Introduction

Reproduction in the canine is unique among all those of our domestic animals in that pregnancy makes no difference in:

 Duration of reproductive cycle stages

 Values of serum estradiol and progesterone concentrations

 Development of the mammary gland.

From a practical standpoint, in the individual bitch the length of pregnancy and the length of non-pregnant diestrus are not distinguishable, and also serum estradiol and progesterone concentrations do not show any appreciable difference in individual animals during this phase, although difference in hormonal values may be observed when comparing data coming from large groups of pregnant and non-pregnant-diestrus bitches. This normal physiological pattern is sometimes a source of confusion in owners who may misinterpret clinical signs in their bitch thinking, for instance, that she is pregnant when she is not. In the bitch, the condition characterized by the presence of signs of pregnancy in a non pregnant animal is defined pseudopregnancy, or false pregnancy or pseudocyesis. The condition is also referred to as false lactation or nervous lactation as it is often accompanied by milk production, albeit in very low quantities and not always from all mammary glands (mostly from the inguinal and abdominal mammary glands).

Etiology

Although it has long been established that canine prolactin (PRL) plays a key role in the development of pseudopregnancy, the precise mode of action of this hormone is still not clear. The condition typically becomes manifest at times of high PRL concentration, such as when there is a decrease in serum progesterone (at the end of pregnancy or at the end of diestrus) or when exogenous PRL is administered (Lyons et al., 1933). Furthermore, antiprolactinic agents constitute a very successful way to treat pseudopregnant bitches (Jochle et al., 1989; Harvey et al., 1997; 1999). PRL is an important luteotrophic factor in the bitch (Concannon, 1980; Okkens et al., 1990) whose increase during the second half of pregnancy is important also for stimulating mammary growth and preparing for milk secretion. Because of this physiological role during pregnancy, and since PRL secretion normally occurs also in non-pregnant bitches, pseudopregnancy should be considered a normal phenomenon. This is further confirmed by the observation that in most bitches pseudopregnancy undergoes spontaneous remission. Despite such a clear link between PRL and pseudopregnancy, only a few studies have observed a higher concentration of serum PRL in bitches with overt clinical signs of false pregnancy as opposed to bitches with no signs (Olschewiski, 1987, Okkens et al., 1997), while in many other reports PRL has never been different between bitches with and without the condition (see Gobello et al., 2001 for a review). As a consequence, PRL concentration cannot be used to confirm the diagnosis and/or discriminate between bitches needing or not needing a treatment. PRL is the most important hormone to control maternal behaviour, mammary growth and milk secretion; however, there is some evidence that estrogens (Hadley, 1975; Olschewiski, 1987) and growth hormone (Graf and Entrebay, 1979) may also play a role in initiating and/or strengthening clinical signs in pseudopregnant bitches. Recently, pseudopregnancy was found to have an incidence on the frequency of mammary neoplasia. The chance to develop a mammary tumour increases with the number of pseudopregnancies and the age of the bitches (Donnay et al. 1994). Bitches with pseudopregnancies appear to have a higher risk to develop mammary tumours and this risk increased with the incidence of pseudopregnancies (Table 1).

Clinical Signs

Pseudopregnancy is a syndrome characterized by one or more the following signs:

 Development of mammary glands with secretion of minute quantities of milk

 Licking behavior: the bitch licks her abdomen, sometimes even suckles on herself

 Maternal behaviour: nest building, adoption of inanimate objects (dolls, small toys, shoes etc.) as if they were puppies

 Ancillary signs such as various degrees of nervousness, mild anorexia, poor performance in sport or working dogs, polyuria/polydipsia, polyphagia, diarrhea, aggressiveness

Table 1. Odds ratio for the risk of mammary tumours development related to the frequency of pseudopregnancies (from Donnay et al. 1994).

In this study, bitches with > 3 episodes of pseudopregnancy in their lifetime had a higher risk of developing mammary tumors. Despite the clinical significance of this interesting report, more research is needed on this topic before definitive conclusions can be made.

Development of mammary glands is normal during diestrus, and unless it is accompanied by milk secretion it should not be a cause of concern or a reason for treatment. However, owners should be instructed that when milk secretion appears the bitch should be watched closely as this is often a threshold for initiating a treatment, especially if milk secretion is accompanied by behavioural signs.

Treatment

Mild cases should be given a few days of close observation before a treatment is instituted, as spontaneous remission is not uncommon especially if the bitch does not lick or suckle on herself. Stimuli for lactation such as licking, milking and the use of cold and hot packing should be avoided. A light fasting regimen for a few days may be of help, especially if the bitch's appetite is unchanged or increased during the condition; water deprivation may also be indicated, although many perceive it as non ethical, and renal function should be checked prior to instituting any water regimen. Treatment is a must whenever licking or maternal behaviour are displayed, as well as when other ancillary signs are present. Pharmacological agents used to treat pseudopregnancy in bitches include dopamine agonists and serotonin antagonists. 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. Ergot alkaloids such as bromocriptine or cabergoline have a strong dopamine D2-receptor agonist activity, and thus can reduce prolactin secretion. The serotonin antagonist metergoline stimulates endogenous dopamine secretion and thus can inhibit prolactin secretion via an indirect mechanism.

