Investigations on the role of progesterone in the endocrine control of overt pseudopregnancy in the bitch: Application of an antigestagen and effects on corpus luteum function

doi:10.1016/0378-4320(94)90043-4

Animal Reproduction Science

Volume 35, Issues 3–4, May 1994, Pages 281-289

https://doi.org/10.1016/0378-4320(94)90043-4 Get rights and content

Abstract

To test the role of progesterone in the onset and maintenance of overt pseudopregnancy, three groups of dogs were treated with the antigestagen Mifepristone (RU 38486, dose: 2 mg kg⁻¹ body weight) commencing on Days 23.6± 1.9 (Group 1, n=5), 35.0± 1.2 (Group 2, n=5) and 42.8±3.5 (Group 3, n = 6) after onset of pro-oestrous bleeding. In all three groups, onset of overt pseudopregnancy occurred earlier in the treatment than in the control cycle (P<0.01 − P<0.05), clinical symptoms were significantly less and duration of pseudopregnancy was shortened in Groups 1 (P< 0.01) and 2 (P<0.05). Treatments with RU 38486 did not affect blood cortisol levels and had no measurable effects on luteal function. The results demonstrate the role of progesterone in onset and maintenance of overt pseudopregnancy. While onset may result from a decrease in progesterone concentrations, mammary gland development and expression of other symptoms seem to depend on the continuing availability of progesterone. In contrast to other reports in the literature, RU 38486 did not affect luteal function in this study. Possible dose-related phenomena are discussed.

