

 Do not treat diabetic patients. Although not always necessary, it would be wise to measure blood glucose before and/or after a prolonged treatment to confirm health status with regard to glucose metabolism.

 Do not use PGs in females with prolonged heat. A prolonged heat may be due to ovarian cyst(s), a granulosa cell tumor, or may be due to a split heat (in the bitch) or to a misinterpretation of normal estrous signs by the owner. For none of these categories is a progestogen treatment indicated (although in some cases an ovarian cyst may benefit from administration of a progestogen). Therefore, bitches or queens with a prolonged heat should not be treated with a progestogen, unless a diagnosis of cystic ovarian disease has been carefully confirmed and surgery or administration of GnRH or hCG are not a valid therapeutic option.

Choosing the Right Candidate

The ideal candidate is an adult postpuberal female in anestrus. Prepuberal females should not be treated with long acting compounds because of the risk of precipitating a subclinical uterine, endocrine or mammary condition (such as diabetes, cystic endometrial hyperplasia-pyometra in the bitch or mammary hyperplasia in the queen) which are rare but have been reported in young animals. If one of the above conditions is present the administration of a long acting progestogen prior to diagnosis may pose a serious health threat on the female. A minimum database of clinical information to be gathered prior to administering a long-acting compound should include:

 Collecting a thorough reproductive history to rule out occurrence of estrus within the last 1-2 months (which would mean that the female is in diestrus)

 Performing a complete clinical exam which includes thorough palpation of the mammary gland to rule out presence of mammary nodules

 Collecting a vaginal smear to rule out presence of oestrus

Table 1 shows the suggested dosages of the most commonly used progestogen-based compounds in the bitch and queen.

Table 1. Suggested dosages of the 3 most commonly used progestogen compounds in bitches and queen for the control of estrous.

Prostaglandins

The abortifacient efficacy of prostaglandins (PGF) involves induction of luteolysis, stimulation of uterine contraction and cervical dilation. Of these, the luteolytic effect is the most important in the bitch, while the cervical dilating action has never quite been demonstrated in this species. In dogs, the progesterone supporting pregnancy is entirely from the corpora lutea throughout gestation. PGF will induce luteolysis and depress progesterone concentrations to nearly non-detectable levels very easily after day 25 or 30, although also earlier in pregnancy. The later in the cycle PGF is administered, the easier and more rapid the induction of luteolysis. Use of PGF requires subcutaneous administration 2 or 3 times a day, for 6 days or longer. Treatment should initially be administered under the supervision of a clinician, after which bitches can be sent home once side effects have been carefully after the 1st PGF administration, and the treatment continued at home by the owner. No PGF products are marketed with an indication for use in dogs or cats.

Natural Prostaglandins

A course of natural PGF therapy is successful if injections are given at least twice a day, using a maximum dosage of 80-100 mcg/kg twice daily, starting with half the dose for the first day (or the first 2 administrations). Side effects (which include emesis, salivation, defecation, urination and slight tachypnea) are dose dependent (displayed in 75% of bitches using doses of 250 mcg/kg and only in 25% of bitches using doses of 50 mcg/kg) and self-limiting, decreasing in intensity with repeated dosing. Treatment must be continued until verification of efficacy by ultrasound or palpation. Partial abortion of litters can occur if treatment is discontinued prematurely. With most dosages, 9 or more days may be required to terminate some pregnancies, although 5 to 7 days is usually sufficient. Although the use of premedication with atropine sulphate or prifinium bromide is reported prior to administration of natural PGF compounds, we have never used it and feel that its use is almost always unnecessary.

Synthetic Prostaglandins

Highly potent, synthetic analogs of PGF, such as cloprostenol or alphaprostol have been effectively used for pregnancy termination in dogs, with cloprostenol being used at doses of 1-2.5 mcg/kg, administered three times, at 48 hour intervals, while alphaprostol must be administered twice daily for several days like natural PGF, at the doses of 20 mcg/kg. Side effects have been reduced by administration of various drugs, including anticholinergic drugs like atropine. A study of 67 pregnant bitches demonstrated a 100% efficacy in termination of pregnancy using cloprostenol at the dose of 2.5 ug/kg subcutaneously, administered three times, at 48 h intervals, starting at day 30 of pregnancy. Pre-medication given at 15 minutes before prostaglandin injection included atropine sulfate, prifinium bromide, and metopimazine, it eliminated side effects in 58% of the bitches, and presumably reduced them in others. Cloprostenol at even lower doses has been used in combination with the dopamine agonist cabergoline to terminate pregnancy in dogs shortly after implantation.

