Accepted Manuscript Seasonal Heat Stress: Clinical Implications and Hormone Treatments for the Fertility of Dairy Cows F. De Rensis, I. Garcia-Ispierto, F. López-Gatius PII:

S0093-691X(15)00205-8

DOI:

10.1016/j.theriogenology.2015.04.021

Reference:

THE 13172

To appear in:

Theriogenology

Received Date: 9 February 2015 Revised Date:

11 April 2015

Accepted Date: 11 April 2015

Please cite this article as: De Rensis F, Garcia-Ispierto I, López-Gatius F, Seasonal Heat Stress: Clinical Implications and Hormone Treatments for the Fertility of Dairy Cows, Theriogenology (2015), doi: 10.1016/j.theriogenology.2015.04.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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SEASONAL HEAT STRESS: CLINICAL IMPLICATIONS AND HORMONE TREATMENTS

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FOR THE FERTILITY OF DAIRY COWS

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Running head: Treatments for the heat-stressed cow

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5 F. De Rensisa*, I. Garcia-Ispiertob, F. López-Gatiusb

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University of Parma, Italy

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Agrotecnio, University of Lleida, Spain

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Department of Veterinary Medicine

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University of Parma 43121 Parma, Italy Tel: +39.0521.902659

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e-mail: [email protected]

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Abstract

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Corresponding author: Fabio De Rensis (D.V.M., Italy, M.Ph. UK, Ph.D, Canada)

Heat stress has consequences on both the physiology and reproductive performance of cows, but the

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most dramatic effect for dairy producers is the decrease produced in fertility. The effects of heat

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stress on fertility include an increased number of days open, reduced conception rate and larger

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number of cows suffering different types of anestrus. Once becomes pregnant, heat stress affects

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also the reproductive success of the cow through its direct effects on the ovary, uterus, gametes,

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embryo and early fetus. This paper reviews current knowledge of the effects of heat stress on

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fertility in dairy cows and the hormonal strategies used to mitigate these effects at the farm level.

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Administration of GnRH at the moment of AI can improve the conception rate. Breeding

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synchronization protocols for fixed-time insemination may reduce the calving conception interval

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ACCEPTED MANUSCRIPT and the number of services per conception. Progesterone-based protocols seem resolve better

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reproductive disorders related to a hot environment (anestrus) than GnRH-based protocols. The use

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of combinations of GnRH, eCG and hCG in P4-based protocols can improve results. Progesterone

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supplementation during the late embryonic⁄early fetal period would be useful in curtailing

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pregnancy losses, mainly in single pregnancies, whereas a more positive effect of treatment with

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GnRH than progesterone has been found in twin pregnancies. Melatonin therapy is emerging as a

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promising strategy to improve the natural reproductive performance of cows suffering conditions of

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heat stress.

35 Keywords: Bovine; Estrus; Pregnancy; Breeding protocols

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1. Introduction

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The impact of heat stress on animal production has been known since antiquity. However, because

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of the decline in fertility produced in domestic animals worldwide only recently has this problem

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attracted the attention of researchers. Global warming is also likely already aggravating the effects

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of HS on animals [1]. While heavy rain, strong wind or high humidity can reduce fertility [2] and

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animals may show a genetic predisposition to heat tolerance [3,4] high temperatures have been

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strongly linked to low fertility in dairy cattle [2,5,6]. Homeotherms have optimal temperature zones

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for life with no additional energy above maintenance is expended to heat or cool the body. Heat

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stress (HS) may be defined as the sum of forces external that modify body temperature to above that

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of its resting state [7]. The comfort zone for dairy cows has been estimated at 5 to 25oC [8]. With

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this temperature range, physiological demands are minimal, productivity is optimal [9,10] and

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lactating cows are able to maintain a stable body temperature [11]. However, temperatures higher

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than 25ºC can be reached in tropical or subtropical regions and even in temperate climate regions.

