SCIENCE Animal Reproduction Science 42 ( 19%) 13I- 141 Nutrition and reproduction in the pig: Ovarian aetiology John R. Cosgrove a7b9 *, George R. Foxcroft b ‘Alberta Swine Genetics Corporation, Box 3310, Leduc, Alta. i’9E 6M I. Canada b Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alta. T6C IE7, Canada Abstract All mammalian reproductive processes will ultimately be determined by nutrient availability, from gametogenesis to lactation. The modem production gilt and sow, selected for lean growth rate and optimal milk production over an abbreviated lactation, represent extreme models in which to investigate interactions between the demands of somatic growth and reproduction. The focus of this review is nutritional modulation of the porcine gonad and, more specifically, the ovary, rather than the entire hypothalamo-hypophysial-gonadal axis. The influences and mechanisms of action of metabolic hormones and growth factors of both extra- and intra-ovarian origen are considered. Additionally, regulation of circulating gonadal steroids by nutrition and the consequent implications for gonadotrophin secretion and embryo mortality are discussed. Keywords: Reproduction; Nutrition; Growth; Follicle; Steroid; Pig 1. Introduction The modem domestic pig has been subjected to intense selection pressure for improved lean growth rate. Generally, emphasis has been placed on decreased fatness and increased growth rate in ‘sire’ lines and a combination of these traits plus gross measures of reproductive efficiency, e.g. litter size, in ‘dam’ lines. There is, however, no * Corresponding author at: Alberta Swine Genetics Corporation, Box 3310, Leduc, Alta. T9E 6M1, Canada. Tel.: (403) 986 1250; fax: (403) 986 6523; e-mail: jcosgrov@gpu.srv.ualberta.ca. 0378-4320/96/$15.00 0 1996 Elsevier Science B.V. All rights reserved. PIf SO378-4320(96)01523-O 132 J.R. Cosgrove, G.R. Foxcrofr/Animal 0 I To Appetite 0 “a To Appetite Reproduction To Appetle RC.MCtCd RCSttICted To Appetite , D21 , D28 Science 42 (1996) 131-141 Postweaning PostWeaning PostWeaning , D28 , Fig. 1. PlasmaLH concentrations of threefirstparitysows,duringthree 12h windowson days21 (D21)and 28 (D28)of lactationand postweaning,representative of threetreatmentgroups(28DFed, fed ‘to appetite’ throughout lactation; 7D Restrict, fed at 50% of ‘to appetite’ days 21 to 28 of lactation; 7D Refed, fed at 50% of ‘to appetite’ days 1 to 21, and ‘to appetite’ days 21 to 28 of lactation). (From Foxcroft et al., 1995). reason to suspect that the pig deviates from the classical models of nutrient/energy utilisation and partitioning proposed for all mammalian species (I’Anson et al., 1991 for extensive discussion) and that, as a priority for nutrient utilisation, reproduction ranks below cellular maintenance, thermogenesis and growth. Consequently, should nutrient availability be limited, via either food restriction or the greater demands of growth and/or lactation, gametogenesis will be postponed and fertility compromised. These assumptions probably apply more closely to the female than to the male. While boar steroid synthesis is sensitive to transient reductions in nutrient intake, spermatogenesis is less readily susceptible (Brown, 1994). The gilt and sow, however, exhibit marked reductions in fertility when subjected to less than optimal nutrition (see Kirkwood and Aheme, 1985 for review). As an evolutionary strategy to ensure genetic transmission, the pig, a polytocous, monogastric mammal, should not commit to an extended gestation and metabolically expensive lactation without sufficient assurance of adequate nutrition. A number of studies have considered the impact of nutrient restriction and repletion on the hypothalamo-hypophysial axis of the gilt and sow (see Booth, 1990; Cosgrove et J.R. Cosgrove, G.R. Foxcrofr/Animal Reproduction Science 42 (1996) 131-141 133 al., 1995 for reviews). Fig. 1 demonstrates the potentially dramatic impact of nutrition/metabolism on the primus movens of this axis, the hypothalamic luteinizing hormone-releasing hormone (LHRH) pulse-generator, via changes in pulsatile luteinizing hormone (LH) secretion in the sow. Evidence is growing, however, to suggest that the responses of the ovarian follicle itself, and perhaps also the oocyte, to gonadotrophic signalling are the subjects of nutritional/metabolic modulation. 