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Reproductive cycles in pigs
Animal Reproduction Science 124 (2011) 251–258
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Reproductive cycles in pigs夽 N.M. Soede a,∗ , P. Langendijk b , B. Kemp a a b
Adaptation Physiology Group, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands South Autralian Research and Development Institute (SARDI), Roseworthy Campus, Roseworthy, SA 5371, Australia
a r t i c l e
i n f o
Article history: Available online 23 February 2011 Keywords: Pig Oestrous cycle Follicle development Ovulation
a b s t r a c t The oestrous cycle in pigs spans a period of 18–24 days. It consists of a follicular phase of 5–7 days and a luteal phase of 13–15 days. During the follicular phase, small antral follicles develop into large, pre-ovulatory follicles. Being a polytocous species, the pig may ovulate from 15 to 30 follicles, depending on age, nutritional status and other factors. During the luteal phase, follicle development is less pronounced, although there is probably a considerable turnover of primordial to early antral follicles that fail to further develop due to progesterone inhibition of gonadotrophic hormones. Nevertheless, formation of the early antral follicle pool during this stage probably has a major impact on follicle dynamics in the follicular phase in terms of number and quality of follicles. Generally, gilts are mated at their second or third estrous cycle after puberty. After farrowing, pigs experience a lactational anoestrus period, until they are weaned and the follicular phase is initiated, resulting in oestrus and ovulation 4–7 days after weaning. This paper describes the major endocrine processes during the follicular and luteal phases that precede and follow ovulation. The role of nutrition and metabolic status on these processes are briefly discussed. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Gilts usually reach puberty between 150 and 220 days of age, depending on many factors, including timing of boar contact and body condition. After puberty, oestrous cycles of 18–24 days follow and most gilts are inseminated during the 2nd or 3rd oestrus after puberty. After successful insemination, a pregnancy of 114–116 days duration follows. During the 16–40 days of lactation (depending on e.g., production system and legislation), sows normally experience lactational anoestrus which is then followed by a rather fixed weaning-to-oestrous interval of 4–6 days. These reproductive stages are controlled by a system of positive and negative feedback of the reproductive hormones that are produced and released
夽 This paper is part of the special issue entitled: Reproductive Cycles of Animals, Guest Edited by Michael G. Diskin and Alexander Evans. ∗ Corresponding author. E-mail address: [email protected] (N.M. Soede). 0378-4320/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.anireprosci.2011.02.025
from the hypothalamus (gonadotrophin-releasing hormone, GnRH), the pituitary (follicle-stimulating hormone, FSH; luteinizing hormone, LH; oxytocin and prolactin), the ovaries (progesterone, P4; 17-oestradiol, E2; inhibins and relaxin) and the uterus (prostaglandin F2␣, PGF2␣). Reproduction in pigs is rather exceptional in the sense that they ovulate 15–30 oocytes in one oestrous period. The ovulation rate and the quality of the ovulating follicles depends on the process of follicle development in the preceding period. This paper starts with a description of the pre-follicular phase (being either the luteal phase of the cycle or the lactation period), during which follicle development is largely, but not entirely suppressed. It follows with the follicular phase, during which follicles are recruited and selected from a pool of developing follicles. Thereafter, the period of oestrus and ovulation is briefly discussed, followed by luteinisation and the (early) pregnancy period. Most of the reproductive stages/processes are affected by environmental and management factors (such as nutrition/energy balance and stress) and examples of such influences will be incorporated when appropriate.
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Fig. 1. Plasma concentrations of 17-oestradiol and progesterone (A) and FSH, LH and Inhibin A (B) and follicular and CL development (C) during the oestrous cycle in sows (based on Noguchi et al., 2010). The vertical line in the figures represents time of ovulation.
This paper does not discuss puberty attainment, the process of luteolysis or farrowing or the use of hormonal manipulations. 2. Pre-follicular phase The pre-follicular phase is the phase prior to the 4–6 day follicular phase that precedes ovulation. During this phase, follicle development is usually largely suppressed, either by progesterone (during the luteal phase of the cycle) or by ongoing lactation. The number and quality of follicles at the onset of the follicular phase are largely determined by processes during the pre-follicular phase. 3. Luteal phase of the oestrous cycle At the onset of the luteal phase, immediately after ovulation, peripheral concentrations of P4 are minimal and pig ovaries are practically void of larger antral follicles (see Fig. 1) due to greater oestrogen and inhibin concentrations prior to ovulation. Inhibin and E2 production decreases
as the ovulation occurs, removing the negative feedback on FSH. Peripheral concentrations of FSH are, therefore, greater at days 1 and 2 after ovulation, which induces a wave of synchronised follicle development and an increase in the number of small and medium sized follicles. Subsequently inhibin production by these follicles increases, which then reduces peripheral concentrations of FSH. The developing corpora lutea produce increasing quantities of P4, that reach peak concentrations by days 8–9 after ovulation (Fig. 1), also suppressing secretion of gonadotrophins. Small antral follicle numbers seem to increase up to day 9 (reviewed by Knox, 2005) but follicle diameters remain relatively small resulting in minimal (Knox et al., 2003) or no (Fig. 1) systemically measurable peripheral concentrations of oestrogen. It is debated whether or not in sows follicle waves exist during the remainder of the luteal phase. If follicle waves are defined as waves of follicles development up to the dominant stage, waves of follicular development do not occur. However, if follicle waves are defined as synchronised development of small antral follicles, there is some evidence this type of follicular development occurs in pigs.
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Fig. 2. Representative pulsatile LH-patterns at the day before weaning (A) and the day of weaning (B) in a primiparous sow. Weaning took place at day 24 of lactation at 0800. Blood samples were taken every 12 min (van Leeuwen and Soede, unpublished results).
Some of the individual FSH profiles shown by (Knox et al., 2003) and (Noguchi et al., 2010) have clear FSH surges, lasting 2–3 days, with matching changes in inhibin and follicle diameter (Noguchi et al., 2010). However, follicle diameter remains limited to at most 3–4 mm during the luteal phase (Hazeleger et al., 2005). 4. Lactational anoestrus During established lactation, peripheral concentrations of LH and LH-pulsatility are suppressed due to the sucklinginduced inhibition of the GnRH-pulse generator (De Rensis et al., 1993). The degree of LH-suppression is related not only to the suckling intensity, but also to the negative energy balance of the sow; in primiparous sows on a lesser amounts of available feed, peripheral concentrations of LH were reduced compared to sows fed greater amounts of feed (Quesnel et al., 1998; Van Den Brand et al., 2000b). Effects of lactation on FSH are less consistent, and are primarily due to negative feedbacks of inhibin (produced by the limited growth of antral follicles) rather than suckling effects (reviewed by (Prunier et al., 2003)). In the course of lactation, LH-pulsatility is normally restored (van den Brand et al., 2000a), which may be related to a decrease in suckling frequency and or to the increase in pituitary LH responsiveness to GnRH (Bevers et al., 1981; Rojanasthien et al., 1987). Concomitantly with this increase in LH-pulsatility, follicle diameter increases during the course of lactation (reviewed by (Britt et al., 1985)). Thus, with progressing lactation, the follicle pool in the ovaries reach a greater diameter, though most sows do not develop follicles beyond a diameter of 3–4 mm after weaning (Lucy et al., 2001), although occasionally sows develop pre-ovulatory diameter follicles (∼8 mm) and ovulate during lactation. At the end of lactation, the majority of sows appear to have synchronized waves of follicle development (Lucy et al., 2001), with follicle diameters reaching 4–5 mm and then regress. The inhibition of LH release during lactation influences both lactational follicle development and the resumption of ovarian activity after weaning (Shaw and Foxcroft, 1985; Quesnel et al., 1998). Additionally, the mechanism of positive feedback of oestradiol on the LH-surge matures in the course of lactation, increasing the ability of sows to mount a pre-ovulatory LH-surge of sufficient magnitude (Sesti and