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ACCEPTED MANUSCRIPT Heat stress can disrupt both the physiology and reproductive performance of cows, but the most

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dramatic effect for dairy producers is the decrease produced in fertility [2,5,6]. The consequences of

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HS not only emerge during periods of high temperature. Heat stress may have long-lasting effects

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on the reproductive physiology of the cow [12-16]. This has meant that in intensive dairy systems,

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preventing HS by using methods such as evaporating cooling and improving feed quality has

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become a main target to preserve cow well-being and the economy of herds [3,17-21]. However,

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because these systems often are not able to full counteract the reduction of the reproductive

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functions of cows, hormonal treatments may be applied to preserve fertility in the herds under heat

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stress conditions [3,18,20]. Therefore, the aim of this paper from a clinical perspective was to

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highlight the negative effects of HS on fertility of dairy cows and to update hormonal strategies to

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minimize these effects.

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2. Assessing heat stress

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The relationship between environmental temperature and rectal temperature has been extensively

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investigated. In Florida, temperatures of 29.7°C and 31.4ºC have been linked to average rectal

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temperatures of 39°C (mild hyperthermia) and 39.5°C (hyperthermia), respectively [22]. Rectal

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temperatures greater than 39°C reflect an extent of HS that will affect milk production and fertility

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[3,10,21]. Besides the environmental temperature, solar radiation, relative humidity (RH), wind

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speed and rainfall all contribute to the degree of heat stress. Attempts to combine environmental

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parameters in one single index have had limited success except for the temperature-humidity index

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(THI) [19].

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The THI incorporates the effects of both ambient temperature and RH. This index was created by

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Thom [23,24] to estimate the sensation of heat in humans. Its efficacy to detect HS in dairy cows

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was later confirmed by several authors [25-28]. Maximum THI, defined according to the maximum 3

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temperature and minimum RH, is more realistic than mean THI because high temperatures are

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always accompanied by a lower RH. Moreover, it has been demonstrated that the maximum THI

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better identifies the conditions producing HS in cows [4,15,16,29,30]. The success of this index is

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probably a consequence of its simplicity and easy measurement.

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A THI value below 68 units generally does not cause safety problems for healthy animals; under

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mild discomfort and discomfort conditions (68≤THI≤74) heat stress begins to first cause problems;

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and for a THI above 75 units animals can show noticeable decreases in performances [31,32]. In a

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study under our work conditions, THI values exceeding 75, and especially 80, around the time of

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artificial insemination were found to dramatically reduce the fertility rate [16]. However, in the

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latter study when temperature was analyzed alone was demonstrated that high temperatures on day

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3 before insemination and 1 day after were correlated with low fertility in agreement with previous

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studies [12,17,28]. Thus, climate factors seem to be highly relevant for conception rate, especially

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during the period encompassing 3 days before to 1 day after AI. The use of the THI or temperature

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to control a farm environment would depend on the individual farm and on each environmental

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situation. The use of maximum temperatures alone gives additional information to that provided by

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THI [5,6].

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3. Main clinical effects of heat stress on fertility of dairy cows

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Clinical signs of heat stress include lethargic behavior, rapid shallow breathing and diminished feed

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intake, milk production and fertility [3,18-20]. The effects of HS on fertility have been widely

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established worldwide and include an increased number of day open, reduced conception rate and

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increased number of cows suffering anestrus, including anestrus condition anovulatory or persistent

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follicles and ovarian cysts [3,18,19,21,33]. For example, in a large-scale retrospective study [34],

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average pregnancy rates to first AI and anestrus rates were 44% and 27%, and 1.2% and 12.9% for 4

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the cool and warm periods, respectively. Therefore, besides losses due to reduced milk production,

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the effects of HS on reproductive performance during periods of elevated temperatures are critical

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in terms of the economic losses incurred.

108 3.1. Estrous behavior

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Estrus in mammals is a behavioral symptom to ensure that the female is mated close to the

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time of ovulation. The main clinical effect observed in animals under HS is that as many as 80% of

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estruses are not detected [35] because a seasonal effect on estrous behavior [36]. An extended

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period of high temperature shortens the duration and intensity of estrus signs [37-40]. Furthermore,

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ovulations without estrous signs are more common during the warmer months of the year [41,42].

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Probably, the main cause of impaired heat detection is that HS reduces the steroidogenic capacity of

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theca and granulosa cells leading to diminished blood estradiol concentrations [14,43-45].