Prostaglandins in Cats

PGF treatments have been successful in terminating pregnancy in cats when injected after day 40 in some studies but not in all. Recently it has been shown that natural PGF alone, at a dose of 2 mg/cat IM once a day, beginning at day 33 of pregnancy, can induce luteolysis and terminate pregnancy by expulsion of fetuses in pregnant cats. Side effects included prostration, vomiting and diarrhea. The PGF analogue cloprostenol has been successfully used in combination with cabergoline in cats, at the dose of 5 mcg/kg administered once daily from day 33 post-mating onwards.

Dopamine Agonists

Prolactin secretion by the lactotroph cells of the anterior pituitary gland is regulated by multiple neuro-transmitters and hormones, with the major control mechanism being the activation of prolactin-inhibiting dopaminergic neurons in the hypothalamus. Prolactin is a major luteotrophic hormone and appears to be an absolute requirement for canine and feline progesterone secretion by day 30 after ovulation. Dopamine agonists like bromocriptine or cabergoline are ergot alkaloids, with strong dopamine D2-receptor agonist activity, and thus can reduce prolactin secretion and thereby suppressing progesterone levels. The serotonin antagonist metergoline stimulates endogenous dopamine secretion and thus can inhibit prolactin secretion as well.

Cabergoline has a slow clearance, which allows for a single oral daily administration. Furthermore, its action is longer than 48 hours due to its particularly long (minimum 48 hours) half-life at the hypophyseal level. Because of its more specific D2-type action, cabergoline presents only few side effects when used at clinical dosages. Bromocryptine mesylate inhibits PRL secretion during relatively short periods of time (half-life: ± 4-6 hours) and in a dose-dependent mode. In order to effectively inhibit PRL tone in a continuous fashion for therapeutic purposes, bromocryptine should be administered at least twice a day, administered orally at doses 10-50 mcg/kg. Its lack of specificity leads to side effects on the cardiorespiratory system, causing hypotension due to vasodilatation (adrenergic type effect), or emesis due to stimulation of the Chemoreceptive Trigger Zone (CTZ).

Metergoline is essentially a serotoninergic antagonist with dopaminergic agonist properties when used orally at doses >0.3 mg/kg. Its shorter half-life requires at least administrations twice a day. Its antiserotoninergic properties can induce marked central effects such as depression, nervousness, increased excitability, changes in appetite (anorexia or bulimia), psychotic effects (escaping from home, aggressiveness). Gastrointestinal side effects due to stimulation of the CTZ are evaluated by the emetic dosage in 50% of the bitches or DE50. The DE50 of cabergoline and bromocryptine are identical. However, when considering dosages commonly used in a clinical setting, the emetic effect of bromocryptine is almost always present while it is negligible with cabergoline. The DE50 of metergoline is much higher, but it is very close to the therapeutic dosage. Therefore, emetic effects are sometimes observed when using metergoline, especially when overdosing it.

Antiprolactinic drugs can be used in the bitch and the queen with three indications: pseudopregnancy, induction of abortion and induction of estrus.

Pseudopregnancy

The antilactogenic action of both metergoline and cabergoline is well known. Their administration for 4-5 days at pharmacological doses is effective in treating pseudopregnancy signs and reducing milk production. Occasional failures can be dealt with by repeating the treatment protocol and extending it to 8 to 10 days, and also by administering at the same time metergoline (at the usual antigalactogenic dosage of 500 mcg/kg BID) or bromocriptine (10-20 mcg/kg BID) (see Table 2).

Table 2. Dosages of the 3 antiprolactinic most commonly used in small animals.

Cabergoline (Galastop^TM, CEVA-VETEM, a veterinary compound) and bromocriptine (Parlodel^TM, Sandoz, a human compound) are dopamine agonists (they increase the concentration of dopamine, a PRL-inhibiting factor) while metergoline (Contralac^TM, Virbac, a veterinary compound) is a serotonin antagonist (it lowers the concentration of serotonin, a PRL-stimulating factor).