Britt, 1993). These mechanisms together form the basis for lactational effects on subsequent fertility variables, such as: weaning-to-oestrus interval, ovulation rate and even embryo survival (reviewed by (Prunier et al., 2003)), eventually affecting farrowing rate and litter size. Allowing post-weaning follicle regression, either by feeding a progesterone analogue for at least 4 days post weaning or by inseminating sows at the second oestrus after weaning, will benefit subsequent fertility of sows with compromised follicle development at weaning (Patterson et al., 2008). 5. Follicular phase The follicular phase of the pig oestrous cycle lasts 4–6 days and either follows a luteal phase or lactation. At the start of the follicular phase or, possibly, at the end of the pre-follicular phase, depending on the peripheral concentrations of progesterone (luteal phase) or the suppressive effects of lactation (depending on days after parturition, negative energy balance and suckling intensity), the largest antral follicles in the pool (usually 2–4 mm) are recruited and start to develop. Recruited follicles may still undergo atresia during the follicular phase, but once selected, escape atresia and eventually ovulate at a diameter of 7–8 mm (reviewed by Guthrie, 2005; Knox, 2005). 5.1. Recruitment and selection The antral follicle pool that is present at the onset of the follicular phase has developed during the late luteal phase of the oestrous cycle or during lactation and may consist of on average 100 follicles, varying in diameter up to 6 mm (reviewed by (Knox, 2005)). Immunisation against GnRH halts follicular development at the early antral stage (Esbenshade et al., 1990), showing the importance of GnRH-induced FSH and LH release for the further development of the antral follicle pool. Recruitment of follicles from the pool takes place when pulsatile GnRH/LH release shifts from a lesser frequency/greater amplitude pattern to a greater frequency/lesser amplitude pattern, as illustrated in Fig. 2 for a sow around weaning. This change in LH-release pattern has been established for both weaned sows (Shaw and Foxcroft, 1985) and for animals that have initiated oestrous cycles (Flowers et al., 1991). Its relevance for subsequent follicle development has been
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demonstrated in studies where frequent administration of GnRH during lactation, during anoestrus and in prepubertal gilts induced development of large antral follicles and subsequently oestrus (Britt et al., 1985). In weaned sows, frequency of LH pulses both before and after weaning, is compromised in sows with a more negative energy balance during the preceding lactation (van den Brand et al., 2000a) and this results in a prolonged weaning-to-oestrus interval (Shaw and Foxcroft, 1985; van den Brand et al., 2000a). Pulsatile GnRH release may induce the release of both LH and FSH from the anterior pituitary (Guthrie et al., 1990) studied the relative importance of these two hormones for follicle growth during the follicular phase. Prepubertal gilts were treated with purified FSH or purified LH every 8 h for 64 h or with PG600 (which binds to both FSH- and LH-receptors). After 72 h, FSH-treated gilts had a relatively greater number of antral follicles (3–6 mm), but no larger sized follicles. LH treated gilts had fewer follicles, but these follicles had reached preovulatory diameter (7–9 mm) and PG600-treated gilts had larger numbers of pre-ovulatory sized follicles. These and other studies confirm that FSH is important in increasing the number of follicles that reach the medium/larger sized category (recruitment) and that LH is necessary for the further growth of these follicles to preovulatory size (selection) (see reviews by Kemp et al., 1998; Knox, 2005). Once LH has stimulated the development of the larger follicles that contain sufficient numbers of LH-receptors, these follicles then start to produce 17oestradiol. Interestingly, in post-pubertal gilts (Flowers et al., 1991) found that follicle development, as measured by increased peripheral concentrations of 17-oestradiol in the utero-ovarian vein, had already progressed at the end of the luteal phase during the early decrease in progesterone, whereas the change in LH-pulsatility did not appear until peripheral concentrations of progesterone had almost returned to basal concentrations. In post-pubertal gilts, therefore, the decrease in progesterone may be the signal for initial recruitment, rather than the increase in LHpulsatility. Nevertheless, an increase in systemic peripheral concentrations of 17-oestradiol only appeared after the increase in LH-pulsatility. Plasma profiles of the major reproductive hormones in the follicular phase of the oestrous cycle are depicted in Fig. 1 (based on Noguchi et al., 2010). At approximately 9 days before ovulation, luteolysis commences and peripheral concentrations of progesterone start to decrease (panel A), immediately followed by an increase in the number of small follicles (panel C) and increased inhibin production by those follicles (panel B). Thus, follicles already seem to be recruited from the antral follicle pool while peripheral concentrations of progesterone are still in greater concentrations. In Noguchi’s data (see Fig. 1), the initial increase in inhibin is followed by a decrease in FSH 2 days later (panel B). When luteolysis is complete and peripheral concentrations of progesterone have decreased to basal (at approximately 6 days before ovulation; panel A), larger sized follicles (>6 mm) develop in the ovaries (panel C) that contribute to the increase in peripheral concentrations of 17-oestradiol (panel A). The 17-oestradiol has a negative feedback effect on the hypothalamus. The resulting reduction in GnRH subsequently reduces both LH and
FSH output, but the inhibin dimers specifically inhibit FSH release (Noguchi et al., 2010). Because smaller follicles have insufficient LH-receptors and are, therefore, dependent on FSH, they undergo atresia when peripheral concentrations of FSH decrease (Lucy et al., 2001). The remainder of the follicular phase is characterised by an increased development of LH-dependent larger sized follicles and an increased atresia of the smaller and medium-sized follicles. Besides LH and FSH, the ovarian IGF-system plays an important role in the selection and development of healthy follicles. The bio-availability of IGF-1 (regulated by the presence of both IGF-1 and its binding proteins) is crucial in folliculogenesis after the early antral stage. IGF-1 increases the numbers of FSH receptors and thereby the physiological responses to FSH (Guthrie, 2005). 5.2. Follicle growth and time to ovulation Follicle growth patterns from weaning to ovulation vary substantially between sows, as illustrated in Fig. 3 for primiparous and multiparous sows. Primiparous sows had small follicles at weaning (on average 2.5 mm; Langendijk et al., 2000), relatively small follicles at ovulation (∼7 mm) and longer weaning-to-ovulation intervals. In these sows, there appeared to be no relationship between follicle diameter at weaning and subsequent weaning to ovulation interval. The majority of primiparous sows are likely to have compromised follicle development at weaning, related to the negative energy balance during the preceding lactation, and follicle development (and subsequent weaning-to-ovulation interval) will depend on the intensity of LH-pulsatility post-weaning (Shaw and Foxcroft, 1985). Multiparous sows, however, had larger follicles at weaning (on average 3.3 mm) (Gerritsen et al., 2008), large follicles at ovulation (∼8 mm) and a short weaning-toovulation interval (of at most 6 days). This suggests that follicle development was minimally or not compromised by lactation in multiparous sows. Unexpectedly, the multiparous sows with the longest WOI, on average, seemed to have the largest follicle diameter at weaning (although not significantly so), and their follicle diameter increased at a slower rate during the first 2 days after weaning. This seems to confirm the suggestion made by (Lucy et al., 2001), that in sows with synchronised follicle waves at the end of lactation the weaning-to-oestrus/ovulation interval may depend on the stage of follicle development at weaning. For example, when sows are weaned when the cohort of (large) follicles is regressing, such sows may return to oestrus later than sows in which the large follicles are not regressing, because a new wave of follicles must first develop. This would explain the relatively slow increase in follicle development after weaning in sows with a longer WOI (6 days) in Fig. 3b compared to the sows with a shorter WOI. Additionally, there is a category of sows (Langendijk et al., 2007b) that has larger follicles (5–6 mm) at weaning, and very short weaning-to-ovulation intervals (3–4 days). The large follicles seem to have escaped from regression and progressed to a stage where they develop to the preovulatory stage as soon as pulsatile release of LH increases at weaning. These sows may have already experienced increased LH secretion at the end of lactation, salvaging
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Fig. 3. Increase in follicle diameter (3–5 largest follicles, mean ± sem) during the weaning-to-ovulation interval in (A) primiparous sows with weaning-toovulation intervals of <6 days (n = 10; open diamond), 6–7 days (n = 17; solid square), 8–9 days (n = 11; open triangle) and >10 days (n = 57; asterisk) (based on data from Langendijk et al., 2000) and in (B) multiparous sows with weaning-to-ovulation intervals of 4 days (n = 6; triangle) 5 days (n = 9; square) and 6 days (n = 3; diamond) (based on data from control sows in Gerritsen et al., 2008). ab P < 0.05.