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Despites estrous behavior, in a study examining ovulation in dairy cows, the risk of ovulation

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failure was 3.9 times higher for AI performed in the warm period (12.4% of 663 AI) versus the cool

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period (3.4% of 1254 AI) [46]. All cows showed estrous signs, and estrus was confirmed (as the

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absence of a corpus luteum and presence of a preovulatory follicle) by palpation per rectum at AI

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[47,48].The ovulation rate (detection of at least one corpus luteum in the ovaries) was determined

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by ultrasound 11 days post-AI. In cows suffering ovulation failure, luteal structures were absent

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and the preovulatory follicle became persistent follicle (8-15 mm diameter) in 23 cows and

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resembled ovarian cyst (18-32 mm diameter) in 102 further cows [46].

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3.2. Oocyte quality

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Oocyte development is extremely sensitive to high temperatures. As demonstrated in vitro, heat 5

ACCEPTED MANUSCRIPT stress hastens oocyte maturation [49-51] and disrupts nuclear and cytoplasmic processes

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through oocyte maturation [52]. These in turn might compromise subsequent fertilization

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and embryonic development. The effect of HS on reproductive performance could therefore be

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the result of a direct effect of high ovarian temperatures on oocyte quality. In fact, recent studies

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have shown that reduced oocyte quality is among the main factors determining infertility in cows

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under HS [53-55]. Despite of this, oocytes collected from heifers showed a higher tolerance to heat

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shock in the warm compared to the cool season of the year [56]. The later observation suggests a

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strong correlation between the metabolic demand for milk production and heat tolerance of oocytes.

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Of course, oocyte quality in vivo should be taken into account besides preovulatory follicular health

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and size. In a cow under HS, dominance period of the dominant follicle is shorter [44], and this is

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negatively correlated with fertility [13] while there are generally more medium-sized subordinate

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follicles [13,43,44]. Most of the heat stressed cows ovulate the second wave dominant follicle

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which results in ovulation of an aged dominant follicle [13].

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4. Pregnancy losses

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Cows under HS show reduced blood flow to the uterus increasing uterine temperature [28,57]. This

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could mean an inappropriate genital tract environment for both oocyte and sperm survival.

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Moreover, although gametes may survive the increase in temperature produced, the zygote created

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will also have to do this. In effect, a high ambient temperature has been reported to affect pre-

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attachment stage embryos though the magnitude of this effect decreases as embryos develop [58].

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Most pregnancy losses occur during the early embryonic period, between Days 8 and 17 of

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pregnancy [59-62]. At the clinical level, early embryonic losses may be grossly underestimated

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since they are difficult to distinguish from the effects of insemination failure. Heat stress can

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compromise embryo growth up to Day 17 [63], which is a critical time point for embryo production 6

ACCEPTED MANUSCRIPT of interferon-tau [64]. Adequate amounts of interferon-tau are critical for reducing pulsatile PGF2α

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secretion and then blocking CL regression and maintaining pregnancy [64]. A question that

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remains unclear is the factor responsible for early embryo death in periods of HS. Possible

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candidates are: (1) low-quality embryo [3] and (2) poor-quality CL [18]. Perhaps, the two factors

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are inseparable and early embryo death is a consequence of the poor quality of both the embryo and

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CL.

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The effects of HS on the late embryonic/early fetal period have been more recently described.

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Pregnancy loss following a positive pregnancy diagnosis peaks just before Day 50 of gestation

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when the placenta is still not fully established [65,66]. This disorder is becoming the commonest

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non-infectious complication of pregnancy in high producing dairy cows in which more than 90% of

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pregnancy losses may occur before pregnancy Day 90 [67]. In warm countries like Spain,

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summer HS dramatically affects pregnancy loss during this period [15,30,66,68-70]. Based on

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the odds ratio [66], the risk of abortion in the warm season was 3.7 or 5.4 times more likely for

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cows bearing singletons or twins, respectively, compared to the cool period [66]. Besides such

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immediate effects on pregnancy, a long-lasting effect of HS has also been observed [15]. In this last

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study, cows experiencing a rise in the THI during the peri-implantation period showed an increased

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risk of pregnancy losses (by a factor of 1.05 for each additional unit of the THI over Days 21 to 30

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of gestation) until Day 90 of gestation. Implantation requires intricate signaling interactions

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between the conceptus and mother for embryo attachment [64,71-73] so that any stress factor,

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including HS, can disrupt this process [61,73]. The peri-implantation period is therefore critical

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in the life of the embryo and acute HS during this period predisposes pregnant cows to

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subsequent early fetal loss [15]. All these observations taken together confirm epidemiological

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data indicating that late embryonic/early fetal death after a positive pregnancy diagnosis (for

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example at Day 28 of gestation) can onwards 20% in high-producing systems under HS [75]. The

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highest proportion of losses during the warm period (54%) was registered in twin pregnancies [66].