*There is no scientific information available for the queen.

Antiprolactinics are currently considered the treatment of choice for pseudopregnancy. Until the last part of last century, when antiprolactinics became commercially available, progestogens were thought to be an appropriate treatment for false pregnancy due to their lowering action on PRL concentrations at the end of the luteal phase; in fact, progestogen administration is clinically demonstrated to be effective in preventing the occurrence of lactation and of pseudopregnancy as well as in eliminating related clinical signs. However, a rebound effect is frequently observed following treatment withdrawal, similarly to what occurs at the end of a normal luteal phase, when the progesterone decline triggers a PRL peak. Therefore, progestogens should not be used as a treatment for false pregnancy.

Induction of Abortion

The abortion induction properties of antiprolactinic drugs have been well studied for cabergoline, while not as much is known for metergoline. Cabergoline is effective in terminating pregnancy in dogs when administered at mid-gestation or later. When administered after day 40 at doses of 5 mcg/kg, PO, for 5 days cabergoline is approximately >50% effective in causing abortion in treated bitches. If cabergoline administration is started earlier in pregnancy, at day 25, treatments that are effective later in pregnancy fail in most bitches and the pregnancy continues until terminated by retreatment at day 40. Cabergoline produces little if any side affects at pharmacological doses.

Estrus Induction

The estrus inducing action of antiprolactinic drugs was initially thought to be due to the lowering of prolactin concentrations, but studies done at Utrecht have demonstrated that shortening of anestrus occurs irrespective of prolactin concentrations. All the 3 antiprolactinic products (cabergoline bromocriptine and metergoline) have been used for oestrus induction in the bitch. Cabergoline and bromocriptine have consistently given positive results, while metergoline's results have been more variable depending on dosage. Using low dose (0.1 mg/kg BID) of the commercial oral preparation of metergoline administered from 100 days after ovulation until the following proestrus, the interoestrous interval can be significantly shortened. The administration of bromocriptine in anoestrus will induce oestrus within 28-50 days. We have used bromocriptine at the dose of 10-25 mg/kg in 5 bitches with prolonged anoestrus: 4/5 came in oestrus within 13-28 days, and all 4 conceived and whelped. Using cabergoline (5 μg/kg, once daily for up to 28 days) or natural PGF2alpha (100 μg/kg SC, BID for 5 days starting on cytological dioestrus day 10) we achieved an interoestrous interval of 6 months in 6 treated bitches as opposed to an interval of 9 months in 9 control bitches. We have also used cabergoline (5 μg/kg, once daily for up to 28 days) in 9 bitches for a total of 11 cycles: fertile oestrus was induced in 10/11 cycles in 24+11 days with a reduction of the interoestrous interval of 1.8+0.2 months. In our experience, the clinical use of antiprolactinics to induce oestrus has proven to be safe and highly effective. Side effects are minimal (particularly with cabergoline), being mostly related to the gastrointestinal tract (nausea, rare vomiting) with no other reproductive effect (unlike estrogens or PMSG which can both cause estrogen toxicity).

Dopamine Agonists in Cats

The use of dopamine agonists alone appears not to have been studied extensively in cats. Production of litters by feral cats was prevented by addition of cabergoline to the diet of pregnant individuals at a dose of 5-15 ug/kg/day for 4-12 days. In a controlled laboratory study, cabergoline at doses of 1.7 ug/kg given i.m. daily for 5 days, starting at day 30 of pregnancy, induced luteolysis and terminated pregnancy in 4 of 5 cats, with negligible side effects. In another study, the oral cabergoline formulation administered per os at a dose of 15 mcg/kg for 4 to 7 days terminated pregnancy in 8 cats when started between day 30 and 42, but failed in 2 cats when started at day 45. This failure of abortifacient efficacy in late pregnancy is perhaps not surprising, since the feline placenta is thought to produce progesterone during the last 3 weeks of pregnancy. Emesis was a side effect in some animals. Cabergoline has been used to induce estrus in the queen with some efficacy.

