Abstract
Reproductive capabilities of females in all species have been known to be affected by their nutritional status. This is true particularly of malnutrition, for example, mineral imbalance that influences almost all facets of female reproduction, right from the onset of puberty to ovarian activity, ovulation, estrus exhibition, fertility, and conception rate. Mineral deficiencies lead to disturbances along hypothalamic-pituitary-ovarian axis, causing reproductive failure. Evidence gathered from in vitro studies and laboratory animal models suggests involvement of mineral ions in regulation of upstream pathways involved in synthesis and release of gonadotropin-releasing hormone inside hypothalamic nuclei as well as downstream pathways involved in its action on pituitary gonadotrophs. In contract, mineral availability of specific reproductive tissues during various physiological states and their actions in these tissues are poorly defined in any livestock species. Declaration of mineral deficiency of individual animals based on concentration in blood is often misleading due to extreme dietary influences. Moreover, mineral deficiencies are mostly subclinical and by the time symptoms start appearing, the reproductive symptoms thereof get overlooked due to the overall deterioration of the animal’s physiology. The present review offers a summary of biochemical, enzymatic, and endocrine actions of macromineral (calcium, phosphorus, and magnesium) and micromineral (copper, zinc, and manganese) ions along the reproductive axis. We hope to encapsulate research findings to understand the role of specific minerals in female reproduction and identification of biomarkers of impairment of reproductive axis in event of mineral malnutrition, to help us in the development of new nutritional and reproductive strategies for increasing fertility of livestock.
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6.1 Introduction
Mineral ions are inorganic substances that serve as essential components of physicochemical processes vital to life. Minerals are distributed throughout all body tissues, having a structural role in some tissues and a regulatory role in others (Underwood and Suttle 1999). The major minerals such as calcium, magnesium, sodium, potassium, phosphorus, sulfur, and chlorine are present in the body in relatively larger amounts. Minerals like Ca and P are important components of bone and other tissues; K, Na and Cl play an important part in the maintenance of acid/base balance and membrane electric potential; Na helps to maintain osmotic pressure, whereas Ca has a role to play in nerve transmission. On the other hand, the trace minerals which include iron, copper, zinc, cobalt, molybdenum, manganese, iodine, and selenium, influence enzyme activity as metalloenzymes (Mn, Zn) or as cofactors (Co), are associated with endocrine hormones (I) and serve as stabilizers of secondary molecular structure. Productive and reproductive efficiency of the animal is the most important factor for the success of a dairy farm. Mineral deficiencies are associated with loss of reproductive performance and related production parameters of economic importance. The hypothalamic–pituitary–gonadal axis as a vital bodily system governs the production and release of gonadal steroid hormones, which further regulate species-specific patterns of sexual development and behavior. Presumably, altered hormonal milieu and ultimately disruption of reproductive functions occur due to disturbance of one or more minerals along this axis. In general, minerals especially, Ca, P and Mg (major elements), and Cu, Zn and Mn (trace elements) influence the reproductive process by their action on hypothalamo-pituitary-gonadal axis (Michaluk and Kochman 2007; Pradhan and Nakagoshi 2008; Dicken et al. 2010). Reproductive performance is, however, affected not only by the absolute concentrations of the major elements, but also by their relative proportions, most notably that of Ca and P (Steevens et al. 1971).
6.2 Hypothalamic-Pituitary-Ovarian Axis
Hypothalamic-pituitary-ovarian axis refers to endocrine coordination between the hypothalamus, pituitary, and the gonads (ovaries) responsible for initiating and regulating the cyclic changes in the female reproductive tract (Fig. 6.1). The gonadotropin-releasing hormone (GnRH), produced by the hypothalamus, regulates gonadotropin secretion by the anterior pituitary, which in turn regulates ovarian functions. Potent stimulators of GnRH include members of the kisspeptin family of peptides. It is believed that GnRH neurons express GPR54 (kisspeptin receptor, KISS1R) and kisspeptin neurons target the GnRH neuronal network to influence the release of GnRH. The hypophyseal portal system picks up GnRH at the median eminence and transports it to the anterior pituitary. The pulsatile release of follicle-stimulating and luteinizing hormones is in response to rhythmic pulses of GnRH reaching the pituitary gonadotrophs. The pulsating nature of gonadotropin release drives follicular maturation, secretion of estrogen during proestrus, and ovulation and secretion of progesterone during diestrus. At the ovaries, the granulosa cells bind follicle-stimulating hormone and theca cells bind luteinizing hormone, to produce progestins, androgens, and estradiol – a model popularly known as two-cell–two-gonadotropin theory (Schiffer et al. 2019).
