Progesterone and stress response: mechanisms of action and its impact in domestic ruminants. Review

Freitas-de-Melo, Aline; Ungerfeld, Rodolfo; Freitas-de-Melo, Aline; Ungerfeld, Rodolfo

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Revista mexicana de ciencias pecuarias

versión On-line ISSN 2448-6698versión impresa ISSN 2007-1124

Rev. mex. de cienc. pecuarias vol.7 no.2 Mérida abr./jun. 2016

Revisiones bibliográficas

Progesterone and stress response: mechanisms of action and its impact in domestic ruminants. Review

Aline Freitas-de-Melo^a^*

Rodolfo Ungerfeld^b

^{^a}Departamento de Biología Molecular y Celular, Universidad de la República, Lasplaces 1620, Montevideo (11600), Uruguay. tel.: (598) 26221195.

^{^b}Departamento de Fisiología, Facultad de Veterinaria, Universidad de la República. Uruguay.

ABSTRACT

In rodents, progesterone (P4) administration reduces stress responses or anxiety through the action of some metabolites of P4 (allopregnanolone and pregnanolone). Although, there are few studies on these effects in ruminants, P4 administration has a great potential for practical application in animal production. The aim of this review was to summarize the information about the stress response and the main mechanisms studied in rodents by which P4 administration reduces this response. We also include information on the effects of P4 treatment on reactive behavior and stress response in ruminants. We show that P4 administration decreases the stress response of ewes to abrupt weaning of lambs, and also affects the response to tests of assessment of temperament in female beef calves. We also present information about the stress response of shearing in pregnant ewes, therefore ewes with high serum concentrations of P4. In summary, high serum concentrations of P4 reduces the stress response and provokes changes on the reactive behavior in ruminants. However, more studies are needed to include P4 in practical managements or to consider it in the selection of animals according to their temperament.

Key words: Abrupt weaning; Temperament; Shearing; Neurosteroids; Ungulates

RESUMEN

En roedores, los tratamientos con progesterona (P4) reducen la respuesta de estrés o ansiedad a través de la acción de algunos metabolitos de la P4 (allopregnanolona y pregnanolona). Aunque existen pocos trabajos que hayan estudiado estos efectos en rumiantes, los tratamientos con P4 tienen una gran potencialidad para su aplicación práctica en sistemas productivos. El objetivo de esta revisión fue sintetizar información básica sobre la respuesta de estrés y los principales mecanismos estudiados en roedores, por los que la P4 mitiga la respuesta de estrés. Además, se presenta información primaria sobre los efectos del tratamiento con P4 en el comportamiento reactivo y la respuesta de estrés en rumiantes. Se muestran los efectos del tratamiento con P4 sobre la respuesta de estrés al destete en ovejas, y sobre algunas pruebas de temperamento en terneras. También se presenta información sobre el estrés de la esquila en ovejas gestadas, y por tanto con altas concentraciones séricas de P4. En síntesis, altas concentraciones de P4 reducen la respuesta de estrés, y pueden generar cambios en el comportamiento reactivo de los animales. Sin embargo, para que el tratamiento con P4 o sus concentraciones endógenas sean utilizados como herramienta práctica durante manejos estresantes, o como un factor a ser considerado a la hora de seleccionar animales por temperamento, es necesario realizar más estudios aplicados.

Palabras clave: Destete artificial; Temperamento; Esquila preparto; Neurosteroides; Ungulados

INTRODUCTION

The stress response is triggered when the animal perceives a stressor. There are two almost simultaneous responses: the sympathetic autonomic nervous system and the endocrine axis (hypothalamus-pituitary-adrenal)¹. Altogether, both produce physiological and acute behavioral cahnges, which facilitate the animal to adapt and respond to the stressor¹. In rodents, treatments with progesterone (P4) reduce the response of stress or anxiety, basically through some P4 metabolites called neuroactive metabolites, such as allopregnanolone and pregnanolone²^,³. These metabolites can reduce the perception and reaction to the stressor, producing an anxiolytic effect⁴, and therefore decreasing the response of the hypothalamic-pituitary-adrenal axis²^,⁵^,⁶, and thus the global stress response³^,⁷^,⁸.