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Revisiting canine pseudocyesis
2021, Theriogenology
Citation Excerpt :
Prostaglandins induce an abrupt luteolysis which could also provoke this syndrome acting as a pharmacological luteal ovariectomy [13]. Pseudocyesis has also been caused in bitches by early luteal administration of antiprogestins probably due to P4 withdrawal mimicking [38]. Both prostaglandins and antiprogestins shorten the diestrus and whole the interestrous interval.
Canine (Canis familiaris) pseudocyesis, pseudopregnancy, false pregnancy or nervous lactation is a frequent syndrome observed in non-pregnant, late diestrous or early anestrous females that is characterized by different degrees of mammary gland enlargement, maternal behavior and lactation. Further education about this frequent canine physiological event is still necessary to ensure optimal diagnosis and treatment strategies. Thus, the aim of this article was to review and update the physiopathology, physical and behavioral signs, diagnosis, treatment and prevention of pseudocyesis in bitches in which it is a clinical problem.
Aglepristone (RU534) administration to non-pregnant bitches in the mid-luteal phase induces early luteal regression
2010, Theriogenology
Citation Excerpt :
In bitches, both progesterone antagonists can prevent unwanted gestation when administered before embryo implantation and induce resorption, abortion, or parturition [30–36]. However, treatment with RU486 at different intervals after proestrus bleeding did not affect luteal function of bitches with overt symptoms or previous history of pseudopregnancy [37]. In addition, mifrepristone given at 2-day intervals for 80 days soon after proestrus bleeding did not modify the luteal function of a hysterectomized dog [37].
The effect of the antiprogestagen aglepristone (10 mg/kg bw), administered at days 29 and 30 following the estimated day of LH surge (day 0), on corpora lutea (CL) function was examined during the diestrus phase of non-pregnant bitches. Aglepristone shortened (P < 0.01) the luteal phase and complete luteolysis (progesterone <2 ng/mL) was observed at days 40.8 ± 3.5 and 71.5 ± 4.6 (means ± SD; n = 9/group) in treated and control bitches, respectively. Peripheral estradiol-17β concentrations declined from 91.5 ± 14.3 pg/mL at day 9 to 50 pg/mL at day 18, remaining at approximately the same levels thereafter in both treated and control bitches. Intraluteal in vitro synthesis of progesterone and estradiol-17β released by CL explanted at day 38 from control bitches (511.9 ± 285.6 and 40.7 ± 17.2 pg/mg protein, respectively) did not differ from that of treated. From day 38, intraovarian hemodynamic variables (arterial blood flow, systolic peak, and end-diastolic velocities), monitored by color-coded and pulsed Doppler, decreased more steeply (P < 0.01) in aglepristone-treated (n = 4) than in control (n = 4) bitches, whereas the resistance index increased (P < 0.01) in treated animals. All the blood flow parameters were undetectable at 60 ± 3.6 and 68 ± 2.0 days (medians ± SD) after LH peak in treated and control bitches, respectively. In conclusion, aglepristone administration to dogs during the mid-luteal phase markedly accelerates the luteolytic process which is accompanied by a parallel decline in ovarian blood flow supply with a shift from approximately 8 to 10 days.
Investigations on the expression of cytokines in the canine corpus luteum in relation to dioestrus
2005, Animal Reproduction Science
Control of luteal regression in the dog is still poorly understood. Unlike other domestic animal species, luteolysis is not prevented by hysterectomy. Indications that PGF_2α may act as an endogenous luteolytic agent have been found only in pregnant animals during the prepartal decline of progesterone. Evidence from several species indicates that the immune system plays an important role in corpus luteum (Cl) function, possibly by the release of cytokines from immigrant immune cells. Hence, in the present experiment we attempted to examine the expression of cytokines in the canine Cl during the course of dioestrus (formation and regression of the Cl), using RT-PCR. Groups of 4–5 bitches were ovario-hysterectomised on days 5, 15, 25, 35, 45 and 60–80 after ovulation. Canine-specific primers for IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNFα, IFNγ and TGFβ1 were used. Positive and negative controls were included in all tests. Adequate expression was confirmed by sequencing selective samples of positive PCR products. The expression of mRNA for IL-8, IL-10, IL-12, TNF-α and TGF-β1 was detected in all samples at each stage of dioestrus, without any obvious variations indicating a likely modulatory function of these cytokines in differentiation, maintenance or regression of the canine Cl. All tests for the expression of mRNA for IL-4, IL-1β and IL-2 were negative. More negative than positive results were obtained when testing for the expression of mRNA for IL-6 and IFN-γ, leading to the conclusion that expression of these two cytokines is at a low level, and no conclusion can be drawn as to their involvement in control of Cl function.
Effects of aglépristone, a progesterone receptor antagonist, administered during the early luteal phase in non-pregnant bitches
2004, Theriogenology
Aglépristone, a progesterone receptor antagonist, was administered to six non-pregnant bitches in the early luteal phase in order to determine its effects on the duration of the luteal phase, the interestrous interval, and plasma concentrations of progesterone and prolactin. Aglépristone was administered subcutaneously once daily on two consecutive days in a dose of 10 mg/kg body weight, beginning 12±1 days after ovulation. Blood samples were collected before, during, and after administration of aglépristone for determination of plasma progesterone and prolactin concentrations. The differences in mean plasma concentration of progesterone and of prolactin before, during, and after treatment were not significant. Also, the duration of the luteal phase in the six treated bitches (72±6 days) did not differ significantly from that in untreated control dogs (74±4 days). However, the intervals during which plasma progesterone concentration exceeded 64 and 32 nmol/l were significantly shorter in the six treated bitches than in untreated control dogs. The interestrous interval was significantly shorter in beagle bitches treated with aglépristone (158±16 days) than in the same group prior to treatment (200±5 days).
It is concluded that administration of aglépristone during the early luteal phase in the non-pregnant bitch affects progesterone secretion, but not sufficiently to shorten the luteal phase. The shortening of the interestrous interval suggests that aglépristone administered in the early luteal phase influences the hypothalamic–pituitary–ovarian axis.
Receptor blockers - General aspects with respect to their use in domestic animal reproduction
2000, Animal Reproduction Science
Receptor blockers compete with the respective agonist for binding to a given receptor without inducing complete signal transduction. In recent years, major interest has focused on sex-steroid hormone receptor blockers (antagonists). Indications have been obtained that inadequate changes in receptor conformation and subsequent failure of transcriptional activation are major events preventing hormonal activity. However, various subtypes and variants of receptors and receptor mutations have also been identified. Expression of antihormonal effects may vary depending on the type of receptor the blocker is bound to. Hence, receptor blockers may also have an inherent agonistic activity. Aglepristone® is the first antiprogestin registered for veterinary use with the indication “interruption or prevention of pregnancy”; similarly, these types of compounds were successfully used for induction of parturition in the dog and cat and for conservative treatment of pyometra in the dog. Moreover, application of antiprogestins has clearly demonstrated the role of progesterone as a major factor controlling overt pseudopregnancy in dogs. With respect to farm animals, parturition was induced in cows without an increased incidence of retained fetal membranes. Other than antiprogestins, antioestrogens and antiandrogens are still in a more experimental phase. In particular for use in humans, high-affinity blockers binding to the oxytocin/vasopressin receptor are in development; they exert distinct tocolytic activities. Also, the release of GnRH can be inhibited by respective antagonists; however, their use in reproduction is still hampered by the high dose requirement and the side effects observed.
Reproductive endocrinology of bitches
1996, Animal Reproduction Science
Domestic dogs are mono-oestrous and predominantly non-seasonal breeders with ovarian cyclicity unrelated to uterine function. During the first phase of dioestrus or pregnancy luteal function seems to be independent of gonadotrophic support and the gradual decline of progesterone concentration thereafter occurs in spite of an increased availability of prolactin and luteinising hormone (LH). Thus, the mean area under the curve (AUC) for LH (ng per 360 min ml⁻¹) increased from 1672 in early dioestrus to 2510 in late dioestrus and from 2940 on day 20 to 5089 on day 55 of pregnancy. LH pulse frequency remained unchanged. An induced release of LH during each quarter of dioestrus had no immediate effect on progesterone concentration but production over the whole period of dioestrus was increased (P < 0.03). Results from blocking cyclooxygenase activity indicated that the rather precipitous luteolysis prior to parturition was PgF_2α-mediated. During anoestrus LH pulse frequency did not change. The AUC for LH decreased from late dioestrus to early anoestrus (6332 vs. 3257 ng per 360 min ml⁻¹) and increased from mid to the end of anoestrus (5830 ng per 360 min ml⁻¹). Only during the terminal phase of anoestrus could resumption of ovarian activity be induced by treatment with oestradiol-17β. There was a depression of oestradiol-17β during mid anoestrus while it increased at the end of anoestrus.

