Reproductive Physiology and Advanced Technologies in Sheep Reproduction
2023 Volume 11 Pages 171-180
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2023 Volume 11 Pages 171-180
Reproductive efficiency is a crucial factor in the economic viability of small ruminant exploitation. In spite of this, few producers utilize the available reproductive technologies related to hormonal interaction, which are vital for the economic sustainability of their operations. Therefore, this review aimed to investigate the potential effects of reproductive alterations and hormone interactions during pregnancy and lactation and to determine advanced technologies for sheep reproduction. In the modern era, breeding techniques, nutrition, reproduction, and management techniques are used to produce more and better quality livestock. A combination of estrous synchronization and genetic improvements for small ruminants is needed to increase reproduction efficiency, productivity, and quality. A proper match between sheep breeds and nutritional and production environments will allow animals to express their genetic potential for enhanced production. In sheep, little information is available regarding the reproductive physiology during pregnancy and lactation. The availability of such information would enhance sheep production and reduce economic losses through improved dam performance and lamb survival. Understanding ewe reproductive physiology during pregnancy and lactation is essential for flock managers to determine their reproductive potential. Using advanced reproductive technologies could enhance the productivity of sheep, which are the most abundant ruminant livestock species.
The reproductive traits of sheep are highly valuable in all sheep production systems. The production efficiency of sheep flocks can be attributed to improved reproductive performance [1, 2]. The implementation of reproductive management programs is essential for increasing production efficiency. Good reproductive management involves manipulating estrous onset timing [3]. In the breeding season, ewes have an estrous cycle of 15–20 days (average 17 days), and estrus lasts 16–59 hours (average 29 hours). The end of estrus usually marks the beginning of ovulation, typically commencing within an hour after estrus [4]. When estrus periods are prolonged, ovulation usually occurs prior to the end of estrus, while when estrus periods are shortened, ovulation occurs after estrus. The uterus of ewes undergoes morphological and functional changes during the 17-day estrous cycle [5]. These changes including the circulation levels of progesterone, estrogen, and ovarian hormones affect the growth and metabolism of ovarian follicles and corpus luteum cells [6]. Progesterone dominates the first 11 days of the 17-day cycle, followed by estrogen for three or four days. A behavioral estrus appears to result from higher levels of estrogen produced on day 0 by the ovulatory follicles [5]. As a result of high estrogen levels, gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) levels rise, resulting in spontaneous ovulation. At the onset of the follicular phase, progesterone levels are low and GnRH and LH levels are increasing, whereas follicle stimulating hormone (FSH) levels are progressively decreasing [7].
When ruminants ovulate, they release a single oocyte compared to pigs and rodents, which have high ovulatory rates [8]. Additionally, ovulation rates differ between sheep breeds, with Texel and Suffolk sheep ovulating an egg per ovulation while the Booroola Merino sheep ovulate ten eggs per ovulation [9]. The ability to produce a large litter or twins is an economically significant trait that enhances sheep productivity in terms of lamb production, meat production, and wool production [10, 11]. Rojo-Martínez et al. [12] found that ewes presenting estrus during reproductive and non-reproductive periods are 80 and 100% fertile, and prolific is 1.3 and 1.0 lambs born per ewe. Reproductive status in sheep is also controlled by other environmental, hormonal interactions, and nutritional status. There have been several studies on nutrition and heat stress during pregnancy and lactation [13, 14, 15, 16, 17]. Other studies examined the hormones separately, including progesterone and estrogens during pregnancy [18], thyroid hormones during pregnancy [19], placental hormones during pregnancy and lactation [20], and melatonin in early lactation [21]. However, little research has been conducted on hormonal interactions during pregnancy and lactation. When available, this information could improve lamb performance and reduce economic losses to sheep producers. Understanding the reproductive physiology during pregnancy and lactation is vital to flock management in order to determine a ewe’s reproductive potential. Therefore, this review investigated the potential effects of reproductive alterations and hormone interactions during pregnancy and lactation in sheep and investigated the advanced technologies in sheep reproduction.
An animal’s reproductive life revolves around pregnancy, which maintains the genetic integrity of the species [22]. An important part of this process includes changes in the concentration of hormones, cytokines, enzymes, and growth factors in the tissues, of which hormones are the most important. Various hormones are required to prepare a ewe’s uterus for conception, growth, and development of an embryo, and to maintain pregnancy and give birth to a healthy lamb [23]. As the pregnancy progresses, serum levels of estrogen, progesterone, prolactin, growth hormone, osteopontin, and other hormones associated with pregnancy rise. In addition to the above hormones, prostaglandin, cortisone, relaxin, and oxytocin play a key role in parturition [24]. Due to this, it is crucial to understand the hormonal interactions that occur in the uterus of the ewe during pregnancy and lactation.
