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Postby guest » Sun Sep 21, 2003 6:33 am

Clinical Use of Progestins in Bitches and Queens: A Review (Last Updated: 9-Sep-2003 )
S. Romagnoli1 and P. W. Concannon2

1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, University of Pisa, Italy.
2Department of Biomedical Sciences, Cornell University, Ithaca, New York, USA.

Introduction and Terminology
Progestational compounds (progestins) are used clinically in a variety of applications in dogs and cats, including reproductive applications such as suppression of sexual behaviors, suppression of ovarian cycles, and supplementation of endogenous progesterone in pregnancies potentially compromised by insufficient luteal function. Veterinary and research applications at doses above those now considered safer yet efficacious for dogs and cats generated a number of reports on unwanted side effects the relevance and importance of which remain controversial. Nevertheless, these compounds can likely be used in some clinical situations with a reasonable level of confidence and safety if applied at doses near or at the minimal effective dose. The following review was prepared based on the authors’ clinical and research experience with the use of progestins, and on a significant body of literature dealing with this topic, including but not limited to the references cited in this chapter [1-58].

The terms progestin, progestagen, and progestogen are used interchangeably to refer to any of the manufactured steroids with progestational activity and derived from progesterone or related steroids. Progesterone itself is also manufactured as a drug, and has also been considered by some authors to be included in the general category of progestins. Natural progesterone is synthesized and secreted in relatively large amounts by the corpora lutea during the luteal phase of the cycle, and by the placenta in some species. Progesterone also synthesized as a precursor steroid in several tissues, including in the ovarian follicle(s) as a precursor to androgen and thus estrogens, in the testis as a precursor to testosterone and other androgens, and in the adrenal cortex as a precursor to corticosteroids.
Progestins are widely used in small animal medicine, with indications ranging from dermatological to behavioral problems, but the main use involves the control of the reproductive cycle. This chapter reviews the clinical use of the progestins most commonly used in the dog and cat, and provides comments and considerations on their side effects, on suggested dosages and on indications vs. contraindications for their use. Minor consideration is given to non-reproductive applications.

The topic covered in this chapter include, in order, the following topics:


History
Physiological and other Effects of Progestins
Mechanism of Action of Progestins
Modes of Estrus Cycle Suppression
Progestational Compounds used In Veterinary Medicine
Medroxyprogesterone, Megestrol, Proligestone, Chlormadinone Acetate and Delmadinone Acetate, Melengestrol acetate, Progesterone
Side Effects of Progestins in Small Animals
Clinical Considerations and Caveats for the use of Progestins
Non-Contraceptive Indications for use of Progestin in Dogs or Cats
Dosage Regimens for Progestins Marketed for Contraception
Literature



History
A progestational principle capable of maintaining pregnancy in ovariectomized animals and of causing endometrial gland secretion was identified, isolated, and eventually synthesized in the first half of the 20th century. In the 1930’s it was discovered that progesterone administered by intramuscular injection was capable of blocking ovulation in rabbits. A quest for progesterone-like substances that could control reproduction ensued, leading to the synthesis and characterization of a number of progestins with potential contraceptive application. These included medroxyprogesterone acetate (MPA), melengesterol acetate (MGA), megestrol acetate (MA) and others. In the 1960’s, some progestins being evaluated for use in humans were found to produce mammary tumors in Beagle bitches during toxicity studies. Thereafter, long term animal toxicity studies became an FDA requirement for any progestin to be marketed for human use, and many progestins were evaluated in dogs for toxicity as well as biopotency.
In the veterinary area, depot-injectable MPA rapidly became and remained for a few decades the most widely used progestogen in Europe. In the United States it was quickly withdrawn from the veterinary market because of a high incidence of uterine disease reported in dogs administered MPA. Other progestins that were developed as potential human contraceptives have also been subsequently marketed for contraceptive use in dogs and/or cats in one country or another, including oral megesterol acetate, oral MPA, oral delmadinone acetate, oral clormadinone acetate, and depot-injectable proligestone. In a variety of in vivo and in vitro assays in various species, such compounds have been examined for relative biopotency, bioavailability, estrogenic activity, androgenic activity, and the like. Often, however, different compounds have not been evaluated in the same way, and therefore relative differences are not clear-cut. Species differences in potency and efficacy are also known to exist.

Physiological and other Effects of Progestins
Reproductive effects - In addition to its progestational activity in maintaining pregnancy, progesterone was initially characterized and assayed based on its ability to increase uterine weight acting synergistically with estrogen, and its ability to increase endometrial glandularity and endometrial secretory activity. Numerous studies have attempted to characterize and define the mechanism of action of progesterone. Many if not most effects of progesterone involve progesterone combining with progesterone receptors within cells of target tissues such that the progesterone-receptor complexes interacts with progesterone-response-elements in the genome, and thereby activate and/or suppress the transcription of various genes to the respective mRNA.
Numerous reproductive studies on progesterone and other progestins demonstrate that their administration can have actions that can be classified as progestational, anti-estrogenic, anti-androgenic, anti-gonadotrophic, and contraceptive. However, under some circumstances, the same compound(s), in at least some species, may acutely stimulate gonadotrophin secretion, have an androgenizing effect, or have self-limiting progestational effects.

Progestational actions. Pregnancy supporting actions of progesterone and other progestins include the following:
a. stimulation of endometrial gland development and secretion by acting on progesterone receptors, especially after estrogen priming of the endometrium;
b. promotion of cervical closure;
c. suppression of uterine motility by depressing myometrial sensitivity and contractility directly; and also by decreasing the availability of myometrial oxytocin receptors;
d. stimulating proliferation of mammary tissue, especially lobulo-alveolar tissue.
Anti-estrogenic action. Prior progestin administration reduces or prevents estrogen-induced phenomena including vaginal bleeding, estrus behavior, and ciliation of the oviduct by suppressing the synthesis of estrogen receptors normally stimulated by exposure to estrogen.
Anti-androgenic action. Progestin administration reduces, inhibits or reverses some effects of androgen, including libido (sex drive), possibly by interfering with androgen or other steroid receptors’ responses to their own hormone ligands, in addition to any anti-gonadotrophic action.
Anti-gonadotrophic action. Progestin administration, through an ability to reduce or modulate secretion of the gonadotrophins LH and FSH secretion, can suppress follicle development and prevent ovulation. Progestins do not appear to lower basal gonadotrophin secretion, but rather appear to prevent increases in pulsatile gonadotrophin secretion that would normally otherwise occur in a normal ovarian cycle.
Contraceptive actions. Progestins, via multiple mechanisms, can prevent, diminish, or desynchronize normal changes in the reproductive tract, prevent follicle maturation and ovulation, and interfere with sperm transport.
The anti-gonadotrophic action is by far and large the most important clinical effect in small animal reproduction. Administration of a progestin to an intact bitch or queen will invariably cause some degree of suppression of ovarian cycles. However, the same dosage of a progestin will have different effects on the cycle depending on time of treatment relative to stage of estrous cycle. The side effects can vary depending on whether treatment is administered prior to the onset of proestrus, after the onset of proestrus, during estrus, during metestrus, or during anestrus; Likewise, duration of efficacy can vary - cycles may resume after days, weeks or months, respectively (Table 1).


Table 1. Terminology commonly used to describe the action of a progestin on canine and feline reproduction depending of the desired level of efficacy, and the preferred stage of the reproductive cycle when the drug is administered (adapted from Evans & Sutton, 1989 [23]).
Effect on Reproductive
Cycle Time of Drug
Administration Duration of Treatment
or Action Duration of
Effect
Acute Suppression After onset of Proestrus Days Weeks
Temporary Postponement Prior to onset of proestrus Weeks Weeks to Months
Permanent Postponement During Anestrus Months Multiple cycles


Contradictory Effects - Despite the significant anti-androgenic actions progestins may have, they can also have masculinizing effects, as observed when female fetuses are masculinized by progestin administration during pregnancy. Despite the anti-gonadotropic effects progestins possess, they can acutely be pro-gonadotrophic and cause the release of a surge in LH and FSH when administered immediately after a large bolus of estrogen, or at the end of proestrus when endogenous estrogen is exceptionally high.

Species Differences - Not every progestin will display all the above actions to the same extent in all species, and clinicians should not freely transpose findings from one compound to another. For instance, there are marked differences in the action the same compound will show in humans vs. dogs. Some progestins with apparently purely progestational actions in humans have been reported to display some degree of estrogenic action when administered to bitches (Table 2). In addition, many species require preceding or simultaneous exposure to estrogen to elicit the full effects of progesterone, especially on mammary tissue. In contrast, dogs may undergo full mammary development in response to progestin alone, in the absence of estrogen, as seen experimentally in ovariectomized bitches administered progestins.


