Calcium, parathyroid hormone, oxytocin and pH profiles in the whelping bitch

doi:10.1016/j.theriogenology.2009.12.008

Theriogenology

Volume 73, Issue 9, June 2010, Pages 1276-1283

https://doi.org/10.1016/j.theriogenology.2009.12.008 Get rights and content

Abstract

Despite the high prevalence of primary uterine inertia in whelping bitches, the underlying pathogenesis remains unclear. The objectives were to i) determine serum concentrations of total calcium, ionized calcium (iCa), parathyroid hormone (PTH), and blood pH in normally whelping bitches throughout the peri-parturient period; and ii) investigate relationships among iCa, PTH, and acid-base status, and the role that they and oxytocin may have in the underlying pathogenesis of canine uterine inertia. Bitches were randomly selected from a population of German Shepherd Dog bitches with a history of uncomplicated parturition (Group 1; n = 10), and from a population of Labrador bitches with a clinical history of an increased incidence of uterine inertia and stillbirths (Group 2; n = 20). Jugular blood samples were collected daily from -4 d to the onset of whelping (t = 0 h), and then every 4 h until the last pup was born. Overall, bitches from Group 2 had higher mean ± SEM serum concentrations of PTH (4.72 ± 2.45 pmol/L, P < 0.001), lower iCa (1.31 ± 0.08 pmol/L, P < 0.05), and higher venous pH (7.41 ± 0.03, P < 0.005) than bitches from Group 1 (2.9 ± 1.44 pmol/L, 1.38 ± 0.06 mmol/L, and 7.33 ± 0.02, respectively) during the periparturient period. However, there was no significant difference between Groups 1 and 2 for serum oxytocin concentrations during the periparturient period (45.5 ± 40 and 65.5 ± 82 pg/mL). We inferred that low iCa resulting from a rising pH and decreasing PTH during the periparturient period may have contributed to decreased uterine contractility and increased risk of stillbirths. Therefore, manipulating the cationic/anionic difference in diets of pregnant bitches, similar to the bovine model for hypocalcamia, may reduce the incidence of stillbirths in the bitch.

Introduction

Primary uterine inertia is a well recognized clinical complication in the parturient bitch, which is often resolved with slow intravenous administration of calcium gluconate [1], [2], [3], despite total serum calcium often being within the ‘normal reference range’ for non pregnant dogs (clinical observations and [4]). Resolution of dystocia caused by primary uterine inertia with the administration of calcium indicates its potential role in this disease. Oxytocin, alone or in association with calcium, has also been widely used in the treatment of suspected uterine inertia [2], [3], despite equivocal evidence regarding its role in uterine inertia [5], [6]. Indeed, oxytocin is difficult to measure and a ‘normal’ reference range has not been established for whelping bitches. However, resolution of some primary uterine inertia associated with dystocia with oxytocin indicates also its potential role in the pathogenesis of primary uterine inertia.

Unfortunately, the pathogenesis of either ‘complete’ or ‘partial’ uterine inertia in the bitch has not been studied in detail [1], [2], [4], [7]. If hypocalcaemia is involved, there are, to the authors’ knowledge, no reports on the relationship between blood calcium and parathyroid hormone (PTH) concentrations, the effect that acid-base status has on these end points during the peripartum period in the bitch, and their effects on the incidence of uterine inertia.

During the peripartal period, the bitch has an increased demand for calcium resulting from skeletal ossification of the fetuses, initiation of lactation, and increased activity of myometrial muscle. Forceful uterine contractions required for the expulsion of pups during whelping is dependent on the influx of free, ionized calcium into the myometrial cells [2], [8]. However, free calcium availability may be restricted during this period of high demand due to transient inappetence, which many bitches experience on the day of whelping [2], or it may be further exacerbated by an acute respiratory alkalosis caused by panting, anxiety, fear, and pain (Henderson-Hasselbach Equation [9]) occurring in many bitches during whelping [10]. Increased protein binding of serum calcium [11] associated with a reduction in the amount and delay in the secretion of PTH in response to demand [12] may then occur, resulting in subsequent hypocalcaemia. This may then result in uterine inertia with delayed delivery, intrapartal hypoxia, and eventually birth of “stillborn” pups [1], [13]. A pre-existing parathyroid gland atrophy has also been implicated in the underlying pathogenesis of eclampsia [3], [14], and may be a contributing factor in the development of primary uterine inertia.