The neurosecretory mechanism responsible for GnRH secretion from the mammalian hypothalamus is under the influence of a complex interaction involving several excitatory and inhibitory signals. The control of GnRH release from the hypothalamus during the estrous cycle depends mainly upon the feedback mechanism from downstream molecules such as estrogen and progesterone (Kasa-Vubu et al. 1992; Evans et al. 1997; Harris et al. 1999; Richter et al. 2001). The largest healthy follicle in the cohort releases estradiol and inhibin which through a negative feedback mechanism prevent gonadotropin secretion. The lack of gonadotropin stimulation prevents the growth of other follicles in the cohort, whereas only the dominant follicle is selected to grow and destined to be the preovulatory follicle (Hillier 1994). Towards the end of follicular phase (especially during estrous), the peak estrogen production from preovulatory follicle induces GnRH surge from the hypothalamus through a positive feedback mechanism followed by a concomitant luteinizing hormone surge (Adams et al. 2008). This luteinizing hormone surge is responsible for final growth, maturation and ovulation of preovulatory follicle, and formation of corpus luteum. Following ovulation, the granulosa and theca cells of the ovulated follicle luteinize to produce progesterone. In non-pregnant animals, during the late-luteal phase, the luminal epithelium of the endometrium releases luteolytic signal (prostaglandin F2α). However, in a pregnant animal, embryo releases enough quantities of the maternal recognition of pregnancy signal (interferon tau) between days 12 and 32 of the estrous cycle (Bazer 2013). The interferon tau prevents the formation of the luteolytic signal, thereby leading to the persistence of corpus luteum. Evidence gathered from in vitro studies and laboratory animal models suggests involvement of mineral ions in several steps along the reproductive axis.
6.3 Macrominerals
Reproductive events are cyclic in nature so the nutrient requirement of tissues also varies across different physiological stages (Hurley and Doane 1989; Robinson 1990). Macro-minerals regulate various reproductive functions including biosynthesis, secretion, and function of hormones, and their requirement may vary independently according to various physiological stages such as puberty, pregnancy, lactation, and the postpartum period (Ahmed et al. 2000; Ali et al. 2010). A perusal of the scientific literature suggests that even though several macrominerals affect the reproductive health and fertility in farm animals, their precise roles in reproduction are not clearly defined. Among the macro-minerals, because of the role they play in the hypothalamic-pituitary-ovarian axis, Ca, P and Mg have been associated with the various reproductive processes (Table 6.1).
6.3.1 Calcium
Calcium (Ca) is a major macromineral that affects reproduction. This element is involved in various reproductive processes and acts via the hypothalamic-pituitary-gonadal axis to regulate follicular development and atresia. An optimum Ca concentration ensures that reproductive organs are properly sensitized to various hormones and that the normal reproductive cycle is maintained. Blood concentration of Ca varies across the estrous cycle, being maximum at estrous in cattle (Burle et al. 1995) demonstrating the critical role it plays during the follicular phase especially in and around estrus. In contrast, subclinical hypocalcemia has been reported to cause delayed puberty and anestrus in cows (Dutta et al. 2001). The blood Ca homeostasis is under the influence of parathyroid hormone, 1,25-dihydroxyvitamin D3 and calcitonin. The parathyroid hormone and 1,25-dihydroxyvitamin D3, released in response to low Ca concentration, increase blood Ca by increasing bone resorption, decreasing renal excretion, and enhancing Ca absorption from the intestines. Calcitonin from the thyroid gland, on the other hand, decreases blood Ca by inhibiting reabsorption of Ca from bones and increasing urinary Ca excretion (Murray et al. 2008).