2.1 Progesterone and estrogen hormones during pregnancyIn pregnancy, progesterone prevents cycling, prepares the uterus for implantation, and maintains myometrium quiescence [5]. Myometrium quiescence is thought to be promoted by the combination of progesterone, relaxin, prostacyclin, and nitric oxide during pregnancy [25]. Lonergan et al. [26] found that progesterone stimulated the production of endometrial secretions, which are necessary for embryonic development. Ewes with low progesterone levels can have poor embryo development, and progesterone supplementation can enhance embryo growth in ovine [23]. Progesterone works in conjunction with estrogen to transform the endometrium into a secretory tissue that nurtures the conceptus pre- and post-implantation [27]. As the pregnancy progresses, the level of progesterone in plasma gradually rises during the first half of the pregnancy, increases significantly, and slowly decreases in the last few days before delivery [28]. Ewes are also known to benefit from progesterone during pregnancy upon the maintenance of their immune systems [29]. As well, progesterone has a role in regulating or allowing locally produced cytokines and growth factors, including interferons, chorionic gonadotrophins, prolactin, lactogens, transcription factors from homeoboxes, and prostaglandins produced by cyclooxygenase [30].
2.2 Sheep prolactin and growth hormone during pregnancy and lactationThe hormone prolactin (PRL) is crucial to developing neurobiological adaptations to conception and lactation. In this manner, prolactin prepares the maternal body for the demands of pregnancy [31]. Prolactin and growth hormone (GH) signaling cascades are similar, and they depend heavily on signal transducers and activators of transcription 5 (STAT5) proteins [32]. In addition to their roles as cytokines that play a crucial role in fetal development by promoting cell proliferation and inhibiting apoptosis, GH and PRL are also important mediators of embryogenesis, organ development, and postnatal growth [33]. The biological effects of GH receptor (GHR) and PRL are either local or systemic depending on how the hormone binds to cell surface receptors and initiates signaling cascades [34].
Studies have shown that GH signaling can affect the maternal organism even though it is not generally associated with metabolic changes during pregnancy [32, 35]. The GH hormone regulates several metabolic functions on several organ and tissue levels, including pancreatic beta cells [36], liver [37], white adipose tissue [38], and skeletal muscle [37]. Wallace et al. [39] reported that fetal adipogenesis is enhanced by late GH treatment, indicating that GH directly influences adipose tissue composition. Another study found that ewes treated during pregnancy with extended-release GH delivered lambs with a higher birth weight and sustained postnatal growth advantage than lambs of untreated ewes, as well as blunted responses to GH stimulation [40]. The evidence thus suggests that environmental GH exposure may have long-term effects on offspring through alteration of maternal metabolism and placental function [41].
2.3 Placental hormones during pregnancyA pregnant ovine uterus is exposed to both placental prolactin and GH. Ovine endometrial gland morphogenesis and differentiation of secretory functions appear to be regulated by these hormones [42]. In sheep, the placenta secretes hormones related to pituitary GH and prolactin called placental lactogen (PL) [43]. On day 16 of pregnancy, binucleate cells of the conceptus trophectoderm begin releasing ovine PL, and this occurs at the same time as uterine milk protein gene expression initiation (UTMP) and oxytocin receptor gene expression by glandular epithelium (GE) in maternal [44]. Spencer and Bazer [45] reported that PL can be detected from day 50 and peak between days 120 to 130 of gestation. Both homodimers of PRL receptors (PRLRs), as well as a heterodimer of PRLR and GHRs, transduce signals through ovine PL [43], which binds to PRLRs only expressed by GE [42]. The production of PL by the conceptus is related to endometrial gland morphogenesis and increased production of UTMP, an ovine uterine milk protein, and osteopontin (OPN) by the GE during pregnancy [45]. During days 35 to 70 of gestation, the ovine placenta also expresses GH, which correlates with glandular epithelium hypertrophy and maximal expression of UTMP and OPN genes [42]. Figure 1 depicts the placental hormonal mechanisms that regulate the morphogenesis and function of the uterine glands during pregnancy in the ovine.
Figure 1: Illustrates the placental hormonal mechanisms regulating uterine gland morphogenesis and function during pregnancy in ovine. Placental lactogen (PL), prolactin receptor (PRLR), growth hormone receptor (GHR), osteopontin (OPN), oxytocin receptor (OXTR), uterine milk proteins (UTMP)
The pituitary gland produces hormones that regulate metabolism, growth, reproduction, and other endocrine glands [46]. The posterior pituitary gland releases oxytocin into the bloodstream [47]. Several local oxytocin-producing organs, including the uterus, the placenta, and the corpus luteum, indicate that oxytocin has more biological functions than previously anticipated [48]. As one of its many functions, it stimulates smooth muscle contractions of the uterus during labor/parturition and milk ejection from the mammary gland. Moreover, oxytocin regulates numerous functions, including follicle luteinization, steroidogenesis, and hormonal regulation of estrous cycles [49]. Oxytocin action is mediated by a G protein-coupled receptor that is known as the oxytocin receptor (OTR) [50]. As the OTR is activated by oxytocin, several second messengers are released, including intracellular Ca2+, which activates MAP-kinase pathways, facilitates smooth muscle contractions, and increases protein synthesis. Oxytocin appears to be involved in numerous physiological processes through its activation of the OTR [51]. In the granulosa cells, oxytocin receptors become active before ovulation, which suggests that oxytocin is involved in follicle development. Further, evidence suggests that oxytocin influences GnRH secretion, LH production, and progesterone production as well [52]. A study conducted in sheep found that progesterone and estrogen improve maternal behavior by enhancing oxytocin mRNA synthesis in brain regions associated with maternal behavior [53]. According to Konno et al. [54], oxytocin/oxytocin receptor connections play a crucial role in pair bonding between parents and offspring, as well as between sexual partners in monogamous species.