2. Nutritional modulation of ovarian function While it is generally accepted that, given appropriate follicle stimulating hormone (FSH) and pulsatile LH stimulation, the porcine ovary is capable of folliculogenesis and ovulation from the neonatal period onwards (Casida, 1935; Elsaesser, 19821, it has long been recognised that nutrition will modify the scale of this response. Flowers et al. (1988) increased ovulation rate and LH pulse frequency by doubling energy intake of prepubertal gilts during the follicular phase. The incorporation of ad libitum diets and ‘flush feeding’ of gilts in commercial pig farming establishes the practical recognition of this fact. It remains an open question as to whether the effects of ‘flushing’ in the late luteal phase of the gilt are actually a function of altered LH pulsatility or purely ovarian-mediated phenomena. The increased frequency of extended weaning to oestrus intervals, lower conception rates and decreased litter sizes of lower (particularly first) parity sows also implicates a complex interaction between metabolic state and ovarian responsiveness to a similar gonadotrophic milieu (see Quesnel and Prunier, 1995 for review). Clowes et al. (1994) clearly demonstrated differential impacts of delayed breeding (‘skip-a-heat breeding’) between parity 1 or 2 sows and multiparous animals, concluding that metabolic state was a major determinant of subsequent fertility. Koketsu (1994) extended weaning to oestrus intervals in sows by reducing energy intake during any week of a three week lactation (e.g. 9.3 + 3 days vs. 18 f 3 days), without differences in mean LH concentrations on day 21 of lactation or post-weaning. In the study of Zak et al. (see Foxcroft et al., 1995), mean ovulation rate of primiparous sows subjected to a single week of reduced feed intake, from day 21 to 28 of a lactation suckling six piglets, was reduced compared with that of ad libitum fed controls (15.4 vs. 19.9 corpora lutea per sow). These results were in spite of a similar and robust increase in pulsatile LH secretion upon weaning in all sows (Fig. 1). Moreover, weaning to oestrus interval was only slightly extended by feed restriction (5.0 days compared with 3.7 days in full-fed controls). These data greatly contrast with previous studies which failed to show nutritional effects on ovulation rate in weaned sows (Kirkwood and Aherne, 1985; Koketsu, 1994) and suggest the possibility that an extended interval between weaning and oestrus permits a more robust ovarian follicular response to subsequent gonadotrophic stimulation, similar to the ‘skip-a-heat’ effects described by Clowes et al. (1994). These results also represent some of the first data indicating potential influences of nutrition on the recruitment/selection of the follicular pool in late lactation, a phenomenon perhaps best described as nutritional ‘imprinting’ of follicles. 134 J.R. Cosgrove, G.R. Foxcroji/Animul Reproduction Science 42 (19%) 131-141 3. Mechanisms underlying nutrition-ovarian interactions The work of Cox and colleagues has focused on metabolic hormones as integrators of nutritional status and ovarian function. Insulin treatment, irrespective of changes in gonadotrophin secretion, increased ovulation rates of cyclic gilts (Cox et al., 19871, stimulated follicular steroid synthesis and/or decreased follicular atresia in cyclic (Matamoros et al., 1990) and pregnant mare serum gonadotrophin (PMSG) treated (Matamoros et al., 1991) gilts. Similar results have been reported in insulin-treated, streptozotocin-induced diabetic gilts (Meurer et al., 1991). Insulin may directly affect granulosa cell glucose utilisation since changes in follicular fluid glucose concentrations did not parallel those in the periphery (Britt et al., 1988). Realimentation-induced increases in follicular aromatase activity and/or development have also been associated with marked increases in insulin status (Cosgrove et al., 1992; Charlton et al., 1993; Booth et al., 1994). Insulin status, however, responds dramatically and transiently to immediate glucose availability. While the reduced insulin concentrations reported in metabolically challenged gilts (Cosgrove et al., 1992; Booth et al., 1996) and sows (Tokach et al., 1992; Clowes