At the level of the hypothalamus, the neuronal circuitry responsible for the pulsatile secretion of GnRH from axonal terminals near median eminence is dependent on voltage-sensitive Ca2+ influx for its maintenance (Bourguignon et al. 1987; Goor et al. 2000). As GnRH concentrations increase beyond a threshold, isolated gonadotrophs have also been shown to respond by presenting dose-dependent intracellular Ca2+ signals (Leong and Thorner 1991; Stojilković et al. 1993; Tomić et al. 1996; Sánchez-Cárdenas and Hernández-Cruz 2010). The GnRH receptor (GnRHR) on the gonadotroph membrane is a member of the G-protein-coupled receptor (GPCR) family (Naor 2009). The binding of GnRH to the receptor, activates phospholipase C, which in turn hydrolyzes membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Naor 2009). IP3 initiates Ca2+ release from the intracellular pool, the rise which is responsible for the fusion of gonadotropin-laden secretory vesicles with the plasma membrane to release hormones (Stojilković et al. 1991; Martin 2003). In addition, DAG-induced protein kinase-C activation also drives the influx of extracellular calcium into gonadotrophs through voltage-gated Ca2+ channels for sustained release of gonadotropins (Durán-Pastén and Fiordelisio 2013). Ca withdrawal either due to deficiency or due to presence of Ca blockers inhibits the release of GnRH, follicle-stimulating hormone and luteinizing hormone (Stojilković et al. 1988; Krsmanović et al. 1992; Dhanvantari and Wiebe 1994). It is believed that the detection of Ca by Ca-binding synaptotagmins is involved in both vesicle docking as well as synaptic vesicle fusion with the cell membrane by using SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) proteins as effectors (Durán-Pastén and Fiordelisio 2013).
At the ovarian level, the level of Ca in the follicular fluid increases with the increase of follicular size in cattle (Wise 1987), suggesting a possible role in the gonadotropic regulation of ovarian steroidogenesis (Veldhius and Klase 1982; Carnegie and Tsang 1984). Ca influences cholesterol delivery to and utilisation by mitochondria, and stimulates conversion of pregnenolone to progesterone, which might further explain how this mineral affects ovarian stereogenesis (Shemesh et al. 1984). As the follicle develops from early follicle to the ovulatory stage, an increase in the mineral content (including Ca) of follicular fluid osmotically drives the movement of water from the blood to antrum (Kalmath and Ravindra 2007). Moreover, an increase in Ca concentration increases plasmin activity which in turn weakens the follicular wall and initiates the process of ovulation (Espey 1970). Calcium dependent endonucleases have also been recognized for causing follicular and luteal cell apoptosis.
6.3.2 Phosphorus
The importance of Phosphorus (P) for the normal functioning of all animal tissues is underlined by its involvement in the process of energy exchange at tissue level, besides its role in growth, lactation and reproduction (Little 1970). P is an essential component of phospholipid–dependent protein kinase and cAMP-dependent protein kinase, and is, therefore, crucial in mediating hormone action at the target tissues (Hurley and Doane 1989). The deficiency of P leads to disturbances along HPO-axis, resulting in dysregulation of the normal reproductive rhythm including ovulation (Bhaskaran and Abdulla Khan 1981; Ullah et al. 2010). P-deficiency is manifested as an alteration of ovarian activity resulting in delayed puberty, irregular cyclicity and cessation of behavioral estrous (Hurley and Doane 1989; Ahmed et al. 2010). As compared to anestrous cattle and buffaloes, significantly higher serum concentrations of P (total as well as free form) have been reported in normal cyclic animals (Dutta et al. 2001; Chaurasia et al. 2010). Similarly, in comparison to blood, higher concentrations of P have been reported in follicular fluid (Abd Ellah et al. 2010; Tabatabaei and Mamoei 2011). The concentration in follicular fluid tends to increase towards (Abd Ellah et al. 2010; Eissa 1996).