the follicles from atresia and commencing the process of selection. 5.3. Ovulation rate Factors influencing the growth and development of follicles during early antral follicle development and recruitment determine the number of larger sized follicles that are responsive to LH and able to escape the reduction in FSH caused by the increase in inhibin, and will therefore determine ovulation rate. A specific role for FSH in the control of ovulation rate seems, therefore likely, by influencing the initial recruitment of follicles. Indeed, Shaw and Foxcroft (1985) found differences in peripheral concentrations of FSH between sows with greater and lesser ovulation rates and (Knox et al., 2003) found that gilts with greater ovulation rates had greater peripheral concentrations of FSH during the mid- and late-luteal phases. They also found greater peripheral concentrations of inhibin throughout the cycle, and – as a direct consequence of the greater ovulation rate – greater peripheral concentrations of progesterone during the luteal phase. Additionally, they found greater pre-ovulatory peripheral concentrations of FSH and LH, the relevance of which remains unclear. In studies in which peripheral concentrations of FSH are experimentally reduced at the onset of the follicular phase by injecting inhibin containing-follicular fluid, as expected, a decrease in antral follicle numbers was recorded and when peripheral concentrations of FSH were experimentally increased by injecting FSH or its analogue, antral follicle numbers increased (Guthrie, 2005). However, increased recruitment of antral follicles only seems to lead to greater ovulation rates when concentration of LH is sufficient to sustain ongoing development of the selected follicles, as supported by treatment with eCG, but not with pFSH led to greater ovulation rates (Guthrie, 2005). In his review, Knox (2005) concluded that the pre-destination of follicles for ovulation can be both during the late luteal phase (or late lactation), and the early follicular phase. Suppression of FSH before and at the time of luteolysis reduces
the number of medium and large follicles but may not reduce ovulation rate. This shows that FSH is involved in the maintenance of a pool of medium sized follicles, but these follicles need to be selected by LH for final maturation and ovulation. The selection process of follicles continues during a large part of the follicular phase, but seems finalized at the first day of oestrus, as shown by the close correlation between follicle numbers at that stage, as assessed by ultrasonography, and subsequent post mortem evaluation of ovulation rate (JGM Wientjes, difference between follicle count at the first day of oestrus and number of corpora lutea at day 10 of the luteal phase of 0.8 ± 0.4, unpublished results). The process of recruitment and selection can be affected by external factors. Nutrition has been the one most intensely studied; particularly the consequences of the negative energy balance during lactation and the luteal phase on follicle dynamics and ovulation rate. Sows with a more severe negative energy balance have impaired follicle development during and after lactation (Quesnel et al., 1998), accompanied by a lesser LH-pulsatility at weaning, which results in fewer recruited and selected follicles and a lower subsequent ovulation rate at the post weaning oestrus, have reduced oocyte maturation and after ovulation may have lower peripheral concentrations of progesterone and lower embryo survival (reviewed by (Hazeleger et al., 2005)). Many nutritional factors have been proposed to be involved in these ‘nutritional imprinting’ effects, such as growth hormone, IGFs, insulin, leptin and NPY (Barb et al., 2006). Such nutritional influences on follicle development can be either indirect (through effects on the hypothalamus, affecting GnRH and thereby LH- and FSH- release; Tokach et al., 1992) or direct (affecting the follicles through receptor binding, as demonstrated for insulin and IGF-I; Matamoros et al., 1991). Specifically, insulin stimulation seems to be beneficial for follicle development, at least in the pre-follicular and early follicular phase (van den Brand et al., 2000a; Quesnel et al., 2007), thereby affecting the quantity, quality and/or homogeneity of follicles. Besides nutritional factors, other factors such
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as stress may affect ovarian function; Turner and Tilbrook (2006) concluded that a prolonged increase in cortisol (sustained stress), can result in a delayed LH surge or even prohibit the LH-surge through a reduction in GnRH output. 5.4. Ovulation During the selection process and, while follicles are growing to ovulatory diameter, LH pulsatility and FSH release gradually decrease to hardly detectable concentrations 2–3 days before ovulation (Prunier et al., 1987). During this period, oestrogen production from the preovulatory follicles reaches its maximum (Prunier et al., 1987; Noguchi et al., 2010). The pre-ovulatory follicle pool is not homogeneous, but consists of smaller and larger follicles with different endocrine profiles (Hunter and Wiesak, 1990). In pig reproductive research, a lot of effort has been placed on understanding the causes and consequences of this heterogeneity in follicle development and of factors that influence it (Hunter and Wiesak, 1990), but this falls beyond the scope of this paper. Increased peripheral concentrations of oestrogens induce the pre-ovulatory LH surge (and a small FSH surge) via positive feedback (see Fig. 1, panel B) causing an immediate decrease in peripheral concentrations of 17-oestradiol (see panel A). The LH surge also initiates the follicular changes that result in ovulation and luteinisation of the follicle wall, triggering progesterone production. In pigs, ovulation takes place at on average 30 ± 3 h (mean ± SD) after the peak of the LH surge, which is 44 ± 3 h (mean ± SD) after the onset of the LH-surge (e.g., Soede et al., 1994). The ovulation process (period between rupture of the first and last follicle) only lasts 1–3 h in spontaneously ovulating sows and up to 6 h in induced sows (Soede et al., 1998). Follicle diameter at ovulation (average of the 3–5 largest follicles, as measured by ultrasonography) usually is 6–8 mm in diameter, but may be influenced by experimental treatments, such as postweaning altrenogest treatments (van Leeuwen et al., 2010). It is not clear whether the follicle diameter at ovulation is related to the quality of the follicles, although relationships have been found with subsequent luteal diameter (Soede et al., 1998). Several aspects of peri-ovulatory hormonal changes seem important for subsequent embryo survival, e.g., a lesser amplitude pre-ovulatory LH-surge may either result in (partly) cystic ovaries (Gerritsen, 2008), or inadequate luteinisation of the follicle wall (Einarsson and Rojkittikhun, 1993). Also, an increased interval between peak concentrations of 17-oestradiol and peak concentrations of LH may result in lesser embryo survival rates (Soede et al., 1994) and lesser luteal phase concentrations of progesterone which may result in lesser embryo survival (Van Den Brand et al., 2000b). 6. Oestrus and timing of ovulation Oestrus is the period around ovulation in which sows show receptive behavior characterised by the ‘standing response’ in presence of a boar; the sow stands immobile, arches her back and cocks her ears (Signoret, 1970), thus allowing a boar to mate. Besides these behavioural changes, vulvar changes are also seen (increased red-
ness, swelling and mucus production). Although these signs of oestrus are orchestrated/caused by oestrogens produced by pre-ovulatory follicles, there appears to be no direct relationship between the peripheral concentrations of oestrogens and the intensity and or duration of the symptoms of oestrus in intact animals (Soede et al., 1994). The olfactory and tactile stimuli from the boar are most important for the standing response (Signoret, 1970) and oestrous detection is often performed by mimicking these tactile stimuli using the so-called ‘back pressure test’ (BPT), in the presence of a boar. In the presence of a boar, oestrus lasts on average 40–60 h, but varies from less than 24 h to more than 96 h for individual sows (reviewed by (Soede and Kemp, 1997)). The duration of oestrus varies considerably between farms (Steverink et al., 1999) and is affected by the intensity of boar contact during oestrous detection (chronic) stress of the sows, parity (often shorter in gilts) and weaning-tooestrous interval (shorter at intervals of more than 6 days). The exact mechanisms causing these effects are not clear. The reasons why there is interest in both the duration and variation in the duration, are because of their relationships with the time of ovulation. In the majority of sows, ovulation takes place at approximately two-thirds of the oestrous period. Thus, establishing the duration of oestrus aids in establishing an optimal insemination strategy on farms. 7. Luteinisation After rupture of the pre-ovulatory follicles at ovulation, extensive reformation and reorganization of tissue take place, ultimately resulting in the formation of fully functioning corpora lutea in the mid-luteal phase. Angiogenesis is one of the major processes which take place in the early luteal phase, and angiogenic factors such as VEGF influence corpus luteum formation and function in this phase (Schams and Berisha, 2004). Corpora lutea reach their full diameter at about a week after ovulation, with total luteal mass ranging between 6 and 10 g. One of the factors contributing to total luteal mass being the number of corpora lutea. Circulating concentrations progesterone is related (r = 0.2–0.4; unpublished results) to total luteal mass. During formation of the luteal tissue, factors other than angiogenic factors, like IGF-I, affect formation and function of luteal tissue. In vitro studies have shown not only a positive effect of IGF-I on progesterone secretion by luteal cells (Ptak et al., 2003), but also an anti-apoptotic effect on luteal cells (Ptak et al., 2004), indicating a role of IGF-I on both the formation and secretory function of luteal cells. Furthermore (Miller et al., 2003) demonstrated an acute increase in progesterone production when IGF-I was infused in the ovarian vasculature in the pig Langendijk et al. (2008) report a positive relationship in vivo between systemic IGF-I and concentrations of progesterone in the first few days after ovulation. IGF-I is related to nutritional status, which probably explains why (intermittently suckled) sows (Gerritsen et al., 2008) that are one a greater plane of nutrition during the luteal phase form more luteal tissue than those fed a lesser plane of nutrition.
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In pigs, development of the corpus luteum after ovulation and the secretion of progesterone occur independent of LH input from the pituitary, at least until 10–12 days after ovulation (Peltoniemi et al., 1995). Hypophysectomy on the day after oestrus or mating does not prevent the development of normal-sized, progesterone-secreting corpora lutea by day 12 after oestrus (Anderson et al., 1967), but corpora lutea do regress between days 16 and 20 in mated, hypophysectomised sows. Beyond days 10 and 12 of the luteal phase, support of the corpora lutea by LH does become important, although it seems that reduction in gonadotrophic support has to be severe and chronic to result in luteal regression and pregnancy failure. Chronic treatment with a GnRH agonist from days 14 to 21 of pregnancy abolished LH secretion and resulted in a decrease in progesterone secretion and loss of pregnancy in all sows at around 15 days after the start of treatment (Peltoniemi et al., 1995). However, single injection with a GnRH antagonist between days 14 and 19 after ovulation resulted in disruption of LH secretion for a period of 2.7 days, on average, and loss of pregnancy in only three of 15 sows (Virolainen et al., 2004). LH secretion in the luteal phase is characterised by a lesser frequency of greater amplitude LH pulses (Langendijk et al., 2007a), and similar to LH secretion during lactation (Fig. 2). Progesterone secretion by the ovaries follows a pulsatile fashion as well, but this can only be assessed when blood is sampled in the vena cava close to the utero-ovarian vein (Virolainen et al., 2005). In the systemic circulation progesterone is less variable and much less than in the utero-ovarian vein. Systemic progesterone has been related to embryo survival (Foxcroft, 1997), and because providing greater amounts of feed to females reduced systemic concentrations of progesterone due to increased hepatic clearance (Prime and Symonds, 1993), feeding maximal amounts of energy is generally believed to reduce embryo survival (Jindal et al., 1996), although results of studies on nutritional state during early pregnancy are equivocal (Quesnel et al., 2010). Measurement of systemic concentrations of progesterone may not be reflective of the effects of nutritional state on embryo survival, because there is also a local supply of progesterone directly from the ovary to the uterus (Krzymowski et al., 1990). Negative effects of nutritional state on systemic concentrations of progesterone may be counteracted by a positive effect on ovarian secretion of progesterone through an increase in IGF-1 and other nutritional cues, the balance of the two determining the effect on embryo survival. In pigs that have initiated oestrous cycles, luteolysis occurs around day 15 after ovulation, and is caused by prostaglandins secreted by the uterus. Prostaglandins secretion increases earlier than day 15, but it is only by days 12–13 that corpora lutea of pigs become sensitive to prostaglandins, as opposed to cattle, and hence prostaglandins cannot be used to synchronise the time of oestrus in pigs. In pregnant pigs, the gravid uterus also secretes prostaglandins, but oestrogen signalling from the elongating embryos causes the prostaglandins to be secreted into the uterine lumen rather than into the circulation as in non-pregnant pigs. For an extensive review see (Waclawik et al., 2009).