Although those treatments may be applied in productive systems, there are scarce studies on the effects of P4 on reactive behavior and the stress response in ruminants. It has been reported that treatment with P4 reduces the stress response of ewes to weaning⁹. In addition, the stress response of pregnant sheep (physiological situation where animals have high P4 concentrations) to social isolation¹⁰ and shearing, is week than in non-pregnant ewes. It has also been recently reported that treatment with P4 affects the reactive response of calves against human management¹¹. In this context, treatment with P4 may be a practical alternative to reduce the stress generated by stress management in ruminants, thereby improving their well-being. In addition, it would be important to consider the physiological concentrations of P4 when reactive responses are studied to optimize the results of this selection processes.

The objective of this review was to summarize basic information of the stress response in mammals, and the main mechanisms studied in rodents by which P4 mitigates the stress response. In addition, it presents information about the effects of the treatment with P4 in the reactive behavior and the response of stress in ruminants.

STRESS RESPONSE

Acute response

When an individual perceives a stressor (agent that triggers a stress response) of short duration (from minutes to hours), both, the sympathetic autonomic nervous system and the endocrine are simultaneously activated¹^,¹²^,¹³. The sympathetic response is displayed a few seconds or even minutes earlier than the endocrine response after the animal is exposed to the stressor¹³. However, although the endocrine response takes a little longer to displays, it lasts longer (minutes to hours). Although both responses are triggered simultaneously, the glucocorticoids should be secreted at the moment, thus requiring more time the response to be measureable¹²^,¹⁴. Altogether, both systems produce physiological and behavioral changes that help the adaptation and response to the stressor¹. The magnitude of these responses may depend on factors of the animal such as previous experience with that stressor, temperament, and the perception of the stressor by the individual¹⁵^,¹⁶.

Sympathetic response

When the sympathetic autonomic nervous system is stimulated, it releases the neurotransmitters adrenaline and noradrenaline into the adrenergic synapses. Catecholamines are also released into the bloodstream by cells located in the medulla of the adrenal glands¹⁷. In general, the effects induceed by the catecholamines are an increase of heart and respiratory rates, temperature rise, increase of blood glucose concentrations through glycogenolysis, mydriasis, vasodilation in skeletal muscle and peripheral vasoconstriction¹⁴^,¹⁷. It also increases alertness, vigilance and animal excitement¹⁸.

Endocrine response

When the hypothalamus-pituitary-adrenal axis is activated, the hypothalamus releases corticotrophin-releasing hormone (CRH), and vasopressin, which stimulate the release of the adrenocorticotrophic hormone (ACTH) by the adenohypophysis¹⁴. ACTH stimulates the secretion of glucocorticoids in the cortex of the adrenal gland, mainly cortisol and corticosterone¹⁴, being cortisol the most abundant glucocorticoid in ruminants¹⁹. Glucocorticoids stimulate gluconeogenesis and lipolysis and the catabolism of proteins, thus raising blood glucose concentration to provide main body energy to respond to the stressor²⁰. In addition, glucocorticoids increase cerebral perfusion, the use of glucose, blood pressure and cardiac performance²¹. Glucocorticoids have also an action on the immune system, causing lymphopenia, eosinopenia, and neutrophilia²². The inactivation of the hypothalamus-pituitary-adrenal axis occurs via a negative feedback, where the secreted glucocorticoids inhibit the secretion of CRH, vasopressin and ACTH¹⁸.

CHRONIC RESPONSE

The chronic stress response occurs when an animal is continuously or intermittently exposed to stressors during longer periods of time (from days to weeks)²³. This type of stress response is more common in ruminant productive systems, as the stressors usually remain active for hours or weeks. Sustained exposure to glucocorticoids produces deleterious effects on the productive results, health and animal welfare. Generally, high concentrations of glucocorticoids affect the immune system, and may cause immunosuppression in the animal, and therefore leave it more susceptible to diseases²². Glucocorticoids also promote behavioral changes as the expression of stereotypic movements, reduction of sexual behavior and appetite²¹^,²⁴. As a consequence, it is common that the animal to lose weight, reduce the quality and quantity of hair or wool, and negatively affect their reproductive status.