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. Bromocriptine 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, bromocriptine should be administered orally at least twice a day at doses of 10-50 mcg/kg (Figure 1). Its lack of specificity leads to side effects on the cardiorespiratory system, causing hypotension due to vasodilatation (adrenergic type effect), or emesis (the most common side effects, especially at doses > 20 mcg/kg) due to stimulation of the chemoreceptive trigger zone. Attempts to improve side effects by gradually increasing an initially low dose, or by pre-treating with an anti-emetic drug have proved only partially effective. Among the antiemetic drugs, metoclopramide should be avoided as it may cause PRL release in the dog. Although its effectiveness has never been questioned, bromocriptine is not approved in most countries as an anti-PRL in small animals and its extra-label use has not caught on, in spite of its world-wide availability as a human drug.

In the bitch, the anti-lactogenic 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 in most bitches. Occasional failures can be dealt with by repeating the treatment protocol and extending it to 8 to 10 days, and also by using joint protocols of cabergoli+metergoline or cabergoline+bromocriptine (see Table 2 for dosages).

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 (England, 1998). Therefore, progestogens should not be used as a treatment for false pregnancy.

Figure 1. Overtime changes in plasma prolactin concentrations after one administration (oral) of 25 , 200 and 5 µg/kg of Bromocriptine, Metergoline and Cabergoline, respectively.

A clear and significant effect of the 3 drugs is observed after 1.5, 4 and 4 hours for Bromocriptine, Metergoline and Cabergoline, respectively. The maximum of effect is observed after 4 hours for Bromocriptine and lasts for ± 2 hours before a return to normal values, for Metergoline the maximum of effect is detected after 4 hours and lasted for 2 hours, for Cabergoline the maximum of prolactin inhibitory effect is observed after 6-8 hours but remained present for up to 48 hours after the administration (Verstegen, Onclin and Romagnoli, 2000).

Oral cabergoline and metergoline formulations are commonly available in Europe. An injectable formulation of cabergoline was recently introduce in the Italian market (Galastop iniettabile^TM, Ceva-Vetem). When administered at the dose of 1.5 µg kg, injectable cabergoline is effective in reducing the circulating PRL concentration in lactating bitches, with mean PRL values showing an average reduction of 50% with respect to the placebo period 3 days after the administration, and PRL concentration remaining significantly low for 60 hours post-injection.

Complications

Albeit rare, mastitis and mammary dermatitis have been observed to occur in pseudopregnant bitches. A role of pseudopregnancy in increasing the risk of development of mammary tumors has been hypothesized for the dog (Donnay et al., 1994; Verstegen, 1999). Although more research is needed on this issue, the gravity of the potential outcome (neoplasia of the mammary gland) and the ease with which overt pseudopregnancy can be treated early in the course of the syndrome, should induce small animal clinicians to be inclined to treat pseudopregnant bitches rather than waiting for the condition to disappear.

References

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2.  England G. Complications of treating presumed pseudopregnancy in pregnant bitches. Vet Rec 142:369-371, 1998

3.  Gobello C, Scaglia H, Colombani M, de la Sota L, Goya RG. Characterization of prolactin molecular variants in pseudopregnant bitches. In: Forsberg M, Greve T, Gustafsson H, Katile T, Kinqahl H, Ropstad E (eds): Proceedings 14th Int Congress Animal Reprod, Stockholm, Sweden; Elsevier, Stockholm, abstract pag 117

4.  Graf K, Entrabay K. Endocrinology of reproduction in the female Beagle dog and its significance in mammary gland tumorigenesis. Acta Endocrinological 90, Suppl 222: 1-33, 1979

5.  Jochle W, Arbeiter K, Post K, Ballabio R, D'ver AS. Effects on pseudopregnancy, pregnancy and interoestrus interval of pharmacological suppression of prolactin secretion in female dogs and cats. Journal of Reproduction and Fertility, 1989, Supplement 39, 199-207.

6.  Hadley JC. Unconjugated oestrogen and progesterone concentrations in the blood of bitches with false pregnancy and pyometra. Vet Rec 96:545-547, 1975

7.  Harvey MA, Cauvin A, Dale M, Lindley S, Ballabio R. Effect and mechanism of the antiprolactin drug cabergoline on pseudopregnancy in the bitch. JSAP 38:336-339, 1997

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10. Lyons WR, Chaikoff IL, Reichert FL. Proceedings of the Society for Experimental Biology and Medicine 31:303, 1933

11. Okkens AC, Bevers MM, Dieleman SJ, Willemse AH. Evidence for prolactin as the main luteotrophic factor in the cyclic dog. The Veterinary Quarterly, 1990, 12, 193-201.

12. Okkens AC, Dieleman S, Kooistra HS, Bevers M. Plasma concentrations of prolactin in overtly pseudopregnant Afghan hounds and the effect of metergoline. J Reprod Fertil Suppl 51:295-301, 1997

13. Olschewski C. Die lactation falsa der Hunden: Klinische und hormonanalytische Untersuchungen unter besonderer Berucksichtigung einiger Therapieverfahren. Inaugural Dissertation, Justus-Liebig University Giessen, 1987

14. Romagnoli S, Stelletta C, Milani C, Gelli D, Falomo ME, Mollo. Effect of an injectable cabergoline formulation on serum prolactin (PRL) and milk secretion in early postpartum Beagle bitches. Reproduction in Domestic Animals, accepted for publication 2009

15. Verstegen JP. Interet et applications des antiprolactiniques en la cancerologie chez la cheinne. Proceedings 24th WSAVA congress, Lyon, France, 1999

16. Verstegen JP, Onclin K, Romagnoli S. Prolattina: funzioni fisiologiche dell'ormone ed applicazioni cliniche dell'impiego degli antiprolattinici in cagna e gatta. Rivista di Zootecnia e Veterinaria 28 (1): 3-18, 2000