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8. Concluding remark Recent research, as reviewed in this article, increased understanding of the reproductive cycles in the pig, which has contributed significantly to unraveling the mechanisms underlying the influence of management factors, such as nutrition, stress or season on the oestrous cycle and subsequent reproductive performance. Equally, it has also helped to develop and evaluate the use of exogenous hormonal manipulations, e.g., to delay follicle development (progesterone analogues), control follicle development (FSH-analogues) or induce ovulation (LH- or GnRH-analogues). Conflict of interest statement The authors have no conflict of interest in publishing this review. Acknowledgements The authors gratefully acknowledge that the data in Fig. 1 were kindly provided by M Noguchi and H Kaneko. References Anderson, L., Dyck, G., Mori, H., Henricks, D., Melampy, R., 1967. Ovarian function in pigs following hypophysial stalk transection or hypophysectomy. Am. J. Physiol. 212, 1188–1194. Barb, C.R., Kraeling, R.R., Rampacek, G.B., Hausman, G.J., 2006. The role of neuropeptide Y and interaction with leptin in regulating feed intake and luteinizing hormone and growth hormone secretion in the pig. Reproduction 131, 1127–1135. Bevers, M.M., Willemse, A.H., Kruip, T.A.M., Van de Wiel, D.F.M., 1981. Prolactin levels and the LH-response to synthetic LH-RH in the lactating sow. Anim. Reprod. Sci. 4, 155–163. Britt, J.H., Armstrong, J.D., Cox, N.M., Esbenshade, K.L., 1985. Control of follicular development during and after lactation in sows. J. Reprod. Fertil. 33 (Suppl.), 37–54. De Rensis, F., Cosgrove, J.R., Foxcroft, G.R., 1993. Luteinizing hormone and prolactin responses to naloxone vary with stage of lactation in the sow. Biol. Reprod. 48, 970–976. Einarsson, S., Rojkittikhun, T., 1993. Effects of nutrition on pregnant and lactating sows. J. Reprod. Fertil. 48 (Suppl.), 229–239. Esbenshade, K.L., Ziecik, A.J., Britt, J.H., 1990. Regulation and action of gonadotropins in pigs. J. Reprod. Fertil. 40 (Suppl.), 19–32. Flowers, B., Cantley, T.C., Martin, M.J., Day, B.N., 1991. Episodic secretion of gonadotrophins and ovarian steroids in jugular and utero-ovarian vein plasma during the follicular phase of the oestrous cycle in gilts. J. Reprod. Fertil. 91, 101–112. Foxcroft, G.R., 1997. Nutrition and embryonic survival in pigs. J. Reprod. Fertil. 52 (Suppl.), 47–61. Gerritsen, R., 2008. Lactational Oestrus in Sows: Follicle Growth, Hormone Profiles and Early Pregnancy in Sows Subjected to Intermittent Suckling. Department of Animal Sciences, Wageningen University, Wageningen, p. 142. Gerritsen, R., Soede, N.M., Langendijk, P., Dieleman, S.J., Hazeleger, W., Kemp, B., 2008. Peri-oestrus hormone profiles and follicle growth in lactating sows with oestrus induced by intermittent suckling. Reprod. Domest. Anim. 43, 1–8. Guthrie, H.D., 2005. The follicular phase in pigs: follicle populations, circulating hormones, follicle factors and oocytes. J. Anim. Sci. 83, E79–E89. Guthrie, H.D., Bolt, D.J., Cooper, B.S., 1990. Effects of gonadotropin treatment on ovarian follicle growth and granulosal cell aromatase activity in prepuberal gilts. J. Anim. Sci. 68, 3719–3726. Hazeleger, W., Soede, N.M., Kemp, B., 2005. The effect of feeding strategy during the pre-follicular phase on subsequent follicular development in the pig. Domest. Anim. Endocrinol. 29, 362–370. Hunter, M.G., Wiesak, T., 1990. Evidence for and implications of follicular heterogeneity in pigs. J. Reprod. Fertil. 40 (Suppl.), 163–177.
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Jindal, R., Cosgrove, J.R., Aherne, F.X., Foxcroft, G.R., 1996. Effect of nutrition on embryonal mortality in gilts: association with progesterone. J. Anim. Sci. 74, 620–624. Kemp, B., Soede, N.M., Hazeleger, W., 1998. Control of ovulation. In: Wiseman, J., Varley, M.A., Chadwick, J.P. (Eds.), Progress of Pig Science. Nottingham University Press, pp. 285–302. Knox, R.V., 2005. Recruitment and selection of ovarian follicles for determination of ovulation rate in the pig. Domest. Anim. Endocrinol. 29, 385–397. Knox, R.V., Vatzias, G., Naber, C.H., Zimmerman, D.R., 2003. Plasma gonadotropins and ovarian hormones during the estrous cycle in high compared to low ovulation rate gilts. J. Anim. Sci. 81, 249–260. Krzymowski, T., Kotwica, J., Stefanczyk-Krzymowska, S., 1990. Uterine and ovarian countercurrent pathways in the control of ovarian function in the pig. J. Reprod. Fertil. 40 (Suppl.), 179–191. Langendijk, P., Dieleman, S.J., Gerritsen, R., Hazeleger, W., Mainsant, M., Soede, N.M., Kemp, B., 2007a. Pulsatile release of luteinising hormone during the luteal phase in lactating and weaned sows. Reprod., Fertil. Dev. 19, 961–966. Langendijk, P., Dieleman, S.J., van den Ham, C.M., Hazeleger, W., Soede, N.M., Kemp, B., 2007b. LH pulsatile release patterns, follicular growth and function during repetitive periods of suckling and non-suckling in sows. Theriogenology 67, 1076–1086. Langendijk, P., Van Den Brand, H., Gerritsen, R., Quesnel, H., Soede, N.M., Kemp, B., 2008. Porcine luteal function in relation to IGF-1 levels following ovulation during lactation or after weaning. Reprod. Domest. Anim. 43, 131–136. Langendijk, P., van den Brand, H., Soede, N.M., Kemp, B., 2000. Effect of boar contact on follicular development and on estrus expression after weaning in primiparous sows. Theriogenology 54, 1295–1303. Lucy, M.C., Liu, J., Boyd, K., Bracken, C.J., 2001. Ovarian follicular growth in sows. Reproduction 58 (Suppl.), 31–45. Matamoros, I.A., Cox, N.M., Moore, A.B., 1991. Effects of exogenous insulin and body condition on metabolic hormones and gonadotropininduced follicular development in prepuberal gilts. J. Anim. Sci. 69, 2081–2091. Miller, E., Ge, Z., Hedgpeth, V., Gadsby, J., 2003. Steroidogenic responses of pig corpora lutea to insulin-like growth factor I (IGF-I) throughout the oestrous cycle. Reproduction 125, 241–249. Noguchi, M., Yoshioka, K., Itoh, S., Suzuki, C., Arai, S., Wada, Y., Hasegawa, Y., Kaneko, H., 2010. Peripheral concentrations of inhibin A, ovarian steroids, and gonadotropins associated with follicular development throughout the estrous cycle of the sow. Reproduction 139, 153–161. Patterson, J., Wellen, A., Hahn, M., Pasternak, A., Lowe, J., DeHaas, S., Kraus, D., Williams, N., Foxcroft, G., 2008. Responses to delayed estrus after weaning in sows using oral progestagen treatment. J. Anim. Sci. 86, 1996–2004. Peltoniemi, O.A.T., Easton, B.G., Love, R.J., Klupiec, C., Evans, G., 1995. Effect of chronic treatment with a GnRH agonist (Goserelin) on LH secretion and early pregnancy in gilts. Anim. Reprod. Sci. 40, 121–133. Prime, G.R., Symonds, H.W., 1993. Influence of plane of nutrition on portal blood flow and the metabolic clearance rate of progesterone in ovariectomised gilts. J. Agric. Sci. 121, 389–397. Prunier, A., Martinat-Botté, F., Ravault, J.P., Camous, S., 1987. Perioestrous patterns of circulating LH FSH, prolactin and oestradiol-17[beta] in the gilt. Anim. Reprod. Sci. 14, 205–218. Prunier, A., Soede, N., Quesnel, H., Kemp, B., 2003. Productivity and longevity of weaned sows. In: Pluske, J.R., de Lividich, J., Verstegen, M.W.A. (Eds.), Weaning the Pig. Wageningen Academic Publishers, Wageningen, pp. 385–419. Ptak, A., Gregoraszczuk, E.L., Rzasa, J., 2003. Growth hormone and insulinelike growth factor-1 action on progesterone secretion by porcine corpora lutea isolated at various periods of the luteal phase. Acta Vet. Hung. 51, 197–208. Ptak, A., Kajta, M., Gregoraszczuk, E.L., 2004. Effect of growth hormone and insulin-like growth factor-I on spontaneous apoptosis in cultured luteal cells collected from early, mature, and regressing porcine corpora lutea. Anim. Reprod. Sci. 80, 267–279.