Progesterone Antagonists

Antiprogestins (progesterone antagonists) are synthetic steroids that bind to the progesterone receptor, but fail to initiate activities normally initiated by progesterone, and by occupying the receptors they prevent the actions of endogenous progesterone. Progesterone is required for the maintenance of pregnancy, as it provides the hormonal stimulus for endometrial development and placental attachment, and also acts to maintain uterine quiescence by reducing the contractility of uterine musculature. Anti-progestins disrupt reproduction and terminate pregnancy in all species studied to date. All anti-progestins to date also have anti-glucocorticoid activity, but are more potent as antiprogestins than as anti-corticoids.

Induction of Abortion

The anti-progestin mifepristone (RU486) is a drug developed for human application, is available in a few countries and is not marketed for veterinary use. An injectable formulation of an analog of RU486, i.e., RU 534 or aglepristone, has been made available for veterinary use in France and Sweden since the mid 90's and in many other European countries over the last 2-5 years. Aglepristone is currently marketed with an indication for pregnancy termination in dogs (Alizineä or Alizinä, Virbac). The aglepristone preparation is an oily-alcohol solution containing 30 mg of aglepristone per ml, to be used at a dosage of 10 mg/kg, administered two times 24 hrs apart; it causes no untoward side effects. The early administration of aglepristone at 0 to 25 days after mating always is approximately 98% effective in prevention of pregnancy. The later administration of aglepristone, at Day 26 to 45 after mating induces resorption or abortion within seven days in approximately 95% of cases studied.

Treatment of Pyometra

Antiprogestins can be used also for the treatment of pyometra. In our experience, administration of the usual dosage of 10 mg/kg on days 1, 2, 8 and then also 15 and 28 depending on the clinical situation has resulted in positive results in a preliminary trial in bitches with both open cervix and closed-cervix pyometra. The use of aglepristone can be associated with PGF provided that cervical opening has occurred. In bitches with closed cervix pyometra, administration of aglepristone is often followed by cervical opening within 24-48 hrs.

Antiprogestins in Cats

Aglepristone can induce abortion in cats. The suggested dosage is higher than in the dog, being 15 mg/kg twice 24 hrs apart. There is no information on the effect of aglepristone on pyometra in the queen, but efficacy for this indication is thought to be the same as in dogs.

Estrogens

Estrogens have always been considered as potentially dangerous drugs because of their role in inducing mammary neoplasia and bone marrow aplasia in women as well as in bitches. However, only long-acting synthetic compounds such as diethylstilbestrol, estradiol, estrone and other esther compounds are characterized by such dangerous action because of their prolonged nuclear occupancy time in estrogen receptors of target tissues. Short-acting estrogenic compounds such as estriol, characterized by short nuclear occupancy time and minimal metabolism following absorption (estriol does not bind to sex-hormone binding globulin) prevent development of full (late) estrogenic effects such as endometrial hyperplasia, pyometra and bone marrow suppression.

Unwanted Pregnancy

Several estrogenic compounds have been used for this purpose, but for most of them the risk of side effects has discouraged their clinical application. Only estradiol benzoate, when given at low doses has proven to be fairly efficacious and relatively safe. A compound with estradiol benzoate is marketed for veterinary use in mismated bitches in several European countries (Mesalinâ, Intervet), which is to be administered at the dose of 10 mcg/kg SC on day 3, 5 and 7 post breeding. No side effects have been reported following this protocol, although the only clinical data available for bitches are those produced by the company that is marketing it.

Lotrifen

Lotrifen is an isochinolinic product marketed in some European countries for veterinary use in mismated bitches (Privaprolâ, Fatro). At the dose of 2.5 mg/kg, administered only once no later than 15 days post-mismating it will cause abortion by inhibiting embryonic and placental growth. Although no immediate side effects have been reported (e.g., immediately after administration), anorexia, abdominal pain, gastrointestinal problems and uterine inflammatory diseases have been reported anecdotally. A study done in Spain reported also parturition of live foetuses, parturition of live and dead foetuses, pyometras, prolonged gestation and foetal maceration. Because of potential serious consequence for the health of the bitch, this drug is currently considered unsafe and therefore should not be used in the dog.

References

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