Two reports have documented the plasma concentrations of calcium and PTH in pregnant and lactating bitches [15], [16]. However, in one study, only two bitches were used, only total non-ionized calcium was measured, and concentrations were only determined only once weekly during pregnancy and lactation [16]. The second study measured total and ionized serum calcium concentrations on the day prior to and the day of parturition, but not throughout whelping [15]. Furthermore, the latter authors did not investigate the relationship of calcium and PTH during whelping, nor their relationship with dystocia.

To better understand the pathogenesis of primary uterine inertia and thus eventually implement prevention and management strategies to reduce the incidence of this disease, determination of reference ranges for calcium (total and ionised), PTH, and oxytocin concentrations in bitches during the peri-parturient period is required.

The objectives of this study were to: i) determine the serum concentrations of total calcium, ionized calcium (iCa), parathyroid hormone (PTH), and oxytocin in 10 normally whelping bitches during the periparturient period; ii) investigate the relationship between blood calcium (iCa), PTH, and acid-base status (blood pH); and iii) investigate the potential role of oxytocin during the days around whelping in a subset of bitches randomly selected from a much larger population of breeding bitches, either with a clinical history of uncomplicated parturition (Control; Group 1), or with a clinical history of an increased incidence of uterine inertia and stillbirths (Group 2).

Section snippets

Historical colony data

Group 1: Bitches in Group 1 (n = 10) were randomly selected from a research colony of German Shepherd Dog (GSD) bitches, aged from 2 to 7 yr, which were housed at The College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. This colony had a history of low stillbirth prevalence (<1% over 5 yr).

Group 2: Bitches in Group 2 (n = 20) were randomly selected from a colony of Labrador bitches, aged from 2 to 7 yr, located at “The Guiding Eyes”, NY, USA. This colony had a clinical history of a

Mean concentration of PTH, iCa, total calcium, and pH in bitches from Group 1

Mean concentrations of serum PTH, iCa, total calcium, and venous pH during the periparturient period of bitches from the Control group of experimental bitches (Group 1) are shown (Table 1).

Relationship between iCa, PTH, and acid-base status during the periparturient period of bitches from Groups 1 and 2

Only the main effect of Group had a significant effect on the dependent variables. There was no significant effect of time, or Group by time interaction, except for pCO₂, where time relative to whelping was significant.

Overall, bitches from Group 2 had a higher mean PTH (4.72 ± 2.45; P < 0.001), lower mean serum

Discussion

Despite the small number of bitches in the Control group, this is apparently the first report of serum calcium (total and ionised) and PTH concentrations in normally whelping bitches (Group 1; Control) during late gestation and parturition. Furthermore, this is apparently the first report investigating the changes and interactions that occur in iCa, PTH, and pH during the immediate peripartal period of normally whelping bitches (Group 1; Control).

The total calcium results in this study

Acknowledgments

The authors thank Nestle Purina USA for funding through the resident research grant, and The Guiding Eyes, NY, USA and Dr Sydney Moise, Cornell Univesity, Ithaca, NY, USA for allowing blood sampling of their pregnant bitches.

References (27)

D.A.J. Gaudet
Retrospective study of 128 cases of canine dystocia
Am Anim Hosp Assoc
(1985)
S.D. Johnston et al.
Canine and Feline Theriogenology
(2001)
E.C. Feldman et al.
Canine and Feline Endocrinology and Reproduction
(2004)
A. Bergstrom et al.
Primary uterine inertia in 27 bitches: aetiology and treatment
J Small Animal Prac
(2006)
K. Olsson et al.
Increased plasma concentrations of vasopressin, oxytocin, cortisol, and the prostaglandin F2alfa metabolite during labour in the dog
Acta Physiologica Scandinavica
(2003)
M. Klarenbeek et al.
Plasma oxytocin concentrations during late pregnancy and parturition in the dog
Theiogenology
(2007)
C. Forsberg et al.
A survey of dystocia in the Boxer breed
Acta Vet Scand
(2007)
G.C. Van der Weyden et al.
Physiological aspects of pregnancy and parturition in dogs
J Reprod Fert Suppl
(1989)
L. Nunez Ochoa
Acid-Base Principles and Practical interpretation in small animals
S. Marti
C-Section in the Bitch and Queen

J. Brauman et al.

Factors affecting the determination of ionized calcium in blood

Scand J Clin Lab Invest Suppl

(1983)