et al., 1994) might compromise ovarian responsiveness to gonadotrophic stimulation, a number of additional/alternative metabolic signals may exert longer-term endocrine, paracrine and autocrine regulation of follicular function in the pig. Perhaps most extensively studied and widely implicated amongst these are the various growth factors known to act on, and be expressed by, porcine follicular cells. Concentrations of insulin-like growth factor 1 (IGF-I), secreted by hepatocytes (amongst other cells) in response to growth hormone (GH) stimulation, are determined by nutritional state (see Thissen et al., 1994 for review) and may even influence pituitary gonadotrophin secretion in the pig (Whitley et al., 1995). Feed restriction to maintain body weight and composition in prepubertal gilts results in depression of IGF-1 over 7 days (Cosgrove et al., 1992; Charlton et al., 1993; Booth et al., 1996) and short-term feed restriction in the lactating sow elicits reductions in circulating IGF-1 (Foxcroft et al., 1995). The increased litter size observed in first and second parity sows bred at second rather than first post-weaning oestrus observed by Clowes et al. (1994) was associated with increased circulating insulin and decreased circulating IGF-1 concentrations. These authors suggested that the relatively higher IGF-1 and lower insulin status in sows bred at first oestrus was indicative of recovery from catabolism and a reversal of protein-derived gluconeogenesis and, consequently, enhanced protein accretion. Under these circumstances, therefore, simple elevations of IGF-1 would not appear to be stimulatory to ovarian function. Interactions between GH-stimulated IGF-1 secretion, gonadotrophin sensitivity and follicular development are, however, complex in the pig. Ovarian IGF-1 synthesis may, in fact, mitigate the impact of extreme nutritional challenges to ovarian function (Charlton et al., 1993). Considerable data now exist describing the role of IGF-1 and other growth factors in the porcine ovary (see Guidice, 1992; Ojeda and Dissen, 1994 for reviews). IGF- 1 follicular fluid concentrations and gene expression increase during spontaneous and gonadotrophin- and GH-induced development during the follicular phase, falling after ovulation (see Hammond et al., 1993 for review). Similar, though not identical, J.R. Cosgrove, G.R. Foxcrofr/Animal Reproduction Science 42 (19% ) 131- 141 135 results have been reported during follicular development in the weaned sow (Howard and Ford, 1992). The most potent ovarian actions of IGF-I are apparent as interactions with those of gonadotrophins and other growth factors, e.g. enhancing gonadotrophin stimulated steroidogenesis (Veldhuis and Rodgers, 1987) and transforming growth factor-p (TGF-P) stimulated cellular proliferation and differentiation (May et al., 1988). An added degree of complexity underlying these actions is the regulation of growth factor bioavailability by binding proteins (IGFBP) which is influenced by the gonadotrophin and steroid milieu (Hammond et al., 1993). Transforming growth factor-a (TGF-Al, a member of the epidermal growth factor (EGF) family) is expressed in both thecal and granulosal cells of a number of species (see Mulheron and Schomberg, 1993 for review), including the pig (Sir@ and Armstrong, 1995). Both TGF-a and its receptor are expressed in bovine thecal and granulosal cells suggesting both paracrine and autocrine methods of action. A so-called ‘juxtacrine’ mode of action for the EGF family has also been proposed due to their synthesis as a transmembrane precursor (Massague, 19901, allowing cell to cell communication of similar or different phenotypes, e.g. granulosa and theta. TGF-(Y inhibits the steroidogenic actions of gonadotrophin-stimulation (May and Schomberg, 1989) while stimulating cell proliferation. The apparently opposing actions of TGF-a and IGF-1 on ovarian cell function may actually constitute a coordination of follicular development, allowing concomitant somatic growth and steroidogenesis, prerequisites for the preovulatory follicle (Ojeda and Dissen, 1994). Conversely, TGF-ol has been reported as stimulatory to oestrogen production of granulosa and theta cells in the prepubertal gilt (Gangrade et al., 1991). It is, therefore, feasible that the follicular cell response to TGF-a is dependent upon previous exposure to gonadotrophin hormones. Whether the extended suppression of high frequency LH pulsatility associated with suckling and catabolism in the lactating sow results in an ovarian sensitivity which equates with that of the prepubertal period remains to be investigated. It seems highly probable, therefore, that IGF-1, TGF-u and -p and a variety of other growth factors and binding proteins play important roles in selection of the pre-ovulatory follicular pool and, perhaps also oocyte maturation, and form a tangible link between metabolic status and ovarian function. 