The importance of dietary calcium and phosphorus ratio (Ca:P) for reproductive performance has been stressed by Pugh et al. (1985), suggesting that a disturbed dietary Ca:P ratio with a resultant improper serum ratio of the ions has a blocking action on the pituitary gland and consequently on the ovarian function. Low Ca and inorganic P levels with resultant serum Ca:P imbalance might be responsible for anestrus status in heifers under poor managemental practices (Dunn and Moss 1992). 1α-hydroxylase (key enzyme in synthesis of 1,25-dihydroxyvitamin D3) deficient [1α(OH)ase−/−] female mice have been reported to be infertile and exhibit uterine hypoplasia and absence of corpora lutea which was attributed to the resulting hypocalcemia and hypophosphatemia (Panda et al. 2001). Infertility accompanied by decreased synthesis of sex steroids, defects in follicular and luteal development, decreased expression of ovarian angiogenic factors and hypoplasia of endometrium was observed in response to hypocalcemia and hypophosphatemia in 1,25-dihydroxyvitamin D3-deficient female mice (Sun et al. 2010). The infertility and the associated defective reproductive phenotype in 1α-hydoxylase deficient female mice were reversed when serum Ca and P levels were restored by the rescue diet (Sun et al. 2010). Besides, reproductive problems such as low first service conception rates and silent heat in ewes (Mosaad and Derar 2009) and delayed puberty in buffalo heifers (Ahmed et al. 2010) have been related to abnormally wide Ca:P ratios.
6.3.3 Magnesium
Magnesium (Mg) has a role in reproduction (Stolkowski 1977), but a direct effect has not been demonstrated yet. Low Serum Mg levels have been reported during anestrous in cattle (Dutta et al. 2001) and buffaloes (Chaurasia et al. 2010). Mg on account of its association with ATP is involved in enzymatic reactions that require the transfer of a phosphate group such as protein kinases and ATPases involved in the transport of various ions (Weisinger and Bellorín-Font 1998; Romani 2007; de Baaij et al. 2015). Mg and ATP are essential substrates for adenyl cyclase, an enzyme required for the synthesis of cyclic adenosine monophosphate (cAMP) – an important second messenger for several reproductive hormones. Protein kinases and cAMP, on the other hand, are involved in hormone synthesis, storage and release at different sites in the hypothalamo-pituitary-ovarian axis (Poisner and Douglas 1968; Moriyama et al. 2000), and physiological response in target cells.
High Mg and low Ca in the perifusion medium increases activity of suprachiasmatic nucleus in brain tissue slices (Pan et al. 1992). The nucleus is involved in circadian rhythm and has receptors for estrogen and progesterone (Kruijver and Swaab 2002), and possibly be involved in the regulation of cyclicity. The release of luteinizing hormone releasing hormone (LH-RH) occurs in an Mg dependent manner (Burrows and Barnea 1982a). In an in-vitro assembly, Mg and ATP act jointly to facilitate the release of LH-RH in hypothalamic granules, though Mg alone can also release LH-RH but to a lower magnitude (Burrows and Barnea 1982a). In humans, the risk of polycystic ovarian syndrome was 19 times greater in Mg deficient females than those with normal serum concentrations (Sharifi et al. 2012).
Acute magnesium deficiency is associated with diminished activity of lecithin cholesterol acyltransferase (LCAT), an enzyme involved in reverse cholesterol transport (Gueux et al. 1984). LCAT converts cholesterol to cholesterol esters, which are taken up by follicular cells for steroidogenesis (Cigliano et al. 2002). Mg deficiency can impair estrogen metabolism and deplete brain dopamine (Sircus 2011). In addition, Mg is an essential component of sex hormone-binding globulin (SHBG), a glycoprotein that transports the sex steroids in the blood and regulates their activity in target cells (Maggio et al. 2011). Mg status affects concentrations of cytochrome P450 (CYP450) enzymes involved in both vitamin D–activating (25-hydroxylase and 1α-hydroxylase) and deactivating enzymes (24-hydroxylase) (Dai et al. 2018). It has also been demonstrated that Mg can modulate parathyroid hormone (PTH) secretion (Rodríguez-Ortiz et al. 2014). Hence, Mg influences the absorption of Ca and P, and therefore, its imbalance may also hamper reproductive efficiency indirectly.