I. Lopez et al.

Direct suppressive effect of acute metabolic and respiratory alkalosis on parathyroid hormone secretion in the dog

J Bone Miner Res

(2003)

S. Romagnoli et al.

Prolonged interval between parturition of normal live pups in a bitch

J of Small Anim Pract

(2004)

Cited by (20)

Etiology behind canine uterine inertia: Role of uterine expression of MLCK4, MYH2, and PKC genes
2023, Animal Reproduction Science
Dystocia is an obstetrical emergency, and primary uterine inertia (PUI) is the major etiological reason among the more prevalent maternal causes in dogs. The present study involved the relative expression analysis of genes associated with myometrial contraction in medium-sized dog breeds with uterine inertia. Dogs without any progress in the parturition process even after four hours of the onset of labor and the absence of uterine contractions were considered to have complete primary uterine inertia (CPUI, n = 9). Dogs that had expelled at least one fetus and made no further progress in parturition in the absence of active uterine contraction were considered to be experiencing partial primary uterine inertia (PPUI, n = 6). Dogs with the fetal cause of dystocia (FCD), i.e., obstructive dystocia, were taken as the third (n = 7) group. Uterine tissue samples were collected during cesarean section in each group, RNA was isolated, and the relative expression of myometrial ACTA2, ACTG2, MLCK4, MYH2, and PKC genes was analyzed. The MLCK4 gene expression was downregulated in CPUI (P ≤ 0.05) and PPUI (P ≤ 0.01) when compared to FCD. The MYH2 gene expression was downregulated in PPUI in comparison to CPUI (P ≤ 0.01) and FCD (P ≤ 0.05). The PKC gene expression was upregulated in PPUI in comparison to FCD and CPUI (P ≤ 0.05). The downregulation of MLCK4 and MYH2 gene expressions recorded in PPUI indicated the possibility of myometrial defects. The possibility of myometrial defects was also observed in CPUI, but to a lesser degree, suggesting other etiologies.
Body Condition and Fertility in Dogs
2023, Veterinary Clinics of North America - Small Animal Practice
Canine parturition: what is known about the hormonal setting?
2022, Domestic Animal Endocrinology
Citation Excerpt :
In addition to the possible lower calcium availability and the increased protein binding of serum calcium, the decrease and delayed secretion of parathyroid hormone (PTH) could result inadequate to the physiologic demand around parturition. A study from Hollinshead et al [54] showed that, although a trend of serum PTH concentrations decrease was observed from the onset of parturition, probably due to the increased calcium requests, the effect of time was not significant. Therefore, during normal parturition, significant changes of circulating PTH concentrations does not seem to occur in the dog, while decreasing PTH concentrations may contribute to decreased uterine contractility.
Parturition is a challenging physiological process with perfect timing dictated by the events leading to the end of pregnancy in the female, and by the maturation of the fetus(es). The process of parturition remains an intricate interaction of hormones in a fine-tuned timing that remains to be better elucidated in the dog. In the dog pregnancy is maintained by the progesterone production by the corpora lutea, in which some hormones play a luteotrophic action. At term of pregnancy, the pre-parturient luteolytic cascade is the most apparent event, characterized by a rapid decline in plasma progesterone concentrations and useful in predicting the onset of spontaneous parturition. In contrast, cortisol plasma concentrations measurement showed high variability and suggested to be related to the stress condition instead of the onset of parturition. Both prostaglandin F2α and E2 concur in the process of parturition in the dog. The measurement of oxytocin plasma concentrations, also very variable, is implicated in uterine contractions. The measurement of plasma oxytocin concentrations showed to be useful to distinguish between normal and disturbed parturition, allowing the prompt recognition of dystocia and the immediate obstetrical intervention. In contrast to other species, no significant roles of estrogens for the initiating of parturition were demonstrated. Relaxin, the main pregnancy hormonal marker in the dog, beside an endocrine action, is also supposed to play a paracrine/autocrine role at the utero-placental unit and to support the maintenance of high plasma progesterone concentrations through a luteotrophic action, concurring to the main action of prolactin. Although important information has been provided, some aspects in the understanding the hormonal interactions and action timing implications in the process of parturition in the dog remains to be better investigated and represent intriguing topic for basic knowledge and applied research.