Table 2. Classification of some of the main human and veterinary progestogen compounds based on: A. chemical structure (19-nortestosterone vs. 17-hydroxyprogesterone) of the parent compound; B. presence or absence of estrogenic, progestational and androgenic activity; and C. oral bioavailability in dogs vs. humans (Nelson et al., 1973 [35]; El Etreby et al., 1979a, b [16,17]; Briggs, 1983 [4]; Neill Johnson, 1998 [33]).
Steroid Group 19-C-Progestogen group
Nortestosterone derivatives
(partial list) 21-C-Progestogen group
17-Hydroxyprogesterone derivatives
(partial list)
Examples Norethisterone (norethindrone)
Lynestrol
Norethynodrel
Levonorgestrel
Gestodene Medroxyprogesterone
Chlormadinone
Megestrol
Cyproterone
Chemical structure similar to Testosterone similar to Progesterone
Estrogenic activity in humans Negative Negative
Estrogenic activity in dogs Positive Negative
Progestational activity in humans V. Positive Positive
Progestational activity in dogs Positive V. Positive
Androgenic activity in rodents Present Absent
Oral bio-availability Higher in humans Higher in dogs


Non-reproductive Effects - Apart from the reproductive effects, progestogens display a range of metabolic and non-reproductive endocrine actions. Knowledge of these by the clinician can be relevant to the success of treatment. These non-reproductive effects disappear once the progestogen treatment is discontinued. Some of these effects are displayed at low pharmacological doses, while others will only become manifest following use of high dosages or a prolonged treatment period. Furthermore, while some of these effects have been confirmed in clinical investigations while others have only been noted in experimental studies. These non-reproductive effects include the following:

Potential depression of pituitary ACTH secretion and adrenocortical function, with reduced cortisol levels (clinically reported, at pharmacological doses)
Stimulation of growth hormone secretion (clinically reported, at suprapharmacological doses)
Insulin resistance and increased insulin concentrations, and altered glucose tolerance (clinically reported, at pharmacological doses when using megestrol acetate)
Slightly and transiently increased basal body temperature (observed in experimental studies)
Increased fat deposition through stimulation of lipoprotein lipase (observed in experimental studies)
Decreased serum concentrations of high density lipoprotein (HDL) (observed in experimental studies)
Decreased sodium retention via reduced action of aldosterone on kidneys (observed in experimental studies)
Mechanism of Action of Progestins
Progesterone and other synthetic progestins act in the same manner as endogenous progesterone. In most if not all target tissues, progesterone diffuses through the membrane, and binds to a progesterone-receptor protein. This binding allows the progesterone receptor to then bind to a progesterone-response-element in the nuclear genome, resulting in the suppression or activation of transcription and eventual translation of specific gene sequences regulated by progesterone. The translation products include structural and secretory proteins, enzymes, and other regulating proteins. It is also possible that in some tissues progesterone, like estradiol, can bind to membrane receptors and have cellular effects in response to binding to membrane receptors.

Mechanism of Anti-Gonadotrophic Contraceptive Action
Progesterone, and other progestins, appear to have their main contraceptive effect by preventing an increase in gonadotrophin secretion that would otherwise occur in the normal course of events. This in turn prevents full follicle maturation. The direct effect is primarily if not entirely at the level of the hypothalamus, and perhaps at the level of opioidergic neurons, causing a decrease in the frequency of GnRH pulse secretion, which in turn decreases LH and FSH pulsatility, the major factor regulating follicle development. Progestins can also acutely inhibit the preovulatory surge in LH, an effect that can involve actions both on hypothalamic GnRH secretion, and on pituitary responses to estrogen if administered before estrogen reaches high concentrations.

Modes of Estrus Cycle Suppression
When progestins are used as anti-fertility drugs in dogs and cats, the timing and duration of treatment can vary. The resulting efficacy can be referred to as one of the following:

acute suppression of an ongoing cycle
temporary postponement of an eminent cycle or
protracted or permanent postponement of cycles (Table 1).
In the bitch, a progestin may be administered orally in early proestrus at moderate to high doses as a means to suppress ongoing proestrus, prevent the occurrence of estrus, cause a premature artificial luteal phase, and result in a postponement of the next cycle for several weeks to several months. Oral administration during anestrus, at low doses for several weeks (or an injection of a short acting formulation), can provide an artificial luteal phase that postpones the occurrence of the next cycle for a few months to several months. Continued administration of a progestin starting in anestrus can lead to a prolonged or chronic postponement of the next cycle, using either repeated oral administrations, repeated injections of shorter-acting injectable formulations, or one or more injections of a long-acting depot-injection formulation.

Progestational Compounds Used in Veterinary Medicine
Many progesterone derivatives have been tested in small animals. The most widely used compounds in North America, Europe and Australia / New Zealand are medroxyprogesterone acetate, megestrol acetate and proligestone (Table 4, Table 6 and Table 8). Less commonly used and less available compounds which exist in commercial preparations in some European countries include delmadinone acetate, chlormadinone acetate, and norethisterone acetate [10]. Melengestrol acetate [27] and ally-trenbolone have been experimentally tested in bitches, while more recently the contraceptive action of levonorgestrel has been experimentally tested in cats [2]. All of these modified steroids are orally active. Some progestins are marketed in both tablet formulations of oral administration, and liquid solutions or suspensions for injection or depot-injection. Progesterone itself is not orally active, and it is only marketed in injectable formulations.

Medroxyprogesterone Acetate - Medroxyprogesterone acetate (MPA) was one of the first progestins developed for human use and has therefore been extensively tested in dogs and cats, particularly at high-multiples of the human dose. It is slowly metabolized by the liver. Its anti-gonadotrophic, cycle-preventing efficacy is summarized in Table 3.
MPA is not marketed as a veterinary product in the USA, although the depot-injection of MPA can be encountered in veterinary practice since it is now used as a human contraceptive in that country. Depot injectable MPA is marketed in several countries as a veterinary product for pet contraception, typically with an indication for use in dogs, and unfortunately with a variety of recommended doses and injection frequencies. The minimal effective dose, and the more appropriate dose to use initially, appears to be about 2 mg/kg every 3 - 4 months, and 3 - 5 mg/kg every 5 - 6 months. Because of potentially serious side effects and because of the fact that the drug cannot be rapidly withdrawn with a depot injection, care must be taken to use the lowest possible effective dosing regimen. Use should include an appreciation of the fact that some bitches may develop side effects, especially uterine disease, even though such side effects are usually only observed with higher doses or prolonged use. Uterine, mammary, and metabolic side effects are those seen with progestin, as reviewed later in this chapter. Depot-MPA is typically not marketed with an indication for use in cats.
In several countries, MPA is also marketed as an oral formulation, in tablet form, with indications for use similar to that for other oral progestins, such as megestrol acetate (see below).


Table 3. Efficacy of medroxyprogesterone acetate in bitches for prolonged postponement, temporary postponement or acute suppression of estrus, and the reported intervals from treatment to the first spontaneous estrus and post-treatment fertility.
Cycle regulation by MPA administration in the bitch Efficacy and administration formulation
Prolonged postponement
(anestrus administration) Highly effective when a depot-formulation suspension is administered intramuscularly (IM) during anestrus.
Efficacy is estimated to be 85 - 90% (if injection is repeated every 6 months) or up to 98% (if injection is repeated every 5 months).
Temporary Postponement
(anestrus administration) Effective
Oral formulation (tablet)
Suppression
(proestrus administration) Effective
Oral formulation (tablet)
Subsequent Cycle Results
Interval treatment to heat Variable, unpredictable
From 0.5 to 26 months reported
Average 6 months (bitch)
Post-treatment fertility Normal
Risk of uterine pathology may be increased
Depot-injections should not be used in breeding animals



Table 4. Commercial names, routes of administration and marketing company for medroxyprogesterone acetate compounds used in small animal reproduction in some countries of north America, Europe, and in Australia/New Zealand. (PO = per os; IM = intramuscularly)
Country MPA Veterinary Product, Formulations, and Companies
Australia No compound available
Belgium Depo-Promone® (IM) (Pharmacia & Upjohn)
Supprestral® (IM; PO) (Vetoquinol)
Veramix® (IM; PO) (Pharmacia & Upjohn)
Eire Perlutex inj (Leo)
Promone E (Pharmacia & Upjohn)
France Controlestril® (PO) (Clement)
Depo-Promone® (IM) (Pharmacia & Upjohn)
Hebdo’Pil® (PO) (Thékan)
Supprestral® (IM, PO) (Vetoquinol)
Perlutex® (PO) (Leo)
Gynecalm® (IM) (Virbac)
Germany Perlutex® (IM; PO) (Boehringer)
Supprestral® (IM; PO) (Selectavet)
Sedometril (IM; PO) (Albrecht)
Depot-Alphacort (IM) (Pharmacia & Upjohn)
Italy Perlutex® (IM; PO) (Boehringer)
Depo-Promone® (IM) (Gellini)
New Zealand No compound available
Spain Sin Estro Neosan® (IM; PO) (Neosan)
Gestovex® (IM) (Boehringer)
UK Perlutex® (IM; PO) (Leo)
Promone - E (IM) (Pharmacia & Upjohn)
USA No compound available


Megestrol Acetate - Megestrol Acetate (MA) was developed as a shorter acting drug than MPA. Therefore, its faster metabolism makes it better suited for short-term, temporary estrus-postponement and suppression rather than for prolonged postponement of estrus. Its anti-gonadotrophic, cycle preventing efficacy is summarized in Table 5. Megestrol acetate tablets are marketed in many countries with an indication for administration in dogs, either during anestrus and several weeks before the next expected cycle at low doses for about 32 days, or, during early proestrus at four-times higher doses for about 8 days.
MA is the only contraceptive drug approved and marketed for veterinary use in the USA, and is only marketed with an indication for use in dogs. In several countries MA is marketed with an indication for use in cats, as well. In the USA and some other countries, MA use in cats is an extra-label use, requiring the informed consent of owners. MA is typically marketed in two dosages, 5 mg and 20 mg tablets. In some counties, different dosages or a single dosage is available. Dosing should be done carefully on a body weight basis, according to the manufacturer’s recommendations, using partial tablets where necessary in smaller animals. While MA is also marketed as an injectable formulation in some countries, there are no dose-response data to demonstrate the minimal or most appropriate injection dose or frequency. Uterine, mammary, and metabolic side effects are as for any other progestin, as reviewed later in this chapter.