6.4 Micro/Trace Minerals
Trace minerals are essential for the normal functioning of the body as cofactors, as activators of enzymes, or as stabilizers of secondary molecular structures, even though they constitute a miniscule of the total mass of the organism (Rabiee et al. 2010). These minerals play vital roles in vitamin synthesis, hormone production, collagen formation, oxygen transport, energy production, and other physiological processes related to growth, reproduction and health (Ceko et al. 2016). However, some processes are prioritized over others under various conditions, e.g., reproduction or immune competence may be altered during subclinical deficient states without any effect on growth and feed intake. Most micronutrient deficiencies affect reproduction through analtered enzyme activity that disrupts energy and protein metabolism, hormone synthesis, and the integrity of rapidly dividing cells within the reproductive system (Table 6.2). Besides, microminerals serve as antioxidants and scavenge free radicals to protect cells from free radical-induced oxidative damage (Leung 1998; Spears and Weiss 2008).
6.4.1 Copper
The influence of copper (Cu) on both production and reproduction renders this trace mineral of utmost importance to the livestock industry. Cu related physiological disorders may be due to Cu deficiency in diet or due to presence of molybdenum (Mo) and/or sulfur (S) in diet which interferences with Cu bioavailability (Clarkson et al. 2019).
Cu deficiency appears to play significant roles in two key areas i.e. altered reproductive performance and immune suppression (Corah 1996). The consequences of Cu deficiency (high dietary Mo and S) in grazing ruminants may vary from no alteration in estrous behavior to delayed onset of puberty and depressed estrous, but severe copper-deficient cows may show anovulation and retardation of future estrous cycles leading to low fertility (Annenkov 1981; Ingraham et al. 1987; Phillippo et al. 1987; Corah and Ives 1991). The mean serum Cu level in anestrous cattle and buffaloes is reported to be lower than in cyclic animals (Dutta et al. 2001; Akhtar et al. 2009; Ahmed et al. 2010). Neutrophils and mononuclear cells from heifers fed low Cu diet prepartum exhibited reduced phagocytic activity (Torre et al. 1995; Torre et al. 1996). Cu is essential for the activity of superoxide dismutase (SOD1) enzyme, the deficiency of which is associated with defects in ovarian folliculogenesis and dysregulation of luteal function leading to subfertility and infertility in mice (Matzuk et al. 1998; Noda et al. 2012).
Cu has specific effects on the reproductive axis at the level of the hypothalamus, pituitary and ovary. It maintains optimum fertility by affecting GnRH, FSH, LH and estrogen activity (Desai et al. 1982; Michaluk and Kochman 2007). Administration of Cu salt leads to ovulation in female rabbits (Suzuki et al. 1972; Tsou et al. 1977) and ewes (Murawski et al. 2006), through hypothalamic action. Divalent Cu ion is essential for the activity of peptidylglycine α-hydroxylating-monooxygenase (PHM), an enzyme involved in the first step of generation of C-terminal carboxamides of peptide hormones, the reaction necessary for activation of active GnRH peptide from the prohormone (Prigge et al. 2000) (Fig. 6.2). Cu complex variant of GnRH has been shown to interact with GnRH receptors with enhanced affinity, to bring about a more potent release of LH, and to modulate intracellular signaling by increasing cAMP accumulation in the gonadotrope cells, whereas the non-complexed GnRH utilizes IP3/DAG signaling pathway (Kochman et al. 2005; Michaluk and Kochman 2007; Gajewska et al. 2016).
Cu-deficiency induced perturbation of the follicular growth and development may be due to disturbance in Cu-containing enzyme, lysyl oxidase, which promotes cross-linking of collagen and elastin, and stabilizes the extracellular matrix (Kendall et al. 2003). The basal lamina is constantly remodeled as the follicle matures (Rodgers et al. 1999), thereby requiring the expression of the lysyl oxidase in granulosa cells (Slee et al. 2001). Interestingly, a high concentration of Cu in follicular fluid is seen as an endocrine disruptor leading to polycystic ovary syndrome (Sun et al. 2019).