Investigations on the potential role of prostaglandin E2 in canine uterine inertia
2021, Theriogenology
Citation Excerpt :
Other studies proved a higher progesterone to PGFM ratio [23], lower oxytocin [23], lower vasopressin [23] and higher parathyroid hormone (PTH) [27] concentrations in bitches with uterine inertia or at risk of primary uterine inertia. Different to this, an effect of progesterone (e.g. incomplete luteolysis [28]), estradiol and plasma cortisol concentrations [23] or blood glucose [27,29] and total calcium concentrations [27] on the development and prevalence of uterine inertia could not be verified. Bitches with primary uterine inertia had, however, higher venous pH [27].
Prostaglandin (PG) E2 plays a crucial role in the endocrine network of canine parturition and we hypothesized that PGE2, 15-hydroxyprostaglandin dehydrogenase (HPGD) and PG-transporter (PGT) might be involved in the development of primary uterine inertia (PUI). We investigated PTGE synthase (PTGES), PTGE receptors 2/4 (PTGER2/4), HPGD and PGT expression on the mRNA- and protein-level in interplacental (IP) and uteroplacental (UP) tissues of bitches presented with dystocia undergoing emergency caesarean section. Groups were formed retrospectively based on strict criteria: PUI (n = 12; small/normal/large litter - PUI-S/N/L: n = 5/4/3), and obstructive dystocia (OD, n = 8). Respective mRNA expressions (ratio) between PUI and OD in IP and UP, between PUI dogs with different litter sizes, between PUI-N and OD in IP, and overall between IP and UP were compared. PTGES, PTGER2, PTGER4, HPGD and PGT mRNA expressions did not differ significantly between PUI and OD in IP or UP. PUI-N PTGES mRNA expression was higher than PUI-S/L (P = 0.0203/P = 0.0186) and OD (P = 0.0314). Higher PTGES (P = 0.0112) and a tendency for higher PTGER2 (P = 0.059) mRNA-expressions were detected in UP versus IP. Other than hypothesized, we did not find a difference in PGE2 production and signaling between PUI and OD, indicating that altered uterine PTGES, PTGER2, PTGER4, HPGD and PGT expression was likely not causative for PUI. However, higher PTGES expression in PUI-N compared to OD might point to a possible role of PGE2 during the course of parturition. Higher PTGES expression in PUI-N compared to PUI-S/L indicates an influence of litter size, the underlying cause and biological relevance of which remain to be clarified.
Uterine expression of smooth muscle alpha- and gamma-actin and smooth muscle myosin in bitches diagnosed with uterine inertia and obstructive dystocia
2020, Theriogenology
Citation Excerpt :
Failure of adequate luteolysis and sustained high maternal peripheral progesterone (P4) concentrations were suspected, but not confirmed in a case study on PUI [19], as all four bitches had P4 concentrations less than 2 ng/mL. Lower plasma prostaglandin F2α metabolite (PGFM) levels and higher P4/PGFM ratio [10], lower total or ionized calcium (iCa) [13,20], higher magnesium [21], lower plasma oxytocin and vasopressin [10,13], and higher serum parathyroid hormone concentrations [20], may contribute to canine uterine inertia, whereas downregulation of uterine oxytocin receptors does not seem to play a role [11]. Genetic predisposition, as well as metabolic defects at the cellular level, were also hypothesized [17], implying direct effects on myometrial smooth muscle cells.
Primary uterine inertia (PUI) is the most common type of dystocia in dogs. We hypothesized that PUI develops because of lower than normal expression of the basic contractile elements in the uterus, i.e., smooth muscle (SM) α- and γ-actin and SM-myosin, and that the expression of these proteins is influenced by the number of fetuses present in utero. Full-thickness inter-placental uterine biopsies were collected during Cesarean sections from dogs with PUI (n = 11), and from bitches with obstructive dystocia (OD) still presenting strong labor contractions (designated as the control group, n = 7). Relative gene expression was determined by semi-quantitative real-time (TaqMan) PCR, and protein localization by immunohistochemistry. Gene expression between PUI and OD bitches, and between PUI bitches carrying small, large, or average number of fetuses according to their breed, were compared. Uterine SM-γ-actin and SM-myosin mRNA levels were significantly higher in PUI than in OD dogs, while SM-α-actin did not differ. PUI bitches carrying large litters had lower uterine SM-γ-actin gene expression than those with small litters (P = 0.008). Immunostaining for SM-actin isoforms and SM-myosin