Table 5. Efficacy of prolonged postponement, temporary postponement and suppression of estrus, interval from treatment to the first spontaneous estrus and post-treatment fertility for Megestrol acetate in bitches.
Cycle regulation by MA administration in the bitch Megestrol acetate efficacy and administration
Prolonged postponement
(anestrus administration) Not very effective
Temporary Postponement
(anestrus administration) Effective
To be administered per os. For health reasons it should not be used for more than 40 consecutive days or for more than 4 non-consecutive months.
Suppression
(proestrus administration) Effective
To be administered per os only during the first few days of proestrus.
Subsequent Cycle Results
Interval treatment to next cycle Variable
Shorter than with MPA (bitch)
Post-treatment fertility Normal
Can be used in breeding animals



Table 6. Commercial names, routes of administration and marketing company for megestrol acetate compounds used in small animal reproduction in some countries of North America, Europe, and Australia/New Zealand. (PO = per os; IM = intramuscularly)
Country Megestrol Acetate Veterinary Product, Formulations, and Companies
Australia Megecat (PO) (Vetoquinol)
Ovarid (PO) (Jurox)
Suppress (PO) (Jurox)
Belgium Chronopil® (PO) (Sanofi)
Megecat® (PO) (Vetoquinol)
Ovarid® (PO) (Mallinckrodt)
Eire Ovarid (PO) (Schering-Plough)
France Canipil® (PO) (Veto-Centre)
Oestruval 10® (PO) (Sepval-Sogeval)
Felipil® (PO) (Veto-Centre)
Pilucalm®, Pil. 20® (PO) (Novartis)
Megecat® (PO) (Vetoquinol)
Pill’Kan® (PO) (Thèkan)
Opochaleurs® (PO) (Thèkan)
Pruritex chat® (PO) (Novartis)
Germany No MA formulation compound marketed
Italy Estropill® (IM; PO) (Gellini)
Estroblock® (PO) (ATI)
New Zealand Ovarid (PO) (Schering-Plough)
Suppress (PO) (Jurox)
Spain Pilucalm® (PO) (Ciba Geigy)
UK Ovarid (PO) (Schering-Plough)
USA Ovaban (PO) (Schering-Plough)


Proligestone - Proligestone is a third-generation progestin developed in the hopes of achieving inhibitory effects on the hypothlamic-pituitary-gonadal axis without causing side effects on the uterus or mammary gland. However, studies performed in The Netherlands show that proligestone treatment can also result in many of the same side effects caused by MPA or MA. Nevertheless, some clinicians have suggested that effective contraceptive doses of proligestone do appear to provide a weaker stimulus on the endometrium and on the mammary epithelium, compared to presumably comparable doses of other progestins. Its anti-gonadotrophic, contraceptive efficacy is summarized in Table 7. Uterine, mammary, and metabolic side effects are as for any progestin, as reviewed later in this chapter.


Table 7. Proligestone use in bitches: efficacy of prolonged postponement, temporary postponement and suppression of estrus, interval from treatment to the first spontaneous estrus and post-treatment fertility.
Cycle regulation by proligestone administration in the bitch Proligestone efficacy and administration formulation
Prolonged postponement
(anestrus administration) Effective, administered IM
It must be administered at intervals of 3, 4 and then 5 months and subsequently at a 5-month interval schedule.
Manufacturer recommends that, if the dog cycles during treatment, then retreat, going back one step in the treatment schedule, i.e., if the current interval between treatments was 5 months give the subsequent injection after 4 months.
Temporary Postponement
(anestrus administration) Effective
Administered IM.
Suppression
(proestrus administration) Effective
Administered IM.
Subsequent Cycle Results
Interval treatment to next cycle Typically, 3 to 9 months
Post-treatment fertility Normal
Can be used in breeding animals



Table 8. Commercial names, routes of administration and marketing company for proligestone compounds used in small animal reproduction in some countries of north America, Europe, and in Australia/New Zealand (PO = per os; IM = intramuscularly).
Country Proligestone Product, Formulation, and Company
Australia Covinan (IM) (Intervet)
Belgium Delvosteron® (IM) (Intervet)
Eire (Ireland) Ovarid (PO) (Schaering-Plough)
France Delvosteron® (IM) (Intervet)
Germany Covinan® (IM) (Sanofi)
Delvosteron® (IM) (Intervet)
Italy Covinan® (IM) (Intervet)
New Zealand Delvosteron® (IM) (Chemavet)
Spain Covinan® (IM) (Intervet)
UK Delvosteron® (IM) (Intervet)
USA No compound available


Chlormadinone Acetate and Delmadinone Acetate - Neither of these steroids is marketed as a veterinary drug in most countries. The use of chlormadinone acetate is anecdotally reported to be associated with weight gain, behavioral change and probably the same uterine problems as MPA. Although fertility at the first post-treatment estrus is reported to be good, interval between end of treatment and return to heat can be prolonged, therefore it is probably best not to use CA in breeding animals.
Published information on delmadinone acetate is scant. Reported side effects are weight gain, polydipsia, local skin reaction and an increased risk of uterine pathology. Clinical data indicate that interval between end of DA treatment and return to heat can be prolonged, therefore it is probably best not to use DA in breeding animals.
For both delmadinone acetate and chlormadinone acetate, treatment appears to be rather effective for prolonged postponement of cycle in dogs if injected every 4 months, with occasional breakthrough heats during the treatment reported. Treatments are not very effective for temporary postponement of the cycle or for cycle-suppression during proestrus. The post-treatment fertility is reportedly normal for both. The reported interval from treatment to the next cycle is about 8 months for delmadinone in a small number of dogs, and variable up to two years for chlormadinone.

Melengestrol Acetate - Melengestrol acetate (MGA) has been used as a cycle-synchronization feed additive for cattle. It has also been used as a long term contraceptive treatment in exotic carnivores in zoological displays, in the form of a subcutaneous MGA-releasing silastic capsule. Its use has not been reported in detail in pet animals.

Progesterone - Veterinary formulations of progesterone currently available are not used for contraception, since progesterone is not orally active, and injected progesterone has a very short half life and disappears from the circulation in a matter of hours or a few days, depending on the vehicle, injection volume and injection site. Long term administration of progesterone by subcutaneous silastic implant is difficult because of its low solubility in silastic and the large size of the implants that would likely be required. Testosterone is more soluble in silastic, and similar implants containing testosterone have been reported as efficacious in bitches, but have not been marketed.

Side Effects of Progestins in Small Animals
The following side effects have been observed after prolonged, chronic use of progestins such as during the course of chronic toxicity studies. They are also reported with varying severity, and varying or unknown frequency during the course of treatment with recommended contraceptive doses. It is not known to what extent the occurrence of side effects during clinical application represent animals uniquely susceptible to the drug, errors in dosage or administration regimen, or the aggravation of preexisting problems that would manifest themselves clinically regardless. Healthy adult females undergoing short-term (weeks) or medium-term (months) of progestin treatment are thought to rarely experience side effects, but reliable incidence data are not available. In cases of long-term (6 - 12 months or longer) treatments at carefully monitored doses, most animals are thought to have few if any side effects if progestin administration is initiated during anestrus in healthy young adults. While a side effect becoming manifest may mean that the animal had a subclinical problem exacerbated by the progestin, the following sequellae should be considered as potential side effects of any progestin treatment.

1. Increased Incidence of Uterine Pathology - High doses of progestin, or repeated or prolonged exposure to moderate doses of progesterone or progestins will cause cystic endometrial hyperplasia (CEH). Cystic endometrial hyperplasia involves proliferation of the glandular endometrium, and cystic dilatation of the endometrial glands with endometrial fluid accumulated in their lumen. The length of the canine luteal phase (2 months) and the relatively high progesterone concentrations during the first third of the progestational phase (15 to 80 ng/ml) predisposes the canine uterus to spontaneously develop CEH, a phenomenon which tends to disappear on itself towards the end of diestrus. CEH is typically an incidental finding, and its natural incidence is not known. CEH generally appears only in areas of the endometrium not supporting a placenta, and develops in a more rapid and intensive way if the uterus has been primed by estrogens [9,11,34]. Exposure of the endometrium to progestins causes proliferation of the superficial layers of the endometrium with increased secretory activity of the endometrial glands, which can lead to CEH [11,28]. Histological aspects of normal, stimulated and pathological canine endometrium are shown in Fig. 1, Fig. 2, Fig. 3. The gross morphology of a uterus with cystic endometrial hyperplasia is shown in Fig. 4. CEH predisposes the uterus to infection, typically by otherwise normal vaginal flora, and can result in pyometra. The incidence of pyometra is increased with the use of progestins.