In short, in general the stress response is beneficial for the animal as promotes a rapid adaptation to a new situation, allowing the animal to enhance its status, or even survive when the negative effects could be more important²⁵. However, when the stressor is maintained over time, or the intensity of its' effect is so important to generate a response to intense or sustained duration, the result of the stress response can be negative for the animal. In many situations related to animal production, the response is not enough to modify the situation²⁵. This happens, for example, after weaning, in which animals fail to reunite again²⁶, during the transport in which the animal cannot avoid its transfer, or after social grouping, as animals must adapt to live with new previously unknown individuals²⁷. In these cases, the responses are expensive for the animal, and does not end changing the situation, so the result is deleterious rather than advantageous. In these cases, it may be important to reduce the perception of the intensity of the stressor, or the response triggered to improve the welfare of the animal.

PROGESTERONE AND STRESS RESPONSE: MECHANISMS OF ACTION

Progesterone acts through genomic mechanisms: linkage to intracellular receptors induces changes in the expression of genes, that stimulates or inhibits gene transcription and protein synthesis, thus generating the cellular response²⁸. This is a slow mechanism, requiring from minutes to days to display the effect²⁹. However, both the P4 and its neuroactive metabolites act in a non-genomic way joining ionotropic receptors in the central nervous system. These receptors are members of the superfamily regulating fast neurotransmission, promoting immediate changes, in the order of milliseconds to seconds³⁰.

Progesterone easily crosses the blood-brain barrier and can alter neuronal excitability in the central nervous system (CNS), to antagonize the serotonergic neurotransmitter receptors and inhibit nicotinic receptors³¹^,³². It also features a low affinity to inhibitory neural receptors as the γ-aminobutyric_A acid receptor (GABA_A), present in most neurons of the mammal CNS ³³, and receptor of the glycine³⁴. Based on the foregoing, the P4 can promote inhibitory effects or reduce excitatory effects in the CNS.

Additionally, P4 from mammals generates metabolites that circulate in blood, as the dihydroprogesterone, allopregnanolone and pregnanolone³⁵^,³⁶, which also cross the blood-brain barrier³⁷. The P4 and the dihydroprogesterone can also be metabolized in the brain itself to allopregnanolone and pregnanolone³⁸. Thus, the P4 neuroactive metabolites reach high concentrations in the brain³⁹. Once in the CNS, allopregnanolone and pregnanolone can join GABA_A receptors and glycine receptors⁴⁰, or nicotine, serotonin and glutamate receptors⁴¹^,⁴²^,⁴³. Therefore, the allopregnanolone and the pregnanolone can reduce neuronal excitability in the CNS from interaction with some neurotransmitter receptors. In this sense, among those mentioned, the affinity and effects of P4 metabolites on the GABA_A receptor have been widely studied⁴. The alloapregnanolone and the pregnanolone have high affinity for the GABA_A receptor, modulating it positively allostericaly⁴⁴. This action modulates preferentially the opening of Cl-paths, resulting in a hyperpolarization of the cell, and can generate anxiolytic, sedative and analgesic effects⁴⁵.

The classical action of P4 on intracellular receptors could be related to effects in the reduction of the stress response, but this mechanism has not yet be well establish in the literature. Some evidence using mice knock-out to intracellular receptors of P4 suggests that reduction of the stress or anxiety response could not require a direct action of the P4 on its receptors, although these animals showed a greater sensitivity to the P4⁴⁶. In addition, Bitran et al⁷ did not observe any effect affection of the P4 in the reduction of the stress response using rats pretreated with antagonists to P4 receptors,. However, other studies in rats suggest the existence of an effect of the P4 or dihydroprogesterone on intracellular P4 receptors⁴⁷^,⁴⁸^,⁴⁹, as it was identified a reduction in the stress response in rats treated with medroxyprogesterone (progestin that cannot be metabolized to neuroactive P4 metabolites) or pretreated with P4 receptor antagonists. The P4 could be acting on its intracellular brain receptors, since they are expressed in the amygdala and the bed nucleus of the stria terminalis⁴⁹, which are related to the response of stress, fear or anxiety⁵⁰. Therefore, the P4 or the dihydroprogesterone could directly join these intracellular receptors, reducing the stress response. However, some of these works speculate on the existence of a direct action of P4 or dihydroprogesterone, by an indirect indicator of stress frequency as lordosis⁴⁷^,⁴⁸^,⁴⁹, behavior that is also indicative of sexual receptivity, therefore, confounding those effects.