6.4.2 Zinc
Zinc (Zn) plays a pivotal role in reproduction as an essential component of enzymes in different biochemical pathways (Hurley and Doane 1989). It acts indirectly through the pituitary to influence the release of gonadotropic hormones (Dicken et al. 2010) and directly owing to its presence in Zn fingers (two in number) in steroid receptors (Spelsberg et al. 1989). The second step of the amidation reaction for activation of active GnRH from prohormone is carried out by peptidylglycine α-amidating lyase which requires divalent Zn as a cofactor (Michaluk and Kochman 2007) (Fig. 6.2). It has a physiological role in regulating pituitary prolactin secretion (Brandao-Neto et al. 1995; Lee and Kelleher 2016), and its deficiency is associated with hyperprolactinemia (Dicken et al. 2010), resulting in suppression of hypothalamo-pituitary-gonadal axis.
Zinc deficient animals have depressed serum vitamin A levels as it’s deficiency hampers mobilization of vitamin A from the liver. Zn and vitamin A are necessary for the normal functioning of the germinal epithelium of the ovary, and their deficiency leads to deformed or atretic follicles resulting in failure of the ovarian function (Chhabra and Arora 1985). Lower mean serum Zn levels have been reported in buffaloes suffering from anestrous (Akhtar et al. 2009; Ahmed et al. 2010) than their cyclic counterparts.
Zn deficiency is associated with suboptimal steroid hormone concentrations i.e. estrogen and progesterone (Akhtar et al. 2009) which is attributed to the involvement of the ion in the process of steroidogenesis (Hurley and Doane 1989). Ovarian (follicular fluid and granulosa cell) zinc content is reduced during follicular atresia (Kaswan and Bedwal 1995; Bhardwaj and Sharma 2011; Mahavar 2011), indicating that the ion can serve as a marker for follicular health. Higher follicular fluid concentrations of Zn and Cu positively influence the outcome of IVF in the form of greater MII oocyte retrieval, and higher fertilization and cleavage rates (Sun et al. 2017). Zn is essential for cumulus cell expansion and completion of meiosis-I, and an acute Zn deficiency blocks follicle rupture during ovulation (Tian and Diaz 2012). Additionally, Zn supplementation during in vitro maturation (IVM) significantly increased the meiotic competence of bovine oocytes (Barros et al. 2018), and supplementation during in vitro embryo culture improved the cell number of inner cell mass (Woolridge et al. 2019).
6.4.3 Manganese
Manganese (Mn) is an essential component of bovine nutrition required for carbohydrate metabolism, bone growth, normal brain function, growth, reproduction, and a variety of enzymatic systems (Aschner and Aschner 2005). Corah (1996) suggested that Mn has far more influence on reproduction than actually realized. The effects of Mn deficiency on reproduction have been reviewed over the last few decades (Hidiroglou 1979; Pugh et al. 1985; Sharma 2006; Kumar et al. 2011). Poor follicular development with delayed ovulation, delayed postpartum estrous and delayed puberty in heifers, reduced intensity of estrous, and reduced conception rates are also associated with Mn deficiency (Bentley and Philips 1951; Bourne 1967).
Although the precise mechanism of the involvement of Mn in reproduction is unknown, evidence suggests its role in the activity of certain endocrine organs. Both pituitary and ovarian tissues, particularly Graafian follicle and corpus luteum, are rich in Mn content (Hidiroglou 1979). Mn is carried by transport proteins such as transferrin and divalent metal transporter-1 across the blood-brain barrier into the hypothalamus (Garcia et al. 2006; Aschner et al. 2008). Chronic administration of Mn at low doses has been reported to increase serum levels of LH, FSH and estradiol in female rats, possibly due to the hypothalamic action of the ion (Pine et al. 2005; Lee et al. 2006; Lee et al. 2007). Mn supplementation in female rats activates upstream genes, mainly the Kiss-1 gene, which regulate GnRH release from hypothalamic nuclei (Srivastava et al. 2013). The Kiss-1 gene is responsible for the synthesis of kisspeptins (Thompson et al. 2004; Caraty et al. 2007; Keen et al. 2008; Lehman et al. 2010). The Mn-stimulated kisspeptin synthesis is mediated by the IGF-1/Akt/mTOR pathway in the prepubertal female rat (Srivastava et al. 2016; Dees et al. 2017) (Fig. 6.2).