Figure 1. Histology of normal canine uterus of a bitch in early proestrus. A moderate degree of epithelial hypertrophy is observed. The endometrial glandular epithelium is starting to proliferate increasing its thickness as a result of stimulation by rising estrogen concentrations. - To view click on figure -



Figure 2. Histology of a canine uterus during the first part of diestrus (metestrus) early in the luteal phase. The endometrial glandular epithelium is greatly thickened, glandularity is increased, large quantities of mucous material has accumulated into the lumen of several glands. Areas of normal endometrium are interspaced with areas characterized by the presence of endometrial cysts. This pattern can be defined as physiological cystic endometrial hyperplasia, a phenomenon which develops spontaneously to varying degrees during the progestational phase in the canine and feline uterus and which is generally reversible. However, repeated progestational stimulation (as it occurs with age in the bitch and queen) may lead to areas of endometrium not re-gaining a normal status during the last part of diestrus and anestrus, thus predisposing the bitch to infertility and to developing pyometra. The cellular infiltration in the endometrium suggests that the bitch may have a significant degree of inflammation, a relatively common sequella to a prolonged phase of cystic endometrial hyperlasia. Similar changes can also occur during progestin treatment. - To view click on figure -




Figure 3. Histology of the uterus of a bitch with pyometra. The endometrium is grossly altered and infiltrated with neutrophils. Several cystic glands are observed while the remaining sections of the endometrial lining are atrophic. Large areas of the lumen are filled with exudates. - To view click on figure -




Figure 4. Uterus from a bitch with protestin induced cystic endothelial hyperplasia and pyometra. The uterine fundus and uterine horns were slit longitudinally and the majority of pus previously present in large volumes removed to show the cystic and hyperplastic appearing surface of the endometrium and the tenacious nature of the remaining mucus. (Figure provided by P. Concannon.) - To view click on figure -

2. Increased Incidence of Mammary Tumors - An increased incidence of mammary pathology including development of mostly benign tumors (adenomas) is reported both in the bitch and queen [3,45,51,52]. Tumors are typically mixed adenomas (mixed mammary tumors) although preneoplastic and neoplastic epithelial adenomas have been reported, as well as malignant carcinoma and adenocarcinoma. Progestins act directly on the mammary gland of mammalian species with varying potencies in terms of ability to cause proliferation of one mammary component versus another, and ability to act independent of prior estrogen priming. In all situations, progestational activity is required for maximal mammary gland stimulation, but the maximal effect must be facilitated by one or more other hormones, depending on species - including estrogen and prolactin in the rat and mouse [26], estrogen plus a placental factor and perhaps a novel pituitary hormone in monkeys and humans [16,17,53], and growth hormone in dogs and cats [15]. High levels of growth hormone (GH) cause the development of mammary nodules some of which can be neoplastic. In dogs and cats endogenous progesterone or exogenous progestins can cause increased secretion of GH [8,13]. There appears to be an increase in GH secretion by the pituitary acidophils, and if the progestational stimulus is prolonged it can cause GH to be secreted by the mammary gland as well [37]. Therefore, progestins in the bitch and queen can stimulate mammary gland hyperplasia and neoplasia directly but also indirectly through the increased production of GH.

3. Increased Secretion of Prolactin - Increased prolactin secretion in the bitch has been suggested as an effect of progestins [16,17]. However, recent studies suggest that any increased prolactin secretion due to progestin administration involves an initial suppression of prolactin secretion with exposure to progesterone, and an a rebound-increase in prolactin in response to a decline on progestin or progestin withdrawal. A similar cause-effect scenario presumably occurs in response to changes in endogenous progesterone, with progesterone withdrawal being an active stimulus for prolactin release. This explains why progestin administration can suppress the symptoms of pseudopregnancy, yet result in a reoccurrence of symptoms upon progestin withdrawal.

4. Increased Secretion of GH and Acromegalic Changes - Progestin administration can cause increased secretion of GH in the bitch [8,12,13], with resulting increases in circulating concentrations of both GH and somatomedin (IGF-1). The latter can result in acromegalic changes including enlarged soft tissues of the head and neck, overgrowth of the skin, elongation of bones which growth plates and osteogenic surfaces remain functional, and splanchnomegaly including hepatomegaly. Elevated serum GH can also cause insulin resistance. A bitch showing acromegalic changes in response to long term MPA treatment is shown in Fig. 5. Spontaneous acromegalic changes have been reported in older intact bitches, sometimes transiently, occurring in response to increases in progesterone during the luteal phase of the ovarian cycle.



Figure 5. Beagle bitch showing acromegalic changes after experimentally receiving pharmacologically high (10 mg/kg) doses of MPA every 3 months for a period of 18 months. Enlargement and overgrowth of the toes and nails, and focal nodular mammary enlargements were noted, as well as the facial changes and generalized skin overgrowth depicted. (P. Concannon, unpublished) - To view click on figure -


Also proligestone can be used for the treatment of pituitary dwarfism in the dog. Knottenbelt and Herrtage [58] used proligestone at the dose of 10 mg/kg every 3 weeks and obtained improvement of dwarfism signs (such as body growth and improvement of coat quality) in 3 dogs [58].
While pituitary cytology suggests progestins cause increased GH secretion by pituitary acidophils, progestins can also cause GH secretion by mammary tissue. In fact, the induction of increased secretion of GH from the canine mammary gland by treatment with progestogens can be used for the treatment of pituitary GH deficiency. Kooistra et al. [28] treated 3 dogs with congenital dwarfism with MPA using a SC dose of 2.5 - 5.0 mg/kg. Dogs were treated initially at 3 - week intervals, then at 6 - week intervals. Their body size increased and complete adult hair coat developed.

5. Diabetes Mellitus - Elevated blood glucose resulting from progestin treatment has been reported both in the bitch and queen [8,12,13,31,45]. Such occurrences of hyperglycemia have been reported in experimental dogs during chronic MPA and proligestone treatments, and in cats during clinical trials using pharmacological doses of MA. However, hyperglycemia does not seem to be a major clinical problem in healthy females even during 6 to 12 months of treatments with low contraceptive doses. The mechanism of the diabetogenic effect presumably involves increased secretion of GH, with increased concentrations of serum GH causing insulin-resistance. Whether progesterone or other progestins can directly affect insulin action is not clear. During normal ovarian cycles, changes in steroid hormones including the luteal phase elevation in progesterone are associated with an increase in insulin resistance such that diabetic animals require increased doses of insulin to regulate blood glucose concentrations.

6. Masculinization of Female Fetuses - Masculinization of female fetuses has been reported in the bitch following the use of norethisterone acetate or of MPA [10,42]. When administered to pregnant mice or rabbits, medroxyprogesterone acetate can cause masculinization of female fetuses, feminization of male fetuses and cleft palate.

7. Adrenocortical Suppression - A subclinical adrenocortical suppression has been reported both in the bitch and queen during progestin treatment, and is presumably due to progestins having gluococorticoid-like negative feedback effects on pituitary corticotrophin secretion [8,43,48,54,55]. The extent to which the stress response might be compromised in such animals has not been examined.

8. Delayed Onset of Parturition - Progestins can prevent or delay the onset of parturition in both species [19]. Therefore, extra care must be taken to ensure that the female is not pregnant before initiating progestin therapy, because if undocumented fertile matings have occurred, fetuses will likely die in utero. Administration of supplemental progesterone or a progestin during a confirmed pregnancy must involve protocols that allow for full withdrawal of progestin action before the time of predicted parturition. Normal parturition requires progesterone withdrawal.

9. Local Skin Alterations - Local skin alteration including skin discoloration, alopecia, skin atrophy, and calcinosis circumscripta have been reported at sites of progestin injections [24,56].

10. Behavioral Modification - Behavioral modification including increased appetite with resulting weight gain, polydipsia and mild depression have been reported with progestin treatment in both the bitch and queen [56,57]. Progestins have also been reported to cause decreased libido in males, and have been used therapeutically to suppress male libido in both dogs and humans.

Some side effects of progestins, such as altered prolactin secretion and mammary gland GH secretion, are poorly reported in the cat but should be considered as a possibility in this species as well.

Clinical Considerations and Caveats for the Use of Progestins
The list of side effects of progestogens should not cause clinicians to avoid the judicious use of progestins in dogs and cats. The fact that a large body of information is available on these compounds and their possible side effects allows the physician to be aware of and to monitor patients for known side effects. Nevertheless it is important to critically evaluate animals as candidates for treatment, to carefully determine and monitor doses and treatment intervals, and to educate clients in the use and misuse of these compounds. Apart from some obvious contraindications for the use of progestins in diabetic or other endocrine-disease patients or animals with a history of uterine, mammary or liver disease, the following is a list of considerations on patient selection, treatment modality and type of presenting complaint for which a progestational compound may be considered for use in dogs and cats.