was present in the myometrium, and localization pattern and staining intensity appeared similar in the PUI and OD groups. All proteins stained in blood vessels, and SM-γ-actin was also present in endometrial luminal and glandular epithelium. In conclusion, higher uterine SM-γ-actin and SM-myosin gene expression in PUI bitches, compared with OD dogs, might be an indication of abnormal progression with labor. Whether this is the cause of PUI due to an intrinsic error of the myometrium not becoming committed to labor, or the consequence of inadequate endocrine or mechanical stimuli, is not clear. Litter size was previously shown to be one of the risk factors for the development of uterine inertia in dogs, and our findings suggest possible differing uterine pathophysiology of PUI with respect to litter size.
Expression of uterine oxytocin receptors and blood progesterone, 13,14-dihydro-15-Keto-Prostaglandin F<inf>2α,</inf> and ionized calcium levels in dystocic bitches
2019, Theriogenology
Citation Excerpt :
Hypocalcemia was not diagnosed in any of the bitches in this study. However, there are reports of hypocalcemia in risk groups of uterine inertia [35] and in dystocic bitches [36]. In our study, a single treatment with calcium glubionate and OT did not seem to affect the expression of OXTR mRNA or distribution of OXTR.
This study aimed to examine the etiology of canine dystocia by measuring the relative expression of oxytocin receptor (OXTR) mRNA and the concentration of serum progesterone, plasma PGF_2α metabolite (PGFM), and blood ionized calcium (iCa) near term and in dystocia. Altogether 58 bitches were included in this study, 41 of which underwent cesarean section (CS). The four CS groups were based on history: complete uterine inertia (CUI; n = 7), partial uterine inertia (PUI; n = 13), obstructive dystocia (OD; n = 10), and elective cesarean section (ECS; n = 11). An additional group of medically treated dystocia without CS (MD; n = 8) and a control group (C; n = 9) with normal parturition (without CS and medical treatment) were also formed. Blood samples were taken prior to CS or medical treatment. Progesterone concentrations were highest in the ECS and a significant difference (p < 0.05) was observed between the ECS and the OD and between the ECS and the combined dystocia (CUI, PUI, OD, MD) groups (COMB). Highest concentrations of PGFM was observed in the C, the difference being significant (p < 0.05) between the C and the ECS and between the C and the COMB group. The progesterone:PGFM ratio was significantly (p < 0.05) higher in the ECS than in the C and the COMB group. No significant difference (p > 0.05) was observed in iCa concentrations between the groups. Relative OXTR mRNA expression was evaluated with real-time PCR from full-thickness uterine samples taken from the incision site during CS. The expression was highest in the ECS and the difference in expression was significant (p < 0.05) between the ECS and the OD and between ECS and the combined dystocia (CUI, PUI, OD) groups (COMB2). The study supports previous reports of decreasing progesterone and increasing PGFM during prepartum luteolysis. Upregulation of OXTR occurs near term. In obstructive dystocia, a prolonged influence of oxytocin and uterine exhaustion may lead to downregulation of OXTR. Complete primary uterine inertia may have a different etiology as no clear decrease in OXTR was observed in CUI as in OD. It remains unclear if parturition ceases because of uterine inertia or if uterine inertia occurs because of ceased parturition and desensitization of receptors.

View all citing articles on Scopus

View full text

Calcium, parathyroid hormone, oxytocin and pH profiles in the whelping bitch

Abstract

Introduction

Section snippets

Historical colony data

Mean concentration of PTH, iCa, total calcium, and pH in bitches from Group 1

Relationship between iCa, PTH, and acid-base status during the periparturient period of bitches from Groups 1 and 2

Discussion

Acknowledgments

Retrospective study of 128 cases of canine dystocia

Am Anim Hosp Assoc

Canine and Feline Theriogenology

Canine and Feline Endocrinology and Reproduction

Primary uterine inertia in 27 bitches: aetiology and treatment

J Small Animal Prac

Increased plasma concentrations of vasopressin, oxytocin, cortisol, and the prostaglandin F2alfa metabolite during labour in the dog

Acta Physiologica Scandinavica

Plasma oxytocin concentrations during late pregnancy and parturition in the dog

Theiogenology

A survey of dystocia in the Boxer breed

Acta Vet Scand

Physiological aspects of pregnancy and parturition in dogs

J Reprod Fert Suppl

Acid-Base Principles and Practical interpretation in small animals