Quesnel, H., Boulot, S., Serriere, S., Venturi, E., Martinat-Botté, F., 2010. Post-insemination level of feeding does not influence embryonic survival and growth in highly prolific gilts. Anim. Reprod. Sci. 120, 120–124. Quesnel, H., Etienne, M., Pere, M.C., 2007. Influence of litter size on metabolic status and reproductive axis in primiparous sows. J. Anim. Sci. 85, 118–128. Quesnel, H., Pasquier, A., Mounier, A.M., Prunier, A., 1998. Influence of feed restriction during lactation on gonadotropic hormones and ovarian development in primiparous sows. J. Anim. Sci. 76, 856–863. Rojanasthien, S., Madej, A., Lundeheim, N., Einarsson, S., 1987. Luteinizing hormone response to different doses of synthetic gonadotropinreleasing hormone during early and late lactation in primiparous sows. Anim. Reprod. Sci. 13, 299–307. Schams, D., Berisha, B., 2004. Regulation of corpus luteum function in cattle – an overview. Reprod. Domest. Anim. 39, 241–251. Sesti, L.A., Britt, J.H., 1993. Influence of stage of lactation, exogenous luteinizing hormone-releasing hormone, and suckling on estrus, positive feedback of luteinizing hormone, and ovulation in sows treated with estrogen. J. Anim. Sci. 71, 989–998. Shaw, H.J., Foxcroft, G.R., 1985. Relationships between LH FSH and prolactin secretion and reproductive activity in the weaned sow. J. Reprod. Fertil. 75, 17–28. Signoret, J.P., 1970. Reproductive behaviour of pigs. J. Reprod. Fertil. 11 (Suppl.), 105–117. Soede, N.M., Hazeleger, W., Kemp, B., 1998. Follicle size and the process of ovulation in sows as studied with ultrasound. Reprod. Domest. Anim. 33, 239–244. Soede, N.M., Helmond, F.A., Kemp, B., 1994. Periovulatory profiles of oestradiol LH and progesterone in relation to oestrus and embryo mortality in multiparous sows using transrectal ultrasonography to detect ovulation. J. Reprod. Fertil. 101, 633–641. Soede, N.M., Kemp, B., 1997. Expression of oestrus and timing of ovulation in pigs. J. Reprod. Fertil. 52 (Suppl.), 91–103. Steverink, D.W., Soede, N.M., Groenland, G.J., van Schie, F.W., Noordhuizen, J.P., Kemp, B., 1999. Duration of estrus in relation to reproduction results in pigs on commercial farms. J. Anim. Sci. 77, 801–809. Tokach, M.D., Pettigrew, J.E., Dial, G.D., Wheaton, J.E., Crooker, B.A., Koketsu, Y., 1992. Influence of glucose infusions on luteinizing hormone secretion in the energy-restricted, primiparous, lactating sow. J. Anim. Sci. 70, 2202–2206. Turner, A.I., Tilbrook, A.I., 2006. Stress cortisol and reproduction in female pigs. In: Ashworth, C.J., Kraeling, R.R. (Eds.), Control of Pig Reproduction VII. Nottingham University Press. van den Brand, H., Dieleman, S.J., Soede, N.M., Kemp, B., 2000a. Dietary energy source at two feeding levels during lactation of primiparous sows: I. Effects on glucose, insulin, and luteinizing hormone and on follicle development, weaning-to-estrus interval, and ovulation rate. J. Anim. Sci. 78, 396–404. Van Den Brand, H., Soede, N.M., Kemp, B., 2000b. Dietary energy source at two feeding levels during lactation of primiparous sows: II. Effects on periestrus hormone profiles and embryonal survival. J. Anim. Sci. 78, 405–411. van Leeuwen, J.J.J., Williams, S.I., Kemp, B., Soede, N.M., 2010. Postweaning altrenogest treatment in primiparous sows; the effect of duration and dosage on follicular development and consequences for early pregnancy. Anim. Reprod. Sci. 119, 258–264. Virolainen, J.V., Love, R.J., Tast, A., Peltoniemi, O.A.T., 2004. Effect of a gonadotrophin-releasing hormone antagonist on luteinising hormone secretion and early pregnancy in gilts. Reprod., Fertil. Dev. 15, 451–459. Virolainen, J.V., Love, R.J., Tast, A., Peltoniemi, O.A.T., 2005. Plasma progesterone concentration depends on sampling site in pigs. Anim. Reprod. Sci. 86, 305–316. Waclawik, A., Blitek, A., Kaczmarek, J., Kiewisz, J., Ziecik, A.J., 2009. Antiluteolytic mechanisms and the establishment of pregnancy in the pig. In: Rodruguez-Martinez, H., Vallet, J.L., Ziecik, A.J. (Eds.), Control of Pig Reproduction VIII. , pp. 307–320.
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Animal Reproduction Science journal homepage: www.elsevier.com/locate/anireprosci
Reproductive cycles in pigs夽 N.M. Soede a,∗ , P. Langendijk b , B. Kemp a a b
Adaptation Physiology Group, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands South Autralian Research and Development Institute (SARDI), Roseworthy Campus, Roseworthy, SA 5371, Australia
a r t i c l e
i n f o
Article history: Available online 23 February 2011 Keywords: Pig Oestrous cycle Follicle development Ovulation
a b s t r a c t The oestrous cycle in pigs spans a period of 18–24 days. It consists of a follicular phase of 5–7 days and a luteal phase of 13–15 days. During the follicular phase, small antral follicles develop into large, pre-ovulatory follicles. Being a polytocous species, the pig may ovulate from 15 to 30 follicles, depending on age, nutritional status and other factors. During the luteal phase, follicle development is less pronounced, although there is probably a considerable turnover of primordial to early antral follicles that fail to further develop due to progesterone inhibition of gonadotrophic hormones. Nevertheless, formation of the early antral follicle pool during this stage probably has a major impact on follicle dynamics in the follicular phase in terms of number and quality of follicles. Generally, gilts are mated at their second or third estrous cycle after puberty. After farrowing, pigs experience a lactational anoestrus period, until they are weaned and the follicular phase is initiated, resulting in oestrus and ovulation 4–7 days after weaning. This paper describes the major endocrine processes during the follicular and luteal phases that precede and follow ovulation. The role of nutrition and metabolic status on these processes are briefly discussed. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Gilts usually reach puberty between 150 and 220 days of age, depending on many factors, including timing of boar contact and body condition. After puberty, oestrous cycles of 18–24 days follow and most gilts are inseminated during the 2nd or 3rd oestrus after puberty. After successful insemination, a pregnancy of 114–116 days duration follows. During the 16–40 days of lactation (depending on e.g., production system and legislation), sows normally experience lactational anoestrus which is then followed by a rather fixed weaning-to-oestrous interval of 4–6 days. These reproductive stages are controlled by a system of positive and negative feedback of the reproductive hormones that are produced and released
夽 This paper is part of the special issue entitled: Reproductive Cycles of Animals, Guest Edited by Michael G. Diskin and Alexander Evans. ∗ Corresponding author. E-mail address: [email protected] (N.M. Soede). 0378-4320/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.anireprosci.2011.02.025
from the hypothalamus (gonadotrophin-releasing hormone, GnRH), the pituitary (follicle-stimulating hormone, FSH; luteinizing hormone, LH; oxytocin and prolactin), the ovaries (progesterone, P4; 17-oestradiol, E2; inhibins and relaxin) and the uterus (prostaglandin F2␣, PGF2␣). Reproduction in pigs is rather exceptional in the sense that they ovulate 15–30 oocytes in one oestrous period. The ovulation rate and the quality of the ovulating follicles depends on the process of follicle development in the preceding period. This paper starts with a description of the pre-follicular phase (being either the luteal phase of the cycle or the lactation period), during which follicle development is largely, but not entirely suppressed. It follows with the follicular phase, during which follicles are recruited and selected from a pool of developing follicles. Thereafter, the period of oestrus and ovulation is briefly discussed, followed by luteinisation and the (early) pregnancy period. Most of the reproductive stages/processes are affected by environmental and management factors (such as nutrition/energy balance and stress) and examples of such influences will be incorporated when appropriate.
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Fig. 1. Plasma concentrations of 17-oestradiol and progesterone (A) and FSH, LH and Inhibin A (B) and follicular and CL development (C) during the oestrous cycle in sows (based on Noguchi et al., 2010). The vertical line in the figures represents time of ovulation.