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5. Hormonal treatments to counteract heat stress on fertility

185 Heat stress affects the reproductive success of the cow through its direct effects on the ovary,

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uterus, embryo and early fetus. These effects include diminished steroidogenesis, delayed follicle

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selection and a modified follicular wave length with adverse effects on the quality of oocytes

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[13,14,43-45,74,76] and luteal [38,77-79] and uterine [61,72,80,81] functions. When the control of

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the environment is not affordable or available, hormonal treatments can be applied to stimulate

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ovarian function, thus favoring fertility and maintenance of gestation.

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The optimal hormone treatment to combat the effects of HS should have three basic features: it

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should be suitable for use in cows in a fixed-time insemination program avoiding the need for heat

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detection, it should resolve anestrus, including ovarian cysts or anovulatory follicles, and it should

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be of short duration. The protocols described in the following sections are the treatment strategies

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most commonly used in the HS cow.

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5.1. GnRH- and PGF2α- based protocols

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The variability of the interval estrus-ovulation in the modern dairy cow is frequently worsened

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during periods of HS [2,82]. Thus, the induction of ovulation through the administration of GnRH

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seems appropriate. Administration of GnRH during the estrous cycle results in LH release [83],

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causes ovulation of large follicles present in the ovary, synchronizes the recruitment of a new

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follicular wave [84], and synchronizes follicle development waves [85]. In lactating dairy cows

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under HS, GnRH given at AI proved effective in improving the conception rate by as much as 11%

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compared to spontaneous estrus [86-88]. The limitation of this method is that it depends on the cow

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manifesting estrus.

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ACCEPTED MANUSCRIPT 209 Since the high incidence of cows suffering anestrus [89] and a poor detection of estrus [36] remain

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a major concern in dairy herds, breeding synchronization protocols for fixed-time insemination

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(FTAI) have been developed with the aim to inseminate without the need for estrus detection. One

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of the most popular protocols for FTAI is the Ovsynch protocol. The benefits of the Ovsynch

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protocol: GnRH followed by PGF2α 6 to 7 days later, a GnRH injection 48 h later and FTAI 16-22 h

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after the second GnRH dose [90,91] in cows under HS remain unclear. The effect of Ovsynch

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protocol under HS conditions showed no differences [92-94] or even a decreased [95] conception

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rate when compared with cows inseminated at spontaneous estrus. However, the interval from

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calving to first breeding and the number of services per conception are reduced in treated animals

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[92,94,96-98], thus compensating the decrease of estrus detection in heat-stressed cows. Recently,

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initiating the Ovsynch protocol 6 days after estrus during the first 40 days postpartum in dairy cow

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under heat stress resulted in a greater conception rate compared with cows receiving an Ovsynch

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protocol initiated at random stages of the estrous cycle [99].

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There are some studies that suggest that it should be possible to enhance fertility in the autumn by

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hastening the removal of follicles damaged by exposure to heat stress in the previous summer.

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Restoration of oocyte competence in the autumn has been accelerated by the control of the turnover

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of the follicles using repeated follicular aspiration [100] or GnRH administration [101-103]. In fact,

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when primiparous cows at 50 to 60 days in milk have been treated with repeated GnRH and PGF2α

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administration to induce 3 consecutive 9-d follicular waves, treatment increased conception rate and

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percent of pregnant cows at 120 days in milk [101]. These results indicate that the control follicular

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waves by GnRH may improve reproduction of dairy cows during the summer and subsequent

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autumn.

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5. 2. Gonadotropin chorionic treatments (hCG and eCG) 9

ACCEPTED MANUSCRIPT 235 Human chorionic gonadotropin (hCG) in cow acts in a similar way to LH. Effectively, hCG

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induces ovulation and has a direct luteinizing effect on ovarian cells, extends the lifespan of the

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corpus luteum and increases endogenous progesterone synthesis by the corpora lutea [104-106].