4. Nutritional modulation of gonadal message A plethora of mechanisms along the hypothalamo-hypophysial-gonadal axis may mediate nutritional modulation of reproduction. Relatively little researched, however, except in the area of embryo survival, is nutritional modulation of a major means of ‘gonadal-central’ communication, i.e. the sex steroids. Feed restriction in the pig (Cosgrove et al., 1993a; Cosgrove et al., 1993b; Booth et al., 19941, lamb (Foster et al., 1989) and cow (Day et al., 1986) suppresses pulsatile LH secretion principally via compromise of the LHRH pulse generator and a resultant quiescent gonad. Presumably a decrease in stimulatory neuronal inputs to the LHRH neurone results in decreased LHRH pulsatility, coupled with a potential increase in LHRH/hypophysial sensitivity to steroid negative feedback (e.g. Foster and Olster, 1985) and/or the activation of 136 J.R. Cosgrove, GR. Foxcroj?/Animal Reproduction Science 42 (19% ) 131- 141 inhibitory pathways. More recent results in the pig suggest that nutrition may acutely modify plasma concentrations of steroid and potentially the scale of negative feedback. A serendipitous observation of increased testosterone concentrations in cold, warm and hot temperature acclimatized boars subjected to overnight fasting (Cosgrove and Young, 1991) was confirmed by Cosgrove et al. (1993b). In this study both prepubertal and peripubertal boars were subjected to 24 or 48 h of fasting, followed by ad libitum feeding. Blood samples (hourly over four equally spaced 3 h periods each day) confirmed a fasting-induced increase in circulating testosterone in prepubertal boars and a remarkably rapid suppression of both testosterone and cortisol upon refeeding (Fig. 2(a)). Testosterone was similarly suppressed in peripubertal boars by a glucose infusion equivalent to approximately 10% of an ad libitum meal in place of realimentation (S.J. Cosgrove and J.R. Cosgrove, unpublished observation, 1992) and testosterone concentrations in two similarly treated castrate boars were basal throughout the study, suggesting a gonadal origen. Sex steroid metabolic clearance is more efficient prepubertally than postpubertally in the pig (Elsaesser and Foxcroft, 1978) and may explain why fasting-induced increases in testosterone were only observed prepubertally. Certainly the scale and rapidity of the declines in both testosterone and cortisol support a hypothesis of feeding-induced elevations in steroid clearance. A more recent study in the feed-restricted/realimented prepubertal gilt (Cosgrove et al., 1996) confirm the acute sensitivity of sex steroid concentrations to feed intake (Fig. 2(b)). Previous reports in gilts and sows (Symonds and Prime, 1989; S. Einarsson, personal communication, 1995) and sheep (Parr et al., 1993) suggest reductions in circulating progesterone following increases in feed consumption are associated with increased hepatic portal blood flow and consequent enhanced clearance. Rapid depressions in circulating sex steroids, combined with reduced hypothalamic sensitivity to steroid inhibition, coupled with an enhanced ‘central drive’ in pigs recovering from limited nutrient availability would, presumably, be a stimulus to reproduction. Conversely, nutritionally modulated rapid reductions in early luteal progesterone concentrations may have very serious consequences for embryo survival in the pig (Den Hartog and Van Kempen, 1980). Jindal et al. (1996) have now confirmed a clear correlation between increased embryo survival and more rapid elevation of luteal progesterone concentrations in ‘flushed’ gilts undergoing decreased feed intake 1 day after mating (‘flushed’ gilts, 64.6% embryo survival and 10.4 ng ml- ’ plasma progesterone; ‘non-flushed’ gilts, 84.6% and 4.5 ng ml- ‘>. Decreases in the metabolic Fig. 2. (a) Plasma LH (upper panels; 10 min samples), testosterone (centre panels; hourly samples) and cortisol (lower panels; hourly samples) concentrations during four equally spaced 3-h periods, over 4 days (C, ad libitum feeding; P24, 24 h fast; F48, 48 h fast; A48, resumption of ad libitum feeding), representative of profiles observed in five boars (Cosgrove et al., 1993b). (b) Changes (10 min sampling) in plasma oestradiol concentrations (percentage of hour 0 sample in each profile) for two R8 gilts (upper panel) and two R12 gilts (lower panel), representative of each treatment group, during five sampling periods Rd and Rn (8 h daytime and nighttime periods, respectively, when meal sizes were approximately 15% ad libitum), Rd30% and Rn30% (8 h daytime and nighttime periods, respectively, when morning meal size was approximately 30% ad libitum) and Ad (8 h daytime period when gilts fed ‘to appetite’ in a single morning meal) (Cosgrove et al., 19%). Arrows indicate times of feeding. Plasma Estradiol (% change from hour 0) E CatisoC (nglml) 5 -2 & Testosterone (ngiml) $ G -2” i ? ti t .. .....<.................. ._..., . .. i .5.. . .... -2 I- ... L ...z. J 1 t -2 ..... .... ..... (nglml) 0 in E P 24 *. .._ . . . . . . . . e -5 ‘I..... . .. ................” 3 c-- ...... ............. ‘r A? .. . 27.. / p c: ,& > < \ / U-l ..... 5 ... .... 2 2 E . ... . ....... ..... 5 f 138 J.R. Cosgrove, G.R. Foxcrofi/Animal Reproduction Science 42 (1996) 131- 141 clearance rate of progesterone by reduced post-mating feed intake may prove beneficial to embryo survival. Whether such variability in the timing of progesterone increases around mating alters the degree of synchrony between the developing embryo and the uterine environment, thus affecting embryo survival (see Pope et al., 1990 for review), remains to be established. Progesterone supplementation in pigs (Ashworth, 1991) around breeding can reverse detrimental effects of high-plane feeding. Preliminary results in the prolific Meishan gilt also suggest nutritional influences on steroids may be associated with altered luteal secretion in addition to clearance (Ashworth et al., 1995). In summary, therefore, the participation of short-term alterations of circulating steroid concentrations in the nutritional modulation of the reproductive axis should not be dismissed. 5. Conclusion Nutrition clearly impacts reproduction in the pig at various points along the hypothalamo-hypophysial-gonadal axis. These effects may be transiently expressed such as the short-term modulation of pulsatile LH secretion and circulating steroid concentrations. Serious consideration must be taken, however, of the potential longer-term effects of nutrition/metabolism on the ovarian follicle itself. The wealth of mechanisms described above may ‘imprint’ follicles recruited into the preovulatory pool and determine their ultimate responses to future gonadotrophic stimulation. Appropriate nutritional management of the cyclic gilt, primiparous and multiparous sows will, therefore, differ and be determined by both immediate and recent metabolic history and stage of cycle. Acknowledgements The authors gratefully acknowledge the support of research grants from Natural Sciences and Engineering Research Council of Canada and the Alberta Pork Producers’ Development Corporation and by contributions to the provision of animals by Pig Improvement (Canada) Limited. J.R.C. expresses thanks to E.J.J. for generous support throughout much turbulence! References Ashworth, CA., 1991. Effect of pie-mating nutritional status and post-mating progesterone supplementation on embryo survival and conceptus growth in gilts. Anim. Reprod. Sci., 26: 311-321. Ashworth, C.A., Antipatis, C. and Beattie, L., 1995. Effect of pre- and post-mating nutritional status on embryo survival in the pig. J. Reprod. Fertil. Abstr. Ser., 16: 12 (Abstr. 26). Booth, P.J., 1990. Metabolic influences on hypothalamic-pituitary-ovarian function in the pig. In: D.J.A. Cole, G.R. Foxcroft and B.J. Weir (Editors), Control of Pig Reproduction III. J. Reprod. Fertil. Suppl., 40: 89-100. 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