This paper does not discuss puberty attainment, the process of luteolysis or farrowing or the use of hormonal manipulations. 2. Pre-follicular phase The pre-follicular phase is the phase prior to the 4–6 day follicular phase that precedes ovulation. During this phase, follicle development is usually largely suppressed, either by progesterone (during the luteal phase of the cycle) or by ongoing lactation. The number and quality of follicles at the onset of the follicular phase are largely determined by processes during the pre-follicular phase. 3. Luteal phase of the oestrous cycle At the onset of the luteal phase, immediately after ovulation, peripheral concentrations of P4 are minimal and pig ovaries are practically void of larger antral follicles (see Fig. 1) due to greater oestrogen and inhibin concentrations prior to ovulation. Inhibin and E2 production decreases
as the ovulation occurs, removing the negative feedback on FSH. Peripheral concentrations of FSH are, therefore, greater at days 1 and 2 after ovulation, which induces a wave of synchronised follicle development and an increase in the number of small and medium sized follicles. Subsequently inhibin production by these follicles increases, which then reduces peripheral concentrations of FSH. The developing corpora lutea produce increasing quantities of P4, that reach peak concentrations by days 8–9 after ovulation (Fig. 1), also suppressing secretion of gonadotrophins. Small antral follicle numbers seem to increase up to day 9 (reviewed by Knox, 2005) but follicle diameters remain relatively small resulting in minimal (Knox et al., 2003) or no (Fig. 1) systemically measurable peripheral concentrations of oestrogen. It is debated whether or not in sows follicle waves exist during the remainder of the luteal phase. If follicle waves are defined as waves of follicles development up to the dominant stage, waves of follicular development do not occur. However, if follicle waves are defined as synchronised development of small antral follicles, there is some evidence this type of follicular development occurs in pigs.
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Fig. 2. Representative pulsatile LH-patterns at the day before weaning (A) and the day of weaning (B) in a primiparous sow. Weaning took place at day 24 of lactation at 0800. Blood samples were taken every 12 min (van Leeuwen and Soede, unpublished results).
Some of the individual FSH profiles shown by (Knox et al., 2003) and (Noguchi et al., 2010) have clear FSH surges, lasting 2–3 days, with matching changes in inhibin and follicle diameter (Noguchi et al., 2010). However, follicle diameter remains limited to at most 3–4 mm during the luteal phase (Hazeleger et al., 2005). 4. Lactational anoestrus During established lactation, peripheral concentrations of LH and LH-pulsatility are suppressed due to the sucklinginduced inhibition of the GnRH-pulse generator (De Rensis et al., 1993). The degree of LH-suppression is related not only to the suckling intensity, but also to the negative energy balance of the sow; in primiparous sows on a lesser amounts of available feed, peripheral concentrations of LH were reduced compared to sows fed greater amounts of feed (Quesnel et al., 1998; Van Den Brand et al., 2000b). Effects of lactation on FSH are less consistent, and are primarily due to negative feedbacks of inhibin (produced by the limited growth of antral follicles) rather than suckling effects (reviewed by (Prunier et al., 2003)). In the course of lactation, LH-pulsatility is normally restored (van den Brand et al., 2000a), which may be related to a decrease in suckling frequency and or to the increase in pituitary LH responsiveness to GnRH (Bevers et al., 1981; Rojanasthien et al., 1987). Concomitantly with this increase in LH-pulsatility, follicle diameter increases during the course of lactation (reviewed by (Britt et al., 1985)). Thus, with progressing lactation, the follicle pool in the ovaries reach a greater diameter, though most sows do not develop follicles beyond a diameter of 3–4 mm after weaning (Lucy et al., 2001), although occasionally sows develop pre-ovulatory diameter follicles (∼8 mm) and ovulate during lactation. At the end of lactation, the majority of sows appear to have synchronized waves of follicle development (Lucy et al., 2001), with follicle diameters reaching 4–5 mm and then regress. The inhibition of LH release during lactation influences both lactational follicle development and the resumption of ovarian activity after weaning (Shaw and Foxcroft, 1985; Quesnel et al., 1998). Additionally, the mechanism of positive feedback of oestradiol on the LH-surge matures in the course of lactation, increasing the ability of sows to mount a pre-ovulatory LH-surge of sufficient magnitude (Sesti and
Britt, 1993). These mechanisms together form the basis for lactational effects on subsequent fertility variables, such as: weaning-to-oestrus interval, ovulation rate and even embryo survival (reviewed by (Prunier et al., 2003)), eventually affecting farrowing rate and litter size. Allowing post-weaning follicle regression, either by feeding a progesterone analogue for at least 4 days post weaning or by inseminating sows at the second oestrus after weaning, will benefit subsequent fertility of sows with compromised follicle development at weaning (Patterson et al., 2008). 5. Follicular phase The follicular phase of the pig oestrous cycle lasts 4–6 days and either follows a luteal phase or lactation. At the start of the follicular phase or, possibly, at the end of the pre-follicular phase, depending on the peripheral concentrations of progesterone (luteal phase) or the suppressive effects of lactation (depending on days after parturition, negative energy balance and suckling intensity), the largest antral follicles in the pool (usually 2–4 mm) are recruited and start to develop. Recruited follicles may still undergo atresia during the follicular phase, but once selected, escape atresia and eventually ovulate at a diameter of 7–8 mm (reviewed by Guthrie, 2005; Knox, 2005). 5.1. Recruitment and selection The antral follicle pool that is present at the onset of the follicular phase has developed during the late luteal phase of the oestrous cycle or during lactation and may consist of on average 100 follicles, varying in diameter up to 6 mm (reviewed by (Knox, 2005)). Immunisation against GnRH halts follicular development at the early antral stage (Esbenshade et al., 1990), showing the importance of GnRH-induced FSH and LH release for the further development of the antral follicle pool. Recruitment of follicles from the pool takes place when pulsatile GnRH/LH release shifts from a lesser frequency/greater amplitude pattern to a greater frequency/lesser amplitude pattern, as illustrated in Fig. 2 for a sow around weaning. This change in LH-release pattern has been established for both weaned sows (Shaw and Foxcroft, 1985) and for animals that have initiated oestrous cycles (Flowers et al., 1991). Its relevance for subsequent follicle development has been
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demonstrated in studies where frequent administration of GnRH during lactation, during anoestrus and in prepubertal gilts induced development of large antral follicles and subsequently oestrus (Britt et al., 1985). In weaned sows, frequency of LH pulses both before and after weaning, is compromised in sows with a more negative energy balance during the preceding lactation (van den Brand et al., 2000a) and this results in a prolonged weaning-to-oestrus interval (Shaw and Foxcroft, 1985; van den Brand et al., 2000a). Pulsatile GnRH release may induce the release of both LH and FSH from the anterior pituitary (Guthrie et al., 1990) studied the relative importance of these two hormones for follicle growth during the follicular phase. Prepubertal gilts were treated with purified FSH or purified LH every 8 h for 64 h or with PG600 (which binds to both FSH- and LH-receptors). After 72 h, FSH-treated gilts had a relatively greater number of antral follicles (3–6 mm), but no larger sized follicles. LH treated gilts had fewer follicles, but these follicles had reached preovulatory diameter (7–9 mm) and PG600-treated gilts had larger numbers of pre-ovulatory sized follicles. These and other studies confirm that FSH is important in increasing the number of follicles that reach the medium/larger sized category (recruitment) and that LH is necessary for the further growth of these follicles to preovulatory size (selection) (see reviews by Kemp et al., 1998; Knox, 2005). Once LH has stimulated the development of the larger follicles that contain sufficient numbers of LH-receptors, these follicles then start to produce 17oestradiol. Interestingly, in post-pubertal gilts (Flowers et al., 1991) found that follicle development, as measured by increased peripheral concentrations of 17-oestradiol in the utero-ovarian vein, had already progressed at the end of the luteal phase during the early decrease in progesterone, whereas the change in LH-pulsatility did not appear until peripheral concentrations of progesterone had almost returned to basal concentrations. In post-pubertal gilts, therefore, the decrease in progesterone may be the signal for initial recruitment, rather than the increase in LHpulsatility. Nevertheless, an increase in systemic peripheral concentrations of 17-oestradiol only appeared after the increase in LH-pulsatility. Plasma profiles of the major reproductive hormones in the follicular phase of the oestrous cycle are depicted in Fig. 1 (based on Noguchi et al., 2010). At approximately 9 days before ovulation, luteolysis commences and peripheral concentrations of progesterone start to decrease (panel A), immediately followed by an increase in the number of small follicles (panel C) and increased inhibin production by those follicles (panel B). Thus, follicles already seem to be recruited from the antral follicle pool while peripheral concentrations of progesterone are still in greater concentrations. In Noguchi’s data (see Fig. 1), the initial increase in inhibin is followed by a decrease in FSH 2 days later (panel B). When luteolysis is complete and peripheral concentrations of progesterone have decreased to basal (at approximately 6 days before ovulation; panel A), larger sized follicles (>6 mm) develop in the ovaries (panel C) that contribute to the increase in peripheral concentrations of 17-oestradiol (panel A). The 17-oestradiol has a negative feedback effect on the hypothalamus. The resulting reduction in GnRH subsequently reduces both LH and
FSH output, but the inhibin dimers specifically inhibit FSH release (Noguchi et al., 2010). Because smaller follicles have insufficient LH-receptors and are, therefore, dependent on FSH, they undergo atresia when peripheral concentrations of FSH decrease (Lucy et al., 2001). The remainder of the follicular phase is characterised by an increased development of LH-dependent larger sized follicles and an increased atresia of the smaller and medium-sized follicles. Besides LH and FSH, the ovarian IGF-system plays an important role in the selection and development of healthy follicles. The bio-availability of IGF-1 (regulated by the presence of both IGF-1 and its binding proteins) is crucial in folliculogenesis after the early antral stage. IGF-1 increases the numbers of FSH receptors and thereby the physiological responses to FSH (Guthrie, 2005). 5.2. Follicle growth and time to ovulation Follicle growth patterns from weaning to ovulation vary substantially between sows, as illustrated in Fig. 3 for primiparous and multiparous sows. Primiparous sows had small follicles at weaning (on average 2.5 mm; Langendijk et al., 2000), relatively small follicles at ovulation (∼7 mm) and longer weaning-to-ovulation intervals. In these sows, there appeared to be no relationship between follicle diameter at weaning and subsequent weaning to ovulation interval. The majority of primiparous sows are likely to have compromised follicle development at weaning, related to the negative energy balance during the preceding lactation, and follicle development (and subsequent weaning-to-ovulation interval) will depend on the intensity of LH-pulsatility post-weaning (Shaw and Foxcroft, 1985). Multiparous sows, however, had larger follicles at weaning (on average 3.3 mm) (Gerritsen et al., 2008), large follicles at ovulation (∼8 mm) and a short weaning-toovulation interval (of at most 6 days). This suggests that follicle development was minimally or not compromised by lactation in multiparous sows. Unexpectedly, the multiparous sows with the longest WOI, on average, seemed to have the largest follicle diameter at weaning (although not significantly so), and their follicle diameter increased at a slower rate during the first 2 days after weaning. This seems to confirm the suggestion made by (Lucy et al., 2001), that in sows with synchronised follicle waves at the end of lactation the weaning-to-oestrus/ovulation interval may depend on the stage of follicle development at weaning. For example, when sows are weaned when the cohort of (large) follicles is regressing, such sows may return to oestrus later than sows in which the large follicles are not regressing, because a new wave of follicles must first develop. This would explain the relatively slow increase in follicle development after weaning in sows with a longer WOI (6 days) in Fig. 3b compared to the sows with a shorter WOI. Additionally, there is a category of sows (Langendijk et al., 2007b) that has larger follicles (5–6 mm) at weaning, and very short weaning-to-ovulation intervals (3–4 days). The large follicles seem to have escaped from regression and progressed to a stage where they develop to the preovulatory stage as soon as pulsatile release of LH increases at weaning. These sows may have already experienced increased LH secretion at the end of lactation, salvaging
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Fig. 3. Increase in follicle diameter (3–5 largest follicles, mean ± sem) during the weaning-to-ovulation interval in (A) primiparous sows with weaning-toovulation intervals of <6 days (n = 10; open diamond), 6–7 days (n = 17; solid square), 8–9 days (n = 11; open triangle) and >10 days (n = 57; asterisk) (based on data from Langendijk et al., 2000) and in (B) multiparous sows with weaning-to-ovulation intervals of 4 days (n = 6; triangle) 5 days (n = 9; square) and 6 days (n = 3; diamond) (based on data from control sows in Gerritsen et al., 2008). ab P < 0.05.