Ovarian Mn content is particularly responsive to Mn deficiency (Wilson 1966; Hurley and Doane 1989). Mn deficiency alters the synthesis of gonadal hormones such as estrogen and progesterone in the female (Keen and Zidenberg-Cheer 1990; Pradhan and Nakagoshi 2008), possibly through inhibition of cholesterol and cholesterol precursor synthesis (Doisy 1974). Mn is an essential component of mitochondrial superoxide dismutase (SOD2). SOD2 expression in corpus luteum has been reported to increase from mid-luteal to late-luteal phase in women (Sugino et al. 2000) and sheep (Al-Gubory et al. 2005), but does not alter in pregnant ewes between days 12 and 20 (Arianmanesh et al. 2011) suggesting a role in corpus luteum regression.
Mn supplementation shortens the postpartum anestrous period and increases conception rates in dairy cows (Krolak 1968; Ahmed et al. 2010), and is effective in suspending summer acyclicity in buffaloes (Ahmed et al. 2010). The serum concentrations of Mn are lower in delayed ovulating and anovulating heifers as compared to normal ovulating heifers (Das et al. 2009). This report confirms the earlier claims that delayed ovulation can be experimentally induced by dietary withdrawal of Mn from dairy cows (Rojas et al. 1965), thus underlining the crucial role Mn plays in the normal ovulatory process.
6.5 Conclusion
Dietary mineral elements in excess or otherwise affect the normal physiological processes of an animal. Imbalances in the mineral availability also affect the reproductive process leading to subnormal fertility, anestrous and ovulatory disturbances. The hypothalamo–pituitary–gonadal axis is the primary site of action of mineral ions. Derangements of mineral availablility end up altering the hormonal milieu along the hypothalamo–pituitary–gonadal axis and cause normal reproductive functions to fail. Evidence gathered from in vitro studies and laboratory animal models suggests involvement of mineral ions in regulation of upstream pathways involved in synthesis and release of gonadotropin-releasing hormone (GnRH) inside hypothalamic nuclei as well as downstream pathways involved in its action on pituitary gonadotrophs. However, advances in the understanding of such molecular mechanisms of action of mineral ions have not found their way into ruminant nutrition research and practice, leading to a widespread mineral imbalance in prized livestock. These imbalances not only affect the health of an individual animal or that of a herd, but tend to be a major hurdle in livestock rearing from an economical dimension as well.
Future research should focus on (1) finding better ways of supplementation that will increase bioavailability of minerals ions at specific sites along reproductive axis, (2) the establishment of a panel of biomarkers of reproductive functionality to be used in farm animals for early detection of specific mineral deficiency, (3) understanding how genetics and stages of (re)production of an animal affect the dynamics of mineral requirements as well as their utilisation; (4) understanding the effect of regional as well as seasonal variations on specific and general mineral requirements of an animal instead of a one-size-fits-all approach; and (5) extension of molecular research from laboratory animal models to ruminant nutrition practice.
Abbreviations
- Akt:
-
serine/threonine kinase, also known as protein kinase B
- GnRH:
-
gonadotropin-releasing hormone
- GPCR:
-
G-protein-coupled receptors
- HPO:
-
hypothalamic-pituitary-ovarian axis
- IGF1:
-
insulin-like growth factor 1
- LCAT:
-
lecithin cholesterol acyltransferase
- mTOR:
-
mammalian target of rapamycin
- PAL:
-
peptidylglycine α-amidating lyase
- PGF2α:
-
prostaglandin F2α
- PHM:
-
peptidylglycine α-hydroxylating-monooxygenase
- PIP2:
-
phosphatidylinositol 4,5-bisphosphate
- SHBG:
-
sex hormone-binding globulin
- SNARE:
-
soluble N-ethylmaleimide-sensitive factor attachment protein receptors
- SOD:
-
superoxide dismutase
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We would like to thank Dr. S.S. Dahiya (Director, ICAR-CIRB) for valuable suggestions and comments.
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Jan, M.H., Singh, H., Kapil, S. (2022). Mineral Ions in Regulation of Hypothalamic-Pituitary-Ovarian Axis. In: Yata, V.K., Mohanty, A.K., Lichtfouse, E. (eds) Sustainable Agriculture Reviews 57. Sustainable Agriculture Reviews, vol 57. Springer, Cham. https://doi.org/10.1007/978-3-031-07496-7_6
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