Moreover, in male rats it was determined that allopregnanolone reduces the expression of mRNA for CRH and vasopressin secretion of ACTH and glucocorticoids⁵^,⁶; and as a result the physiological²^,⁴⁴ and behavioral responses indicative of stress⁷. Therefore, the overall effects of these metabolites of P4 is a reduction of the physiological and behavioral responses indicative of stress. Figure 1 presents a possible model to explain the mechanisms by which P4 mitigates the stress response.

ACTH= Adrenocorticotropic hormone; AVP= arginine vasopressin; CRH= Corticotropin-releasing hormone; DHP= dihydroprogesterone; GABA_A= ã-aminobutyric acid type A receptor; RP4= progesterone receptor.

Figure 1 Mechanisms proposed by which progesterone mitigate the stress response

Progesterone and its neuroactive metabolites affect reactive behavior in different animal models. While there are few studies in ruminants, it has been reported that pregnant ewes (therefore with high P4 levels), react less than non-pregnant ewes¹⁰. In addition, treatment with P4 produces anxiolytic and analgesic effects in rats⁸^,⁵¹, and decreases aggressive behavior in hamsters⁵².

EFFECTS OF PROGESTERONE DURING STRESSFUL HANDLING

Artificial weaning in sheep

The ewe-lamb bond is established at birth, and changes throughout the period of lactation, until weaning of the lamb⁵³^,⁵⁴^,⁵⁵. Artificial weaning is a common practice that involves a complete separation of the ewe and the lamb before spontaneous weaning, while there still persists a strong bond.

The permanent removal of lambs before the natural weaning age is a stressful event for both, the ewe and the lamb, which produces behavioral and physiological stress responses. After the separation of her lambs, ewes increase the frequency of behaviors related to search, such as vocalizations, and time pacing and walking, at the expense of reducing their time resting and feeding⁵⁶^,⁵⁷. In addition, weaning causes physiological changes indicative of stress, as increases in serum cortisol concentration⁵⁸, decrease in the total serum protein and globulins, and an increase in albumin concentration⁹.

Administration of sustained P4 by intravaginal devices used to synchronize oestrus (CIDR, Pfizer, NZ), reduces the physiological and behavioral changes indicative of stress in ewes³. In this study, ewes treated with P4 presented a lower frequency of energetically costly behaviors normally displayed by the sheep to join her offspring, as pacing and vocalizing. In addition, this treatment with P4 prevented the reduction observed after weaning in total serum protein concentration, and provoked a minor decrease in the concentrations of globulins. The values of serum globulins after weaning in the untreated sheep reached levels of hipoglobulinemia⁵⁹, which could indicate a immunodeficiency state⁶⁰.

Weaning is a stressful handling, and can leave the animal more susceptible to diseases; for example, weaned lambs have an increased susceptibility to gastrointestinal parasites⁵⁶. An alternative practice may be to administer longlife preparations of P4 the day of weaning, reducing the stress response in sheep. This treatment reduced the frequency of pacing and walking the day of weaning in ewes, as well as tended to vocalize less than the control group (A. Freitas-de-Melo, Ungerfeld R. and R. Perez-Clariget, unpublished data). In short, P4 therapy reduces chronic stress response of ewes to weaning, generating less negative effects on the immune system and animal welfare.