Patient Selection - The ideal candidate for contraceptive progestin therapy is an adult postpuberal female in anestrus, and either intended for breeding at a later date or unlikely to be a candidate for surgical sterilization. Owners can be informed that animals not intended for breeding might best be surgically sterilized in countries where that is a routine procedure. Prepuberal females should be treated with caution when there is an indication for the use of a progestin in such animals. The risk of precipitating or exacerbating a uterine, endocrine or mammary condition (e.g., diabetes, cystic endometrial hyperplasia, pyometra and mammary hyperplasia) may be higher in younger animals since most reports have involved a young bitch or queen. If one of the above conditions is present, the administration of a long acting progestogen intramuscularly prior to evaluation and diagnosis may pose a serious health threat for the female.

It is difficult to assess the possible presence of sub-clinical CEH or the presence of microscopic mammary lesions (both of which would make bitches and queens unsuitable candidates for a progestin treatment), and females to be treated with progestins should only be healthy post-pubertal young-adult or adult individuals. For instance, animals with a history of vulvar discharge or of depression and anorexia following estrus, which may indicate presence of subclinical CEH or subclinical diabetes, respectively, should probably not be treated with progestins unless a subclinical condition can be ruled out and uterine or metabolic clinical signs can be attributed to causes other than uterine or pancreatic disease.

Animals of Reproductive Value - It is likely best to avoid using medroxyprogesterone acetate injections or any long term progestin in animals intended for breeding. Animals intended for breeding need not be contracepted for longer than necessary, i.e., no more than one or two cycle lengths in bitches (6 - 12 months) or one breeding season (5 - 10 months) in cats. Such animals should always be bred at the subsequent cycle.

Cats - One should avoid using use long-acting compounds prior to puberty in cats. Queens sometimes develop a mammary condition known as benign mammary hyperthrophy characterized by a marked increase in size of all the mammary glands without any signs of milk secretion. The condition develops generally only during the first progestational phase of the queen’s life (be it a pregnancy or a psuedopregnancy) and in the majority of cases resolves on its own. However, if the queen receives a depot progestin treatment prior to developing a mammary hyperthrophy, the mammary condition may last for a very long time and thus become a life-threatening problem. Therefore, it is advisable to confirm that cats are mature before considering progestin treatment. In prepubertal animals, it may be best to initially use a short-acting compound for 1 to 2 weeks, during which time potential side effects can be ruled out. Should side effects become evident the short-lasting progestins treatment can be discontinued. If nothing happens during the short acting progestin treatment, a long-acting drug can then be considered.

Treatment Timing, Duration, and Modality - The ideal treatment is one which is not too long, and which uses a dose that is at or below those recommended by the manufacturer or distributor. Although length of treatment has never been standardized, healthy young females can probably safely withstand 12 to 24 months of treatment. However, when adopting treatments longer than 12 months it might be considered advisable to give the female a few months break after the first year or so. Treatments longer than 24 months without interruption should probably be discouraged. Treatments longer than 12 months should especially be avoided in older animals. If such a treatment is necessary, try to give the female some rest during therapy: For instance, treat for 6 - month periods with a few weeks of rest in between, and re-evaluate uterine and endocrine status periodically. Long acting compounds should be used with caution in females of reproductive value. Perhaps a drug with reportedly less progestational action (such as proligestone) should be preferred to medroxyprogesterone acetate.
Treatment during estrus or diestrus (metestrus) should be avoided as both the endometrium and the mammary gland may be harmed by a combined presence of endogenous and exogenous progesterone in the general circulation. Therefore, the reproductive cycle should always be staged using vaginal cytology and/or serum progesterone assay to rule out diestrus.
Remember that about 30% of queens will ovulate spontaneously; therefore a progestational phase should be ruled out in queens as well before a progestin treatment is instituted. Long acting compounds should be used with caution in females of reproductive value. Perhaps a drug with reportedly less progestational action (such as proligestone) should be preferred to medroxyprogesterone acetate.

Dosages and Monitoring - Dosages higher than those prescribed by the manufacturer should not be used. When treating animals for more than six months, consider routinely conducting clinical examinations every 6 to 12 months. Clinical examinations should include: vaginal cytology; transabdominal palpation of the uterus to check for uterine enlargement; palpation of the mammary gland to check for presence of mammary nodules; and evaluation of face, skin and feet for evidence of acromegaly. Further laboratory testing to be considered for particular cases (as done for women on contraceptive steroids) would include the following target parameters: blood cell counts; routine serum chemistry including liver enzymes and coagulation profiles; and urinalysis for protein and glucose. For commonly used doses of progestins, see the section below entitled Dosage Regimens for Progestins Marketed for Contraception.

Estrus and Estrus Abnormalities - Bitches that are in late proestrus, estrus, or diestrus, should not be treated with progestins, as in each case it may result in abnormal stimulation of the reproductive tract and uterine pathology. Bitches in late proestrus may actually ovulate in response to progestin treatment and become pregnant if mated. Progestin therapy is not a good treatment for ovulation failure, prolonged estrus, prolonged proestrus, false heat, false estrus and the like. Any potential for side effects is increased greatly when administering progestin to a bitch with concurrent or recent elevations in estrogen. Likewise, treating queens immediately post-estrus could be problematic. Queens, if treated with progestin, should be in an inter-estrus period or late in seasonal anestrus for cats that demonstrate pronounced seasonality. A queen in heat presented for cycle-prevention therapy might first be given GnRH to induce ovulation. Then, 30 days later, at the end of the induced luteal phase, initiation of progestin therapy can be considered in the absence of any acute evidence of elevated estrogen concentrations.

Veterinary Progestin Formulations - When available, veterinary compounds should always be preferred to human products.

Contraindications
Do not treat females that are potentially pregnant, as this may cause fetal developmental defects especially masculinization of females, as well as delay onset of parturition, thereby causing fetal death in utero due to placental detachment.
Do not treat animals with a history of frequent or excessive vaginal discharge.
Do not treat animals with a history of uterine, mammary or liver disease.
Do not treat diabetic patients.

Non-Contraceptive Indications for use of Progestin in Dogs or Cats
In addition to its use as a contraceptive measure, progestin therapy has been used for other reproductive and non-reproductive conditions, as summarized in Table 8. The drug inserts of commercially available progestin drugs in many countries list many of theses conditions as an indication for progestin therapy, some validly and some inappropriately, as outlined in the table.


Table 10. Commonly reported drug-insert indications for the use of progestins in dogs and cats
Condition Progestin Drugs Suggested Utility and Safety
1. Estrus Suppression all drugs variable
2. Estrus Postponement all drugs yes
3. Pseudopregnancy (bitch) all drugs no
4. Aggressiveness all drugs variable
5. Male Hypersexuality all drugs variable
6. Uterine Hemorrhage most drugs no
7. Pregnancy failure few drugs variable
8. Nymphomania few drugs no
9. Psychogenic Anorexia few drugs variable
10. Urine Spraying (cat) few drugs yes
11. Skin Diseases (cat) all megestrol acetate drugs variable


Of all the reproductive indications of progestogens (indications 1 - 6) only estrus suppression and postponement, aggressiveness and male hypersexuality can be considered "safe" indications. That is, clinicians can prescribe them without fear of harming the animal provided that dosage and timing of administration are correct and that the patient has been properly selected. Indications such as uterine hemorrhage, pregnancy failure, pseudopregnancy and nymphomania can be misleading because in some cases the clinical condition could actually be worsened by the use of a progestin.

Uterine Hemorrhage - Profuse and prolonged blood vulvar discharge following parturition may occur in the bitch and is a critical problem which should either be treated with a uterine contractive drug such as ergonovine, or considered as a surgical emergency. Mild and intermittent vulvar discharge of uterine origin could 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.

Pregnancy Failure - Insufficient progesterone secretion or hypoluteoidism is a condition that has been suggested as a cause of spontaneous abortion in the bitch and queen but which has never been reported. Making a diagnosis of hypoluteoidism requires ruling out all other possible causes of pregnancy failure (infectious disease, use of exogenous drugs, as well as genetic, immunologic, environmental or nutritional factors) and confirming low (<2.0 ng/ml) serum progesterone concentrations as the only abnormality. In such a case a progestogen can be used, but it should be a short acting one such as megestrol acetate, as a long acting compound may hamper the onset of the endocrine cascade mechanism leading to parturition. The use of Ally-trenbolone to maintain pregnancy in the ovariectomized bitch has been reported [14].

Pseudopregnancy - Do not use contraceptive progestins to treat pseudopregnancy, even if that is an indication for the particular formulation. Treatment may ameliorate symptoms, but they typically return, often exacerbated, upon termination of treatment. The clinical manifestations of pseudopregnancy (milk production, adoption of inanimate object, nervousness, anorexia etc.) are caused by elevated levels of serum prolactin. The use of antiprolactinic drugs is currently considered the best choice for this condition: cabergoline (5 ug/kg/day for at least 5 days), metergoline (500 ug/kg BID) or bromocriptine (10 - 20 ug/kg BID for 5 - 8 days) should be used whenever available. Although progestogens have been used for a long period of time to treat pseudopregnancy, it is recognized that their administration, albeit temporarily effective due to the inhibition of pituitary prolactin secretion, is regularly followed by recurrence of symptoms once treatment is discontinued. This is due to a positive effect that lowering progesterone or progestin concentrations has on prolactin release from the pituitary. A prolonged series of progestogen treatment courses may cause the pseudopregnancy condition to become chronic. The use of androgenic steroids such as mibolerone has not been associated with recurrence of the condition upon withdrawal.