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The use of hCG in an Ovsynch-based protocol has some advantages over GnRH: luteolysis is not

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delayed nor is the length of the estrous cycle prolonged [106]. A delayed interval between ovulation

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and insemination can be a main factor affecting fertility during the warm season [96]. Thus,

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replacing GnRH with hCG during periods of HS seems appropriate. Cows under summer HS in an

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Ovsynch program given hCG instead of GnRH, showed an improved cumulative pregnancy rate on

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Day 120 postpartum[107]. The administration of hCG after AI seems to improve conception rates

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under HS. Shabankareh et al. [108] reported a higher pregnancy rate during the warm period for

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hCG-treated cows at 5 days post-AI versus saline-treated cows.

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Equine chorionic gonadotropin (eCG) has long-lasting LH and FSH-like effects that stimulate

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estradiol and progesterone secretion [109]. Thus, eCG administration in dairy cattle results in the

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recruitment of more small follicles showing an elevated growth rate, the sustained growth of

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medium and large follicles and improved development of the dominant and pre-ovulatory follicle.

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In consequence, the quality of the ensuing CL is improved, and thereby progesterone secretion

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increased [109]. Based on these characteristics, eCG treatment is utilized in veterinary medicine to

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control the reproductive activity of the cow. Results indicate that eCG administration after the use

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of a progesterone device may increase the synchrony of ovulation and improve the conception rate

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in FTAI protocols. The positive effects of eCG in these types of protocols are clearly detectable in

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cows suffering anestrus or under seasonal HS conditions [110-112]. In cyclic cows, treatment with

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eCG plus PGF2α and GnRH 48 h later followed by FTAI in cows with a mature CL overcame also

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the negative effects of HS on the conception rate [113]. It should be noted here that doses of more

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than 1000 IU of eCG can induce multiple ovulations [109]. Generally, it is accepted that the

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ACCEPTED MANUSCRIPT “standard” doses of eCG required to favor single ovulation should range between 200 and 1000 IU

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[109]. However, synchronization protocols including 500 or 700 IU of eCG have been recently

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linked to twin pregnancies [114]. More twin pregnancies were recorded in cows fitted with a 9-day

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progesterone releasing intravaginal device and given eCG than in cows subjected to a similar 5-day

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progesterone protocol [114]. These results partly agree with those two recent studies in which short

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protocols including 500 UI of eCG reduced twin pregnancies [111,113]. A 5-day progesterone plus

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eCG protocol reduced twin pregnancies in cyclic cows, compared to spontaneous estrus [111],

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whereas treatment of cows with a mature corpus luteum with prostaglandin PGF2α plus eCG and

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GnRH 48 h later followed by FTAI reduced the twin pregnancy rate in multiparous cows, compared

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to cows inseminated following a prostaglandin treatment [113].

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5.3. Progesterone-based protocols

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Synchronization protocols based on the use of intravaginal progesterone-releasing devices (IPD)

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have proved efficient in cows under heat stress. The Heatsynch protocol is a GnRH- and PGF2α-

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based protocol which consists of GnRH and PGF2α given 7 days apart followed by an injection of

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estradiol 24 h after the PGF2α dose, and FTAI 48 h after estradiol administration [115,116]. This

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protocol plus an IPD given during HS periods has been reported to improve conception rates [117]

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over the use of Heatsynch alone (47% vs 29%, respectively). The combination of both eCG and

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progesterone in a FTAI protocols has been shown to increase estrus expression [110] and

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conception rates [118] in cows inseminated during the warm period. Five-day P4-based protocols,

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including several combinations of GnRH and eCG and one or double PGF2α, favor also fertility

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during the warm season of the year [111,119]. Finally, progesterone administration post-AI can

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improve reproductive performance. Recently, Friedman et al. [103,120] reported that progesterone

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administration five days after AI improved summer fertility in subpopulations of cows such as

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showing low body condition score or suffering postpartum reproductive disorders.

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5.4. Exogenous melatonin

289 Melatonin is a small lipophilic indoleamine mainly synthesized in the pineal gland in a circadian

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manner in mammals, with levels being higher at night [121]. Melatonin has a multifactorial effect

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on animals. It modulates reproduction, the neuroendocrine and immunological systems, pregnancy

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and parturition times, and corpus luteum function, among others [121-123]. The importance of this

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indoleamine has been demonstrated by the presence of its receptors in reproductive organs [124].