the follicles from atresia and commencing the process of selection. 5.3. Ovulation rate Factors influencing the growth and development of follicles during early antral follicle development and recruitment determine the number of larger sized follicles that are responsive to LH and able to escape the reduction in FSH caused by the increase in inhibin, and will therefore determine ovulation rate. A specific role for FSH in the control of ovulation rate seems, therefore likely, by influencing the initial recruitment of follicles. Indeed, Shaw and Foxcroft (1985) found differences in peripheral concentrations of FSH between sows with greater and lesser ovulation rates and (Knox et al., 2003) found that gilts with greater ovulation rates had greater peripheral concentrations of FSH during the mid- and late-luteal phases. They also found greater peripheral concentrations of inhibin throughout the cycle, and – as a direct consequence of the greater ovulation rate – greater peripheral concentrations of progesterone during the luteal phase. Additionally, they found greater pre-ovulatory peripheral concentrations of FSH and LH, the relevance of which remains unclear. In studies in which peripheral concentrations of FSH are experimentally reduced at the onset of the follicular phase by injecting inhibin containing-follicular fluid, as expected, a decrease in antral follicle numbers was recorded and when peripheral concentrations of FSH were experimentally increased by injecting FSH or its analogue, antral follicle numbers increased (Guthrie, 2005). However, increased recruitment of antral follicles only seems to lead to greater ovulation rates when concentration of LH is sufficient to sustain ongoing development of the selected follicles, as supported by treatment with eCG, but not with pFSH led to greater ovulation rates (Guthrie, 2005). In his review, Knox (2005) concluded that the pre-destination of follicles for ovulation can be both during the late luteal phase (or late lactation), and the early follicular phase. Suppression of FSH before and at the time of luteolysis reduces
the number of medium and large follicles but may not reduce ovulation rate. This shows that FSH is involved in the maintenance of a pool of medium sized follicles, but these follicles need to be selected by LH for final maturation and ovulation. The selection process of follicles continues during a large part of the follicular phase, but seems finalized at the first day of oestrus, as shown by the close correlation between follicle numbers at that stage, as assessed by ultrasonography, and subsequent post mortem evaluation of ovulation rate (JGM Wientjes, difference between follicle count at the first day of oestrus and number of corpora lutea at day 10 of the luteal phase of 0.8 ± 0.4, unpublished results). The process of recruitment and selection can be affected by external factors. Nutrition has been the one most intensely studied; particularly the consequences of the negative energy balance during lactation and the luteal phase on follicle dynamics and ovulation rate. Sows with a more severe negative energy balance have impaired follicle development during and after lactation (Quesnel et al., 1998), accompanied by a lesser LH-pulsatility at weaning, which results in fewer recruited and selected follicles and a lower subsequent ovulation rate at the post weaning oestrus, have reduced oocyte maturation and after ovulation may have lower peripheral concentrations of progesterone and lower embryo survival (reviewed by (Hazeleger et al., 2005)). Many nutritional factors have been proposed to be involved in these ‘nutritional imprinting’ effects, such as growth hormone, IGFs, insulin, leptin and NPY (Barb et al., 2006). Such nutritional influences on follicle development can be either indirect (through effects on the hypothalamus, affecting GnRH and thereby LH- and FSH- release; Tokach et al., 1992) or direct (affecting the follicles through receptor binding, as demonstrated for insulin and IGF-I; Matamoros et al., 1991). Specifically, insulin stimulation seems to be beneficial for follicle development, at least in the pre-follicular and early follicular phase (van den Brand et al., 2000a; Quesnel et al., 2007), thereby affecting the quantity, quality and/or homogeneity of follicles. Besides nutritional factors, other factors such
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as stress may affect ovarian function; Turner and Tilbrook (2006) concluded that a prolonged increase in cortisol (sustained stress), can result in a delayed LH surge or even prohibit the LH-surge through a reduction in GnRH output. 5.4. Ovulation During the selection process and, while follicles are growing to ovulatory diameter, LH pulsatility and FSH release gradually decrease to hardly detectable concentrations 2–3 days before ovulation (Prunier et al., 1987). During this period, oestrogen production from the preovulatory follicles reaches its maximum (Prunier et al., 1987; Noguchi et al., 2010). The pre-ovulatory follicle pool is not homogeneous, but consists of smaller and larger follicles with different endocrine profiles (Hunter and Wiesak, 1990). In pig reproductive research, a lot of effort has been placed on understanding the causes and consequences of this heterogeneity in follicle development and of factors that influence it (Hunter and Wiesak, 1990), but this falls beyond the scope of this paper. Increased peripheral concentrations of oestrogens induce the pre-ovulatory LH surge (and a small FSH surge) via positive feedback (see Fig. 1, panel B) causing an immediate decrease in peripheral concentrations of 17-oestradiol (see panel A). The LH surge also initiates the follicular changes that result in ovulation and luteinisation of the follicle wall, triggering progesterone production. In pigs, ovulation takes place at on average 30 ± 3 h (mean ± SD) after the peak of the LH surge, which is 44 ± 3 h (mean ± SD) after the onset of the LH-surge (e.g., Soede et al., 1994). The ovulation process (period between rupture of the first and last follicle) only lasts 1–3 h in spontaneously ovulating sows and up to 6 h in induced sows (Soede et al., 1998). Follicle diameter at ovulation (average of the 3–5 largest follicles, as measured by ultrasonography) usually is 6–8 mm in diameter, but may be influenced by experimental treatments, such as postweaning altrenogest treatments (van Leeuwen et al., 2010). It is not clear whether the follicle diameter at ovulation is related to the quality of the follicles, although relationships have been found with subsequent luteal diameter (Soede et al., 1998). Several aspects of peri-ovulatory hormonal changes seem important for subsequent embryo survival, e.g., a lesser amplitude pre-ovulatory LH-surge may either result in (partly) cystic ovaries (Gerritsen, 2008), or inadequate luteinisation of the follicle wall (Einarsson and Rojkittikhun, 1993). Also, an increased interval between peak concentrations of 17-oestradiol and peak concentrations of LH may result in lesser embryo survival rates (Soede et al., 1994) and lesser luteal phase concentrations of progesterone which may result in lesser embryo survival (Van Den Brand et al., 2000b). 6. Oestrus and timing of ovulation Oestrus is the period around ovulation in which sows show receptive behavior characterised by the ‘standing response’ in presence of a boar; the sow stands immobile, arches her back and cocks her ears (Signoret, 1970), thus allowing a boar to mate. Besides these behavioural changes, vulvar changes are also seen (increased red-
ness, swelling and mucus production). Although these signs of oestrus are orchestrated/caused by oestrogens produced by pre-ovulatory follicles, there appears to be no direct relationship between the peripheral concentrations of oestrogens and the intensity and or duration of the symptoms of oestrus in intact animals (Soede et al., 1994). The olfactory and tactile stimuli from the boar are most important for the standing response (Signoret, 1970) and oestrous detection is often performed by mimicking these tactile stimuli using the so-called ‘back pressure test’ (BPT), in the presence of a boar. In the presence of a boar, oestrus lasts on average 40–60 h, but varies from less than 24 h to more than 96 h for individual sows (reviewed by (Soede and Kemp, 1997)). The duration of oestrus varies considerably between farms (Steverink et al., 1999) and is affected by the intensity of boar contact during oestrous detection (chronic) stress of the sows, parity (often shorter in gilts) and weaning-tooestrous interval (shorter at intervals of more than 6 days). The exact mechanisms causing these effects are not clear. The reasons why there is interest in both the duration and variation in the duration, are because of their relationships with the time of ovulation. In the majority of sows, ovulation takes place at approximately two-thirds of the oestrous period. Thus, establishing the duration of oestrus aids in establishing an optimal insemination strategy on farms. 7. Luteinisation After rupture of the pre-ovulatory follicles at ovulation, extensive reformation and reorganization of tissue take place, ultimately resulting in the formation of fully functioning corpora lutea in the mid-luteal phase. Angiogenesis is one of the major processes which take place in the early luteal phase, and angiogenic factors such as VEGF influence corpus luteum formation and function in this phase (Schams and Berisha, 2004). Corpora lutea reach their full diameter at about a week after ovulation, with total luteal mass ranging between 6 and 10 g. One of the factors contributing to total luteal mass being the number of corpora lutea. Circulating concentrations progesterone is related (r = 0.2–0.4; unpublished results) to total luteal mass. During formation of the luteal tissue, factors other than angiogenic factors, like IGF-I, affect formation and function of luteal tissue. In vitro studies have shown not only a positive effect of IGF-I on progesterone secretion by luteal cells (Ptak et al., 2003), but also an anti-apoptotic effect on luteal cells (Ptak et al., 2004), indicating a role of IGF-I on both the formation and secretory function of luteal cells. Furthermore (Miller et al., 2003) demonstrated an acute increase in progesterone production when IGF-I was infused in the ovarian vasculature in the pig Langendijk et al. (2008) report a positive relationship in vivo between systemic IGF-I and concentrations of progesterone in the first few days after ovulation. IGF-I is related to nutritional status, which probably explains why (intermittently suckled) sows (Gerritsen et al., 2008) that are one a greater plane of nutrition during the luteal phase form more luteal tissue than those fed a lesser plane of nutrition.