Lactation - It is not appropriate to treat with progestin to prevent fertility during lactation. The contraceptive effect of treatment will extend to a later date when treating later in anestrus. There is no need for contraceptive efficacy during lactation in bitches. Furthermore, progestin will reduce or suppress lactation and thus compromise neonate survival. Queens may experience a post-partum or lactation estrus before kittens are weaned, but typically they do not, and lactation suppression would be a concern. Likewise, progestins should not be used to suppress lactation in post-partum bitches.

Nymphomania - The use of progestins in a bitch or a queen with a presenting complaint of prolonged heat should be cautiously evaluated. A presenting complaint of prolonged signs of behavioral heat may be due to a follicular cyst, a polycystic ovarian disease or an ovarian granulosa cell tumor. In all of the above clinical problems ovariectomy or gonadotropin releasing hormone (GnRH) are the treatments of choice. However, while females with a follicular cyst may benefit from possibly a progestin treatment, it has not been documented. Further, such a therapy may be harmful in case of a granulosa cell tumor or of a polycystic ovary, by allowing the condition to persist and synergizing with elevated estrogen to cause uterine disease. Therefore, the use of progestins for the presenting complaint of prolonged heat in the bitch or queen should be carefully considered only once a polycystic ovary or a granulosa cell tumor have been ruled out and alternative therapies have been considered as well.

Dosage Regimens for Progestins Marketed for Contraception
Suggested dosages of progestogens in bitches and queens may vary based on type of patient, its reproductive status and the desired clinical effect. Clinicians should be very careful in extrapolating dosages from one species to another. Also, the quality of scientific and clinical information found on drug inserts tends to be very variable. The senior author has critically reviewed the drug inserts of all drugs available in Italy based on medroxyprogesterone acetate, megestrol acetate and proligestone, and found discrepancies among the dosage regimens suggested companies and what is found in the literature or suggested by other companies for the same generic drug. Therefore, rather than rely entirely and blindly on drug inserts, clinicians should compare suggested doses with the most current scientific literature and other suggestions for dosing the same generic compound. The following information on suggested dosages for medroxyprogesterone, megestrol acetate and proligestone is derived from a critical review of the literature combined and information gained from clinical experience.

Medroxyprogesterone Acetate - In the dog, an IM dosage of 10 mg/kg every 3 months may cause acromegaly in a few cases [36], while the same dosage repeated every 3 weeks will cause acromegaly and diabetes mellitus in all treated animals [37]. GH secretion is so reliably induced following administration of a high dose of MAP that this drug can be used for the treatment of pituitary dwarfism in the dog [28] using a subcutaneous dose of 2.5 - 5.0 mg/kg at a 3-week interval followed by a 6-week interval. Therefore, the suggested dosage for the canine is 2.5 - 3.0 mg/kg IM every 5 months, while it is 2.0 mg/kg IM every 5 months for the feline [19,20].
Unfortunately, the drug insert of at least one MPA-based product commercially available in Italy indicates a single dose of 50 mg IM as adequate for bitches up to 45 kg as well as for queens. Such a treatment regime can be considered safe for example for a 25 kg bitch (as it corresponds to a dose of 2.0 mg/kg) as well as safe or even too low for a 45 kg bitch (as it corresponds to a dose of 1.1 mg/kg); but it could be potentially dangerous in a 5 kg bitch or in a queen, as it would correspond to a 10 mg/kg dose. Although such a treatment for prolonged postponement of estrus is generally administered once every 5 - 6 months, such a high dose might predispose a healthy female to develop one or more of the side effects (see over), or might exacerbate a pre-existing, subclinical condition (i.e., diabetes mellitus, cystic endometrial hyperplasia) into a clinically evident condition.
The drug insert of another product commercially available in Italy advices using dosages of 25 - 50 mg IM for bitches up to 15 kg or of 20 - 50 mg IM for queens. While 50 mg of an MPA-based drug for a 15 kg bitch corresponds to a dose of 3.3 mg/kg is only slightly higher than the ideal dosage of 2.5 - 3.0 mg/kg, the 50 mg dose for a queen could be equivalent to inappropriately high dosing with 6.25 to 12.5 mg/kg, in queens of 8 or 4 kg body weight, respectively.

Megestrol Acetate - In the queen, a single dose of 5.0 mg/day for 8 consecutive days cause can diabetes mellitus [31], while the same dose repeated every other day for 3 weeks does not cause diabetes mellitus [30]. Therefore, a safe dosage might be < 5.0 mg administered every other day, or less frequents, for < 3 weeks. A typical dose regimen suggested for queens in anestrus is 5 mg/cat once every 2 weeks or 2.5 mg/cat/week, while a typical dose regimen suggested for queens in proestrus is 5 mg/cat/day for 4 days, then 5 mg once every 2 weeks. An indicated dosage of 2.5 mg/cat/day for 60 days, as provided in the insert of an MA-product commercially available in Italy, could potentially be very dangerous because of the risk of developing diabetes, acromegaly and cystic endometrial hyperplasia. Dosing on a body weight basis would be preferred to dosing on a per animal basis, but reliable data are not available. Undoubtedly, if 2.5 mg/cat/day is sufficient for a 6 kg cat, then less than half that dose would suffice for a 2 kg cat.

In the bitch, a dose of MA of 2.0 mg/kg/day for 2 weeks will cause adrenocortical suppression [43]. Therefore, a safe dosage would be < 2.0 mg/kg/day administered for < 2 weeks in proestrus, or < 2.0 mg/kg/day administered for a longer duration of time in anestrus. A typical suggested dosage for estrus suppression is 2.0 mg/kg/day for 8 consecutive days, while a typical dosage for temporary postponement is 0.5 mg/kg/day for 32 days in late anestrus. A single dose of 2.0 mg/kg can be used in anestrus, but its efficacy could be questioned because the postponement effect would be observed only if the single treatment was administered during the last week of anestrus. Because MA is metabolized quickly by the liver the effect of a single injection is likely to last no longer than 1 week. Unless the clinician is absolutely sure that the bitch has entered her last week of anestrus (something which in the authors' experience can never be taken for granted), it would be wiser to opt for a longer duration of treatment with a lower dose.

Proligestone - In the dog, a dose of 50 mg/kg SC, every 3 weeks will cause long-lasting acromegaly, diabetes mellitus and adrenocortical suppression [38]. Administration sequentially at intervals of 3, 4, 5, 5 and 5 months presumably does not promote drug accumulation. Recommended doses appear to be the same in all products, as they come from the same company. As described in Table 7, the recommendation in case of breakthrough heat is to decrease the dosing interval by 1 month. This seems appropriate if the break through heat occurs more than 3 months after injection. If the break through heat occurs earlier, the completeness or dosage of the preceding injection should be questioned. Re-administration earlier than 2 months after the preceding injection should be considered carefully, since frequent administration has been reported to result in acromegaly in dogs [38]. In the queen, the protocol indicated in drug inserts is 100 mg/kg SC at sequential intervals of 3, 4 and 5 months, and at intervals of 5 months thereafter.



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Nonsurgical contraceptive measures

Postby guest » Sat Jun 11, 2005 6:20 pm

Contraception in Dogs and Cats
World Small Animal Veterinary Association World Congress Proceedings, 2004
Patrick W. Concannon, MS, PhD, DACT (Hon)
Dept. Biomedical Science, College of Veterinary Medicine, Cornell University
Ithaca, NY, USA

INTRODUCTION

Nonsurgical contraceptive measures include permanent or temporary pharmaco-castration of males, reversible and nonreversible estrus prevention in females, estrus suppression in females, and pregnancy prevention or termination after unwanted mating. As for females, no new products for estrus prevention or suppression have been introduced in the last decade, other than revised formulations and new brands of progestins previously marketed. In fact, contraceptive options in bitches have decreased in some countries with the recent withdrawal of the androgen mibolerone (Cheque Drops©) as an estrus preventative. However, an implant product providing down-regulating amounts of a potent GnRH-agonist has recently been approved as male dog contraception in New Zealand and Australia, and efforts are underway to obtain approval as a contraceptive in bitches as well, as well as application to cats. Depending on price and regulatory hurdles, the product is likely to become available in many countries in the next decade. There are significant advances in protocols and products available for termination of unwanted pregnancies, including extra-label uses of prostaglandin, of PG analogs, of dopamine agonists, and of dexamethasone in selected situations; additionally, the anti-progestin aglepristone is approved and sold with an indication of pregnancy termination in some countries. The goal of non-surgical contraception in males has advanced on two fronts: the above-mentioned GnRH-agonist implant technology, and a new product that provides testis-necrosing doses of a metallic salt injected directly into the testes.