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Recently, it was reported that the treatment under heat stress of dairy cows with melatonin implants

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before calving reduced subsequent days open and incidence of cows requiring 4 or more AI to

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become pregnant [125] and has beneficial effect on blastocyst in vitro production from heat-stressed

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bovine oocytes [126]. The mechanism by which melatonin can improve fertility in HS cows could

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be related to its antioxidant effect. High ambient temperatures during summer increase oxidative

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stress in the cow [40] and melatonin and its metabolites are considered indirect antioxidants and

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powerful direct free radical scavengers [127,128].

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5.5. Progesterone versus GnRH- or hCG- based protocols to reduce early fetal loss

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Suboptimal concentrations of progesterone in blood related to high milk production [79,129] could

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also explain some of the losses during the late embryonic/early fetal period [130-132]. The facts

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that intravaginal progesterone supplementation may reduce the incidence of pregnancy loss during

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the early fetal period [70,79,133] and that the presence of an additional CL (number of CL

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exceeding the number of embryos) has been identified as a strong predictor of pregnancy

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maintenance [67,75,134] support this idea. Since during this pregnancy period lower plasma

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progesterone concentrations [79] and spontaneous CL reduction [135] were registered during the

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warm period of the year, therapeutic strategies to reduce early fetal loss should be based on

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ACCEPTED MANUSCRIPT treatment reinforcing CL function or favoring the presence of an additional CL [134]. However,

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GnRH-induced CL did not reduce losses under heat stress conditions [88]. In fact, although

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treatment through the year with GnRH during the early embryonic period [136,137], and with

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GnRH or hCG at pregnancy diagnosis [138,139] clearly increased the number of additional CL, it

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was not found to reduce fetal loss in any of the studies performed. In a more recent study,

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pregnancy losses were reduced when eCG was applied on Day 22 post AI 7 days before hCG [140].

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This combination of eCG and hCG to be investigated under hot summer conditions. In practical

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terms and concerning heat stressed cows, progesterone supplementation during the late embryonic⁄

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early fetal period would be useful in curtailing losses, mainly in single pregnancies, whereas a more

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positive effect of treatment with GnRH than progesterone has been found in twin pregnancies.

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Therapeutics is not necessary in cows with an additional corpus luteum [134].

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6. Concluding remarks

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The impacts of heat stress on dairy cows have been long described and include milk production

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losses and impaired reproductive performance. In high producing dairy animals with high metabolic

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demands these effects are exacerbated. Cows delivering in a hot environment not only have to cope

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with reproductive disorders prior to conception but also with the interactions among these disorders

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[141]. The problem is further aggravated by global warming determining that the effects of HS are

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now appearing in countries where this was inconceivable some years ago. From a clinical

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perspective, HS is among the most important factor that affects farm economy during the warm

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season. Although veterinarians and farmers often face the question whether to treat or not to treat

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when trying to solve reproductive problems in a herd [142], it is not questionable that hormone

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treatments can both improve diminished reproductive performance of cows and reduce economic

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losses under heat stress conditions in well managed herds. Progesterone-based protocols, applied

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either for FTAI as post-AI, seem solve better reproductive disorders related to a hot environment

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(anestrus) than GnRH-based protocols. Inclusion of combinations of GnRH, eCG and hCG in P4-

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based protocols can improve results. The possible use of melatonin opens a strategy to improve the

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natural reproductive performance of cows under heat stress conditions.

342 References

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scenarios in the Mediterranean basin. Int J Biometeorol 2013;57:451-8.

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[2] De Rensis F, Scaramuzzi JR. Heat stress and seasonal effects on reproduction in the dairy cow-a

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[3] Hansen P J, Arechiga CF. Strategies for managing reproduction in the heat-stressed dairy cow.

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[4] Bernabucci U, Biffani S, Buggiotti L, Vitali A, Lacetera N, Nardone A. The effects of heat

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stress in Italian Holstein dairy cattle. J Dairy Sci 2014;97:471-86.

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[5] López-Gatius F. Factors of a noninfectious nature affecting fertility after artificial insemination

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in lactating dairy cows. A review. Theriogenology 2012;77:1029-41.

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[6] López-Gatius F, 2013: Approaches to increase reproductive efficiency in artificially inseminated

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dairy cows. Anim Reprod 2013;10:143-7.

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