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In pigs, development of the corpus luteum after ovulation and the secretion of progesterone occur independent of LH input from the pituitary, at least until 10–12 days after ovulation (Peltoniemi et al., 1995). Hypophysectomy on the day after oestrus or mating does not prevent the development of normal-sized, progesterone-secreting corpora lutea by day 12 after oestrus (Anderson et al., 1967), but corpora lutea do regress between days 16 and 20 in mated, hypophysectomised sows. Beyond days 10 and 12 of the luteal phase, support of the corpora lutea by LH does become important, although it seems that reduction in gonadotrophic support has to be severe and chronic to result in luteal regression and pregnancy failure. Chronic treatment with a GnRH agonist from days 14 to 21 of pregnancy abolished LH secretion and resulted in a decrease in progesterone secretion and loss of pregnancy in all sows at around 15 days after the start of treatment (Peltoniemi et al., 1995). However, single injection with a GnRH antagonist between days 14 and 19 after ovulation resulted in disruption of LH secretion for a period of 2.7 days, on average, and loss of pregnancy in only three of 15 sows (Virolainen et al., 2004). LH secretion in the luteal phase is characterised by a lesser frequency of greater amplitude LH pulses (Langendijk et al., 2007a), and similar to LH secretion during lactation (Fig. 2). Progesterone secretion by the ovaries follows a pulsatile fashion as well, but this can only be assessed when blood is sampled in the vena cava close to the utero-ovarian vein (Virolainen et al., 2005). In the systemic circulation progesterone is less variable and much less than in the utero-ovarian vein. Systemic progesterone has been related to embryo survival (Foxcroft, 1997), and because providing greater amounts of feed to females reduced systemic concentrations of progesterone due to increased hepatic clearance (Prime and Symonds, 1993), feeding maximal amounts of energy is generally believed to reduce embryo survival (Jindal et al., 1996), although results of studies on nutritional state during early pregnancy are equivocal (Quesnel et al., 2010). Measurement of systemic concentrations of progesterone may not be reflective of the effects of nutritional state on embryo survival, because there is also a local supply of progesterone directly from the ovary to the uterus (Krzymowski et al., 1990). Negative effects of nutritional state on systemic concentrations of progesterone may be counteracted by a positive effect on ovarian secretion of progesterone through an increase in IGF-1 and other nutritional cues, the balance of the two determining the effect on embryo survival. In pigs that have initiated oestrous cycles, luteolysis occurs around day 15 after ovulation, and is caused by prostaglandins secreted by the uterus. Prostaglandins secretion increases earlier than day 15, but it is only by days 12–13 that corpora lutea of pigs become sensitive to prostaglandins, as opposed to cattle, and hence prostaglandins cannot be used to synchronise the time of oestrus in pigs. In pregnant pigs, the gravid uterus also secretes prostaglandins, but oestrogen signalling from the elongating embryos causes the prostaglandins to be secreted into the uterine lumen rather than into the circulation as in non-pregnant pigs. For an extensive review see (Waclawik et al., 2009).
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8. Concluding remark Recent research, as reviewed in this article, increased understanding of the reproductive cycles in the pig, which has contributed significantly to unraveling the mechanisms underlying the influence of management factors, such as nutrition, stress or season on the oestrous cycle and subsequent reproductive performance. Equally, it has also helped to develop and evaluate the use of exogenous hormonal manipulations, e.g., to delay follicle development (progesterone analogues), control follicle development (FSH-analogues) or induce ovulation (LH- or GnRH-analogues). Conflict of interest statement The authors have no conflict of interest in publishing this review. Acknowledgements The authors gratefully acknowledge that the data in Fig. 1 were kindly provided by M Noguchi and H Kaneko. References Anderson, L., Dyck, G., Mori, H., Henricks, D., Melampy, R., 1967. Ovarian function in pigs following hypophysial stalk transection or hypophysectomy. Am. J. Physiol. 212, 1188–1194. Barb, C.R., Kraeling, R.R., Rampacek, G.B., Hausman, G.J., 2006. The role of neuropeptide Y and interaction with leptin in regulating feed intake and luteinizing hormone and growth hormone secretion in the pig. Reproduction 131, 1127–1135. Bevers, M.M., Willemse, A.H., Kruip, T.A.M., Van de Wiel, D.F.M., 1981. Prolactin levels and the LH-response to synthetic LH-RH in the lactating sow. Anim. Reprod. Sci. 4, 155–163. Britt, J.H., Armstrong, J.D., Cox, N.M., Esbenshade, K.L., 1985. Control of follicular development during and after lactation in sows. J. Reprod. Fertil. 33 (Suppl.), 37–54. De Rensis, F., Cosgrove, J.R., Foxcroft, G.R., 1993. Luteinizing hormone and prolactin responses to naloxone vary with stage of lactation in the sow. Biol. Reprod. 48, 970–976. Einarsson, S., Rojkittikhun, T., 1993. Effects of nutrition on pregnant and lactating sows. J. Reprod. Fertil. 48 (Suppl.), 229–239. Esbenshade, K.L., Ziecik, A.J., Britt, J.H., 1990. Regulation and action of gonadotropins in pigs. J. Reprod. Fertil. 40 (Suppl.), 19–32. Flowers, B., Cantley, T.C., Martin, M.J., Day, B.N., 1991. Episodic secretion of gonadotrophins and ovarian steroids in jugular and utero-ovarian vein plasma during the follicular phase of the oestrous cycle in gilts. J. Reprod. Fertil. 91, 101–112. Foxcroft, G.R., 1997. Nutrition and embryonic survival in pigs. J. Reprod. Fertil. 52 (Suppl.), 47–61. Gerritsen, R., 2008. Lactational Oestrus in Sows: Follicle Growth, Hormone Profiles and Early Pregnancy in Sows Subjected to Intermittent Suckling. Department of Animal Sciences, Wageningen University, Wageningen, p. 142. Gerritsen, R., Soede, N.M., Langendijk, P., Dieleman, S.J., Hazeleger, W., Kemp, B., 2008. Peri-oestrus hormone profiles and follicle growth in lactating sows with oestrus induced by intermittent suckling. Reprod. Domest. Anim. 43, 1–8. Guthrie, H.D., 2005. The follicular phase in pigs: follicle populations, circulating hormones, follicle factors and oocytes. J. Anim. Sci. 83, E79–E89. Guthrie, H.D., Bolt, D.J., Cooper, B.S., 1990. Effects of gonadotropin treatment on ovarian follicle growth and granulosal cell aromatase activity in prepuberal gilts. J. Anim. Sci. 68, 3719–3726. Hazeleger, W., Soede, N.M., Kemp, B., 2005. The effect of feeding strategy during the pre-follicular phase on subsequent follicular development in the pig. Domest. Anim. Endocrinol. 29, 362–370. Hunter, M.G., Wiesak, T., 1990. Evidence for and implications of follicular heterogeneity in pigs. J. Reprod. Fertil. 40 (Suppl.), 163–177.
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