PROGESTINS

Progestin administration remains the widest available method of cycle prevention in dogs. They are marketed with an indication for use in female dogs, and in some countries there may be an indication or suggested doses for use in cats. In all cases, progestin administration is intended to produce an artificial luteal phase (i.e., circulating progestin mimicking the normal post-estrus profile of progesterone); during this period a new ovarian cycle will not occur and following it a normal anestrus period is reinitiated. The progestin acts at the hypothalamic-pituitary level, primarily preventing increases in GnRH (and thus gonadotrophin) secretion that would otherwise occur as the stimulus for the next follicular phase and proestrus. Oral formulations are given daily; depot-injectable formulations, by single injections; extended therapy in either instance is by repeating the treatment at 2-5 month intervals, based on manufacturers recommendations. Generic progestin formulations marketed under various brand names in different countries include oral megestrol acetate, depot-injectable medroxy-progesterone acetate (MPA), oral MPA, depot-injectable proligestone, and others. The number of trade names under which each is marketed is large and expanding as these compounds go off patent and are produced as new brand names of the generic drug, often with the progestin identified only by a chemical name that is not typically used but is scientifically synonymous with the more commonly used chemical or generic name. MPA can validly be identified by any one 16 synonymous chemical formulas (e.g., 6-alpha-methyl-4-pregnene-3, 20-dion-17-alphaol acetate; 17-alpha-Acetoxy-6-alphamethylpregn-4-ene-3,20-dione) and an additional 14 generic drug names (e.g., MPA, mespirenone, NSC-26386, farlutin), in addition to 12 or more product brand names (e.g., Promone, Depo-promone, Perlutex, Repromap, Supprestal, Gestovex, etc). The situation is just as complex with megestrol acetate, as it has over 40 different chemical, generic, and trade names, and the number of brand names continues to increase as generic drug companies produce their own brands of same formulations. Unfortunately, doses and treatment protocols vary among manufactures, often markedly and incorrectly, and caution should be exercised because of the modest margin of safety as regards known side effects.

Side effects

There is likely no universally safe and effective dose of any of the progestins in either dogs or cats. In both species, effective dose can in some individuals result in uterine disease or diabetic-like symptoms. In dogs, reported possible side effects seen with recommended doses but more often with higher than recommended doses include mammary hyperplasia and mammary tumors, elevated Growth hormone and acromegalic changes, diabetes, adrenocortical suppression, masculinization of female fetuses, local skin reactions, and behavior changes including increased appetite with weight gain. Nevertheless, many bitches tolerate recommended doses well, without side effects. Of primary concern is the potential to cause cystic endometrial hyperplasia and resulting pyometra, especially if the dose is excessive and/or administered in late proestrus, estrus or the luteal phase, where interaction with a prior elevation in estrogen can magnify potential effects on the uterus. Administration in dogs should be limited to confirmed anestrus or very early proestrus. The latter should be confirmed by vaginal cytology as owners often recognize proestrus too late for safe or even effective administration. Administration late in proestrus can result in induction of a fertile ovulation rather than suppress the impending ovulation. In cats, spontaneous ovulations can occur, and the hormonal and cycle status of the queen should be confirmed before initiation of treatment. Contra-indications include pregnancy, and any history of reproductive tract, mammary or liver disease.

Megestrol acetate

In North America the only drug so marketed is Ovaban, 5 and 20 mg tablets, by prescription only, for use in dogs only, not more than successive cycles of use, not before or during first estrus cycle (i.e., pubertal proestrus), for postponement of estrus; administration in anestrus, at 0.25 mg/lb body weight per day for 32 days administered orally, intact, or crushed and mixed with food; administration in proestrus at 1 mg/lb per day for 8 days-administered orally, intact, or crushed and mixed with food. There is no indication for use in cats. The nearly-or quasi-equivalent metric doses and protocols for dogs, and those usually but not always recommended in European products are, for anestrus, 0.5 mg/kg/day for 32 days or 40 days, and for proestrus, 2.0 mg/kg/day for 8 consecutive days. In some countries there are products with an indication for use in prepubertal bitches and during pubertal proestrus; likewise, there may be indications for use in cats at doses of 5 mg/cat every 2 weeks or 2.5 mg/cat per week, or 5 mg/cat/ day for 4 days, then 5 mg once every 2 weeks It has been suggested that dosing in cats, as in dogs, if considered, should incorporate a dose per unit body weight, such as 0.5-1 mg/kg or less, assuming previously recommended dose would be sufficient for 5 kg or larger cats; dosing by body weight might limit the occurrence of side effect sin smaller cats. Dose response studies for cats have not been published. Where oral MPA is marketed, there are similar anestrus and proestrus protocols, with recommended doses that have not been subjected to dose-response studies that have been published.

Depot-MPA

Greater caution should be exercised with depot injectable progestins, as the treatment cannot be quickly discontinued in the event of overdosing or idiosyncratic occurrences of side effects. Conservative does are on the order of 2.5-3 mg/kg every 5-6 mos. in dogs, and 2-mg/kg/5 mo. in cats. Animals should be monitored for potentially debilitating side effects. Anecdotal reports suggest that experiences with proligestone are not very different from those with MPA, including the potential for undesirable reproductive and metabolic side effects. The typical product, i.e., Covina© or Delvosteron© Intervet 100 mg/ml is recommended by the manufacturer to be administered at doses of 10 to 33 mg/kg, given to bitches at 0, 3 and 7 months of treatment, and subsequently at 5-month intervals.

Progestin implants

In zoo-maintained exotic carnivores silastic implants of melengestrol acetate were used for many years but resulting uterine disease has reduced interest in their use. In dogs and cats, implants of progesterone, androgen and synthetic progestins have been shown capable of providing cessation of cycles, but studies of safety have been limited. One concern is whether the implants can provide steady state release with first order kinetics as opposed to burst release in the initial weeks. Implants of levo-norgestrel (Norplant) marketed for human sue, as well as equivalent implants made with generic levonorgestrel have been show to have a contraceptive efficacy in female cats but not dogs at doses that were multiples of the human dose on a body weight basis. Recently, silastic implants of a new design and containing a synthetic progestin have been reported to have first-order release kinetics when placed subcutaneous in dogs or cats and to provide safe and effective estrus cycle prevention for at least 2 years, without side effects. (Verstegen et al., 2004; Verstegen, personal communication).

ANDROGENS

Mibolerone is no longer marketed in the U.S. Performing dogs and working dogs are often subjected to high doses of synthetic androgens or testosterone esters are a mode of contraception, notwithstanding the potential anabolic effects that may accompany treatment. Clinicians should be aware of such drug abuse in dealing with animals with signs of masculinization, elevate hematocrits, adrenal suppression, and persistent anestrus.

GNRH AGONISTS

Available data suggest that 3 and possibly 4 different GnRH agonists have been shown to suppress gonadal activity in both male and female doges, to have a high margin of safety, to be fully reversible whether administered in adults or beginning prior puberty. The drugs are all decapeptides that represent modifications of the natural GnRH via substitution of one or more natural or synthetic amino acids resulting in potencies 100-200x that of GnRH. Formulation and marking of a commercial product involves or will involve implants to be placed s.c. via a needle/trochar, and which will release effective systemic concentrations for 6 mo. to one year or more. The agonists, when administered continuously, act by causing a protracted down-regulation of the GnRH receptors on gonadotrophin-secreting cells of the pituitary, following a brief period of up-regulation that causes a transient increase in LH and FSH (an effect sufficient to induce estrus in anestrus bitches). The resulting chronic suppression of LH and FSH concentrators results in suppression of gonadal hormone secretion and gametogenesis--a chemo-castration effect in males and a protracted anestrus in females, in each case reversible. Peptic, Australia has gained approval of sale of its implants of the GnRH analog deslorelin analog by the relevant authorities in Australia and New Zealand under the name Suprelorin©. The registered product claims efficacy for at least 6 months in 98% of male dogs as contraception, and use a treatment for benign prostatic hyperplasia (BPH) and as and as an aid in the control of unacceptable behavior. The expectation is to produce an implant with an efficacy per implant that last for one year, and to gain approval for the product being indicated for use as a cycle-preventing contraceptive in female dogs.

One caveat in using GnRH agonists in females is the concern of inducing a fertile estrus at the start of the treatment period, which is a typical response unless the animals are less than 3-5 months of age or have elevated progesterone concentrations (i.e., are within 1 month of a prior estrus or are pretreated with a progestin). Intervet researchers have reported on a formulation of an GnRH-agonist that is a modification of the human drug nafarelin, and the azaglynafarelin is formulated in a controlled release device, Gonazon-CR©. It safely and efficiently prevented puberty in female dogs throughout the treatment period of 1 year beginning at 4-5 months of age. Prevention of puberty did not appear to affect body weight or growth compared to controls in the study. The potential for this product to also come to the veterinary market also seems very promising.