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¹: In grateful memory of my young colleague who passed away in January 1993

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Investigations on the role of progesterone in the endocrine control of overt pseudopregnancy in the bitch: Application of an antigestagen and effects on corpus luteum function

Abstract

Contraception

Fertil. Steril.

J. Small Anim. Prac.

Pseudopregnancy in the bitch: The current view on aetiology and treatment

J. Small Anim. Pract.

Zur Behandlung der Lactatio sine graviditate und von Milchstauungen im Anschluss an die Geburt mit dem Antiprolaktin 2-Brom-α-Ergocryptin

Kleintierpraxis

Reproductive hormone concentrations during estrus, pregnancy, and pseudopregnancy in the labrador bitch

Theriogenology

The physiology of ovarian cycles, pregnancy and parturition in the domestic dog

The ovarian cycle in the bitch: Plasma estrogen, LH and progesterone

Biol. Reprod.

Parturition and lactation in the bitch: serum progesterone, cortisol and prolactin

Biol. Reprod.

Growth hormone, prolactin and cortisol in dogs developing mammary nodules and an acromegaly-like appearance during treatment with medroxyprogesterone acetate

Endocrinology

Effects of the antiprogestin RU 486 on progesterone-dependent uterine development and bioassay of progestational activity in estrogen-primed immature female dogs

Acta Endocrinol.

Termination of pregnancy and induction of premature luteolysis by the antiprogestin, mifepristone, in dogs

J. Reprod. Fert.

Grundlagen der Pharmakologie

Effect of cyproterone acetate, levonorgestrel and progesterone on adrenal glands and reproductive organs in the Beagle bitch

Cell Tiss. Res.

Effect of cyproterone acetate, d-norgestrol and progesterone on the canine mammary gland

Cell Tiss. Res.