Prepartum shearing in sheep

In sheep productive systems, shearing procedures are a stressful event for sheep⁶¹^,⁶². The stress generated by shearing has several components: the movement of animals to the pens, noises and movements related to shearing of other animals, handling and restraint during shearing in an unknown environment, and shearing itself⁶³. In addition, it also adds thermal stress generated by the loss of the naturally insulating layer of wool, especially when it is done in winter⁶⁴. The stress response is similar in sheep sheared by hand or with a shearing machine⁶⁵. As part of the stress response, there is an increase of cortisol⁶² and glucose⁶³ blood concentrations, and a significant increase in body temperature⁶⁶. It has been reported that body temperature remains elevted for several weeks, even without their normal circadian variations⁶⁷. Other acute indicators of stress responses are the decrease in the number of neutrophils, neutrophil/ lymphocyte ratio and eosinophilia⁶⁷.

Immediately after shearing, the ewe increases the deployment of comfort behavior, feed intake, decreases the frequency of water intake⁶⁸. Winter shearing decreases body temperature⁶⁹. During the days after shearing the animal needs to adapt to the lack of wool, activating mechanisms of control, such as the decrease in respiratory rate, heart rate increase, and a lower water intake(⁷⁰). These changes generate greater demands of energy and therefore an increase in feed intake⁷¹. This is associated with an increase in total protein in the blood, increase that stays for a long time, which is independent of any changes in the weight of the sheep⁷². (R. Ungerfeld, J.P. Damian, A. Freitas-de-Melo and R. Kremer, unpublished data) recently demonstrated that the increase in cortisol concentrations after shearing is lower in pregnant than in non-pregnant ewes . In addition, behavioral changes generated by shearing were lower in pregnant ewes (A. Freitas-de-Melo, R. Ungerfeld, J.P. Damian, and R. Kremer, unpublished data). In short, shearing is a stressful management, and shearing at the end of the pregnancy reduces stress, which also opens the possibility of speculating in the use of exogenous treatments with P4.

Tests of temperament and interaction with the human

The individual temperament can be determined by the behavioral changes of the animal resulting from the fear generated by humans or by a novel environment⁷³. In cattle, the results of those tests may vary according to breed, gender, experience and genetics⁷⁴. It has been reported that Bos indicus animals and their crosses are more temperamental than the Bos taurus⁷³, and steers are calmer than heifers⁷⁵. Nervous temperament refers to animals that react violently when they are handled by humans, being more difficult to handle than tame animals⁷⁵. There are several tests to determine the temperament in cattle⁷⁶. Some tests such as the scale score are considered partially subjective, but other tests such as the flight distance are objective tests that evaluate the displacement of the animal against the human presence⁷⁷.

The cattle temperament is a quantifiable and inheritable characteristic⁷⁸, being used to select tame animals⁷⁹. To measure temperament, is important to use objective methods and the factors that can affect the results of these tests. In large herds of cattle temperament has a low heritability⁸⁰^,⁸¹, but this can be related to how these tests are usually applied. Commonly, the temperament evaluation is carried out simultaneously in big bovine herds⁸². Usually, in grazing systems there are cows with a great variability of reproductive status in the same herd⁸³, coexisting pregnant, anestrus and cycling cows⁸⁴^,⁸⁵. The different reproductive status of cows determine variations in P4 concentration; therefore, this can affect the reactive behavior to humans. It was recently reported that variations in the concentration of P4 affect the results of the tests of temperament in heifers¹¹, which had a shorter flight distance to humans while they were treated with a CIDR, indicating lower reactivity to humans when P4 levels are elevated. Therefore, it is suggested that the reproductive status of the animals may affect the evaluation of temperament; this should be considered when these trials are done on farms that can have cows in different physiological stages.

CONCLUSIONS

Progesterone treatments reduce the stress response through several mechanisms. Although the results of several studies are consistent, most of them were conducted in laboratory animals, being still scarce information in farm animals. The reduction of the stress response may be beneficial for the animal when it cannot be modify by the animal. These responses are costly and ineffective, so it is important to reduce the perception of the stressor or the costs of the response. In this sense, while the first results are promising, is necessary to develop further research related to the effects of the P4 on the stress response in ruminants, to understand the mechanisms by which it acts in these species, and how it could be used to improve the productive results and animal welfare.

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Received: April 04, 2014; Accepted: June 30, 2014

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