2.5 Osteopontin hormones during pregnancyThe osteopontin (OPN) hormone, also called secreted phosphoprotein 1, mediates cell-cell and cell-ECM communication by binding to a variety of integrins on the surface of cells [55]. Conceptus implant is achieved by OPN interacting with apically expressed integrin receptors on uterine LE and trophectoderm of the conceptus [56]. As conceptuses implant, they secrete estrogens, which stimulate uterine LE biosynthesis and the release of OPN [55]. Upon attachment of the conceptus to the uterine LE, OPN binds to T-integrins on the trophectoderm and T-integrins on the uterine LE, resulting in implantation [57]. In sheep, progesterone release by corpus luteum (CL) induces OPN synthesis and secretion from the endometrium GE into the uterine lumen; OPN binds to integrins expressed on trophectoderm (αvβ3) and uterine LE to adhere the conceptus to the uterus for implantation [55]. When OPN binds to ovine trophectoderm cells, it induces focal adhesion assembly, which is essential for trophectoderm adhesion and migration. By activating P70S6K through crosstalk between FRAP1/MTOR and MAPK pathways; a combination of MTOR, PI3K, MAPK3/MAPK1 (Erk1/2) and MAPK14 (p38) signaling can stimulate trophectoderm cell migration, along with focal adhesion assembly and myosin II motor activity to induce trophectoderm cell migration [55, 56].
Physiological differences between sheep breeds have led researchers to identify the possibility of controlling breeding activity using improved reproductive technologies. Reproductive biotechnology has made significant advancements in technology and delivery that promise significant advantages for livestock producers [58]. Most sheep reproduction management technologies aim to induce and synchronize estrus and ovulation, which allows out-of-season lambing [59]. Induced estrus and synchronized breeding allow lambs and sheep to produce uniform milk, reduce labor costs, and control nesting and kidding times, as hormones do in sheep using progestogens, prostaglandin (PGF2α), and equine chorionic gonadotropin (eCG) (Fig. 2) [60, 61]. Gonadotropin-releasing hormone or human chorionic gonadotropin (hCG) injections are given concurrently with mating, or just after, to prevent embryo and fetal loss or to enhance ewe reproductive traits [62]. An additional study found that a single dose of GnRH administered concomitantly with a progesterone-loaded CIDR device improved ovarian response in sheep-assisted reproductive technologies under a short-term protocol for synchronizing follicle wave emergence [63]. Currently, FSH is the most common hormonal ovarian superstimulation treatment. With frequent supraphysiological dosages, FSH stimulates and extends growth in the ovary and prevents early atresia of antral follicles by interfering with the somatic and germinal compartments. Sheep superovulated with exogenous FSH doses that range from 176 to 256 mg [64]. Another approach involved traditional superovulation protocols (TRAD) and Day 0 superovulation protocols (SOV) combined with the (D0+GnRH) treatments induced more favorable ovarian conditions (follicles ≤ 4 mm) [65]. In recent years, in vitro embryo production (IVEP) through the collection of oocytes postmortem or by repeated ovation pick-up from live females has emerged as an alternative to multiple ovulation and embryo transfer (MOET) programs. They may be used more frequently, moving away from laboratory research to field applications, becoming more widely used [66].
Figure 2: Scheme of synchronization and induction of estrus using (A) progestogens application, (B) prostaglandin (PGF2α) application, and (C) equine chorionic gonadotropin (eCG) application in seasonal anestrus (a) and reproductive season (b), used in the sheep [61]
In small ruminants, the reproductive function can be controlled by administering exogenous hormones to alter the physiological sequence of events involved in the estrous cycle. Appropriate use of assisted reproduction protocols requires knowledge of reproductive physiology and the interactions between hormones that control reproduction. Through these techniques, researchers are helping to clarify factors that contribute to early pregnancy loss, as well as factors that contribute to a slow embryonic development and growth rate. By identifying improved reproductive technologies and interventions, researchers will be able to improve reproductive strategies for increasing livestock reproductive efficiency.