TESTIS-NECROSING INJECTIONS

In the U.S. the FDA has approved the product Neutersol© (Addison Biological Laboratories) developed by Technology Transfer, Inc. The injectable solution contains 13.1 mg/ml zinc as zinc gluconate that is neutralized to pH 7.0 with L-arginine. The indication is for intra-testicular injection to produce sterilization in 3-10 month old male dogs, the volume injected into each testicle being based on testicular width as determined by measuring each testicle at its widest point using a metric caliper. More than 99.5% of animals studied became sterile, but testosterone levels we only reduced by approximately 50%. Marketing is to both private practices and to animal welfare faculties with an interest in reducing the per overpopulation problem in the U.S. The claim is that by using fine needle injections, the procedure is tolerated by dogs without sedation, and that the side effects are usually minor. Local reactions included the expected testicular swelling, and in some cases pain with biting and licking at the scrotum, swelling of the prepuce and irritation, ulceration, and/or infection of the scrotum. Systemic reactions included an increase in the white blood cell count, vomiting, anorexia, lethargy and diarrhea. Withdrawal of food for 12 h pre injection is suggested. Scrotal swelling without pain may persist for a few months.

CURRENT RESEARCH: NEW MODES OF CONTRACEPTION

These include reports of several promising approaches intended to interfere with GnRH action, with function of pituitary gonadotrope cells responsible for secretion of LH and FSH, or with the action of LH on the ovary. Such approaches include presentation of GnRH or GnRH-like peptide multimers and/or protein conjugates as vaccines in protocols using new and more readily acceptable, less irritating adjuvants; delivery of a GnRH-vaccine expressed by modified virus; administrations of GnRH-peptides with GnRH or GnRH-agonist linked to a cytotoxin and/or membrane-active lytic peptide, intended to result in gonadotrope cell uptake of the cytotoxin and cell destruction; and use of a vaccine for immunization against bovine LH-receptor presented via silastic implants and serial booster injections, intended to prevent ovarian cells from responding properly to endogenous LH. Additional vaccine approaches include myriad proposed methods for immunization against the peri-oocyte zona pellucida proteins, especially ZP3, using as immunogen either a purified ZP protein or crude ZP preparation with one of many proposed acceptable but potentially sufficiently effective adjuvant or carrier system,

PREGNANCY TERMINATION AND PREVENTION: EXTRA-LABEL DRUG USE

Many of the protocols involve the extra label use of drugs marketed for use in other species, or for other indication in small animals, ideally along with ultrasound to confirm efficacy. These include natural prostaglandin F2a (PGF) at doses of 20-100 ug/kg, i.m. or sac., at a minimum of 2 times per day, to effect, and, various PGF-analogs marketed for use in large animals (e.g., Cloprostenol injections every 2 days, to effect), given after confirmation of pregnancy in dogs. Higher doses required in cats have been less well studied. Likewise, dopamine agonists including cabergoline marketed in some countries for suppression of lactation; given orally daily after day 30 (and to effect) in prolactin-suppressing doses will cause luteolysis and terminate pregnancy. In dogs, immunosuppressive oral doses of dexamethasone () given for 10 days will terminate pregnancy probably by mimicking mechanisms similar to those that occur naturally at parturition, and may be justified in certain locales and circumstances; the induced adrenal suppression is reversed immediately upon withdrawal. Recently, combination therapies of PGF or PGF-analog in conjunction with a dopamine agonist (cabergoline or bromocriptine) were show to have high efficacy and the potential to utilize lower amounts of the drugs and minimize side effect. These protocols have been reviewed in detail (Wanke et al, 2002, www.ivis.org).

ANTI-PROGESTIN: AGLEPRISTONE

The progesterone receptor antagonist aglepristone is currently marketed in a limited number of countries in Europe and South America, e.g., Alazine ©, Virbac France, 30 mg/ml, with an indication for termination of pregnancy any time after mating. Doses of 10 mg/kg administered twice, with an interval of 24 h, have been reported to terminate pregnancy given en at day 15, 30 or 34 of pregnancy. The protocol and findings have been reviewed in detail (Fieni et al, 2001, www.ivis.org)

References

1. Baldwin CJ, Peter AT, Bosu WT, Dubielzig RR.. Lab Anim Sci 1994 Jun;44(3):261-9. The contraceptive effects of levonorgestrel in the domestic cat.

2. Concannon, P.W. (1995). Contraception in the dog. In: The Veterinary Annual, No. 35, Blackwell Scientific, Oxford, 35: 177-187.

3. Concannon, P., England, G., Verstegen, J., Farstad, W. and Linde-Forsberg, C. and Doberska, C. (Eds.) Advances in Dog, Cats and Exotic Carnivore Reproduction. Proc. Third International Symposium Canine and Feline Reproduction. J. Reprod. Fert. Suppl. 57. Journal of Reproduction and Fertility, Cambridge., 2001.

4. Concannon, P. 2002. Ovarian cycle suppression in dogs and cats. In: Kirk's Current Veterinary Therapy, Vol. 15 (Bonagura, J. eds), W.B. Saunders, Philadelphia.

5. England, G (1998) Pharmacological control of reproduction in the bitch. Ch. 16 in Manual of small animal reproduction and neonatology. G. Simpson, G E England, M J Harvey (Eds) Brit. Sm Anim Vet Assn., Birmingham. Pages 198-218

6. Griffin, B., Boyle, S., Jochle, W. , and Baker, H. Summaries. International Symposium on Nonsurgical Methods for Pet Population Control, April 19-21, 2002 , Callaway Gardens, Pine Mountain, Georgia.

7. Romagnoli, S. and Concannon, P. 2003. Clinical use progestins in bitches and queens: A review. In: Recent Advances in Small Animal Reproduction (Concannon, P., England, G., Verstegen, J., Linde-Forsberg, C., Eds). International Veterinary Information Service (www.ivis.org)

8. Verstegen , J. (Ed.) 2004. Program Book, 5th Symposium Canine Feline Reproduction, Embu das Artes, Sao Paulo, Brazil.

9. Wanke, M., Loza, M., Monachesi, N. and Concannon, P. (1997). Clinical use of dexamethasone for termination of unwanted pregnancy in dogs. J. Reprod. Fert., Suppl. 51: 233-238.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)
Patrick W. Concannon, MS, PhD, DACT (Hon)
Dept. Biomedical Science, College of Veterinary Medicine
Cornell University
Ithaca, NY

Speaker Information:
Dr. Concannon's current positions: (1) Visiting Fellow and Emeritus Faculty, Dept. of Clinical Sciences and Dept. of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca NY 14853.(2) Visiting Lecturer, University of Florida, Gainesville, FL. (3). President and Chairman, International Veterinary Information Service. He obtained his B.S. Biology, Boston College, Massachusetts, 1963; M.S. Biology, Northeastern University, Boston, Massachusetts, 1965; Ph.D. Animal Physiology (Reproduction), Cornell University, Ithaca NY 1971. He has been Chairman, International Symposium on Canine and Feline Reproduction 1988, 1992, 1996, 2000, 2004. Lecturer in Human Physiology, Animal Physiology, Veterinary Endocrinology and Theriogenology, College of Veterinary Medicine and Division of Biological Sciences, Cornell University. External thesis reviewer (U. Liege, Belgium; Swedish National University, Uppsala, Sweden; U. Pretoria, So. Africa). Also Invited lecturer WSAVA, SCIVAC (Italy), EVSSAR, ACT. He has published over 130 publications (excluding abstracts) dealing with reproductive regulatory mechanisms, endocrinology and pathology, and editor or co-editor of several books, including the Proceedings of the International Symposium on Canine and Feline Reproduction.
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Oral contraception for female dogs to prevent ovulation

Postby animalady » Fri Sep 29, 2006 5:53 am

I have a some questions I would dearly like answered, if anyone can help. I live in Turkey, where the general standards of animal care/welfare/medical treatment is generally appalling. Apart from being instigational in starting up a charity to help organise a neuter and release programme in the resort where I live, and being on the committee of same, and extremely active, I also have 4 rescued dogs of my own. My oldest is now 5 years of age, and was spayed after her first season, at about 10 months of age. She was spayed using the 'old technique' here which involved removal of uterus and one ovary, leaving one ovary intact to allow her to come into season as this was deemed 'heathier'. After 4 years of putting up with packs of male dogs around my home every 5 months or so, I decided to investigate the possibilty of her having a second op to remove the other ovary. Having virtually forced the local council vet to perform not only mid-belly incisions (rather than the side cuts as previously performed), but also to perform full operations, involving the uterus and both ovaries, for all the street dogs we are neutering, I thought I could have this done to my Toffee. However, all three of the vets in my town said this would be dangerous as it would involve a very large cut, and it was finally suggested that I put her on Perlutex, which I have read in this fascinating forum, is an MPA. However, it is only available in tablet form and she is on a dosage of 1 tablet every week at the same time. I want to check if this is healthy, safe and correct for her, but only seem to be able to find information re dosages on the injectable form. She is about 25-30kg in weight, has been on the tablets now for about 4 months and has put on weight even though I do not feed her any more that before, and has become a little lethargic. Not as in depressed-lethargic, but lying around more, and not running as frantically and energetically as she has for over 4 years. I would also like to know if it is possible to acquire Covinan (proligestone) injectable here in Turkey, either as a vet or as an individual, as this has been recommended as having less side effects. My vet says no, but I find this hard to believe, especially that even a vet cannot get it!
I would appreciate any answers with any information at all about this subject or any suggestions, better ideas, recommendations.
animalady
 
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Joined: Fri Sep 29, 2006 5:15 am
Location: Altinkum, Turkey


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