Endocrine regulation of ovarian antral follicle development in cattle

Animal Reproduction Science 78 (2003) 217–237

Endocrine regulation of ovarian antral follicle development in cattle M. Mihm a,∗ , E.C.L. Bleach b a

Department of Veterinary Preclinical Studies, University of Glasgow Veterinary School, Bearsden Road, Glasgow G61 1QH, UK b Department of Agriculture, The University of Reading, Reading, UK

Abstract Antral follicle growth in cattle occurs in two distinct phases; the first ‘slow’ growth phase spans the time from antrum acquisition to a size of approximately 3 mm detectable by transrectal ultrasound, and the second ‘fast’ phase is gondadotrophin-dependent and includes cohort growth, dominant follicle (DF) selection, and DF growth. This review summarises current concepts of the relative roles FSH and LH, ovarian and metabolic hormones play mainly in the second phase of antral follicle growth in animals of different reproductive and nutritional states. It is proposed that differential FSH response may enable one cohort follicle to become selected, and that follicular secretions, particularly inhibin, suppress FSH and thus are responsible for DF selection and dominance. Acute dependence of the DF on LH pulses will determine DF lifespan, and the LH pulse profile can be influenced by metabolic hormones such as leptin, providing one possible link for nutritional state and reproduction. Direct ovarian effects of acute and chronic changes in growth hormone, insulin and insulin-like growth factor (IGF)-I have been described on cohort follicles, DF oestrogen activity and on DF growth. Influences of metabolic hormones on early antral follicles undergoing their first ‘slow’ growth phase are less well described, yet metabolic hormones appear to enhance growth into the cohort available for FSH-induced emergence, and may influence subsequent developmental competence of oocytes. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Endocrine; Ovarian; Follicle

1. Introduction Cattle, in common with other domestic species, show two stages of ovarian antral follicle development. Firstly, a ‘slow’ growth phase which takes more than 30 days from antrum acquisition at 300 ␮m to the ‘small’ follicle stage of 3–5 mm in diameter (Lussier et al., 1987); ∗ Corresponding author. E-mail address: [email protected] (M. Mihm).

0378-4320/03/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0378-4320(03)00092-7

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this growth phase is critical as the oocyte achieves its final size and full developmental competence (Fair et al., 1995, 1997). The second ‘fast’ growth phase may only take 5–7 days, and is usually described as a follicle wave encompassing the sudden ultrasound-detectable emergence of a cohort of small follicles from 3 mm, the final stages of a selection process from the cohort, which allows generally only one follicle to continue to grow and demonstrate enhanced oestradiol synthesis from a size of 8.5 mm (the dominant follicle, DF), and a variable dominance period which may culminate in preovulatory follicle development and ovulation (Sunderland et al., 1994). Very little is known about the endocrine influences or even dependencies of early antral follicles in vivo despite the fact that changes occurring at this time may compromise subsequent follicular or oocyte functions (Cushman et al., 2001; Roth et al., 2001). Experiments conducted on cattle in which GnRH regulation of pituitary gonadotrophin release was abolished (Gong et al., 1995, 1996; Crowe et al., 2001) demonstrate that the first antral growth phase can occur in an environment characterised by basal FSH and no LH pulses. It is still unclear in the bovine whether early antral growth is possible without any FSH; murine follicles without any ability to respond to FSH do not show progression from preantral stages to the early antral stages of development (Abel et al., 2000). Follicle wave growth during the second antral follicle growth phase, however, is absolutely dependent on elevated FSH concentrations and adequate LH pulsatility. Therefore, this review aims to summarise current data on the roles FSH and LH, ovarian secretions and some metabolic hormones play during the second phase of antral follicle growth, specifically in (a) cohort growth and DF selection, and (b) DF fate in different reproductive (before and after puberty, pregnancy, postpartum) and nutritional states. 2. Endocrine regulation of cohort growth and DF selection 2.1. Cohort follicle dependency on transient FSH rises The simultaneous use of frequent hormone estimations and transrectal ovarian ultrasound scanning to monitor antral follicle growth individually and frequently allows us to relate fluctuations in gonadotrophins to follicle wave growth (Fig. 1). Although ultrasound detection of antral follicles from 1 mm in diameter is possible, routine monitoring of individual follicle growth has been restricted to the second ‘fast’ growth phase of antral follicular development from approximately 3–4 mm in diameter. Improvements in ultrasound technology may have overcome limitations regarding the resolution of follicles less than 3 mm, yet assignment of individuality can still prove difficult, especially when the DF arises from a cluster of neighbouring cohort follicles. Such difficulties may be overcome in the future with the routine use of 3-dimensional real-time ultrasound. Each emergence of a cohort is heralded by a transient FSH rise with emergence being detected from the time of FSH peak; sequential FSH rises associated with new follicle waves occur during the oestrous cycle (Adams et al., 1992a; Sunderland et al., 1994), in the postpartum period (Crowe et al., 1998; Stagg et al., 1998), during pregnancy (Ginther et al., 1996) and before puberty in cattle (Evans et al., 1994). Acute dependency of cohort follicles from 3 to 5 mm on elevated FSH was shown in studies where emergence of the first follicle wave is blocked when the periovulatory FSH rise is suppressed using steroid-free bovine

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Fig. 1. Schematic of the first transient FSH rise and ultrasound-monitored cohort growth and dominant follicle (DF) selection in a beef heifer (from Austin et al., 2001). SF: subordinate follicles.

follicular fluid (Fig. 2; Turzillo and Fortune, 1990; Bleach et al., 2001), while emergence occurs when exogenous FSH is concurrently administered (Bergfelt et al., 1994a). Similarly, delaying the second transient FSH rise during the cycle using exogenous oestradiol benzoate will also delay emergence of the second follicle wave (Bo et al., 1995; O’Rourke et al., 1998). Appropriate in vivo models to investigate actual FSH requirements of antral follicles after completion of their first growth phase, are those in which endogenous FSH rises are abolished using GnRH immunisation or long-term GnRH agonist treatment. Such studies showed that development from 4 mm always required a rise in FSH from baseline levels (Prendiville et al., 1995, 1996; Gong et al., 1996; Crowe et al., 2001). When physiological amounts of FSH were administered to GnRH-immunised heifers to mimic a FSH rise and induce growth of a follicle wave, multiple follicles responded but with very low steroidogenic ability, and DF selection did not occur (Crowe et al., 2001). This appears to indicate, that antral follicles growing slowly in an environment free of steroids, LH pulses and elevations in FSH concentrations may have changed steroidogenic function when embarking upon their ‘fast’ growth phase and, therefore, may not be able to undergo the shift in dependency from FSH to LH necessary for DF selection following FSH stimulation. Similarly, antral follicles emerging before puberty with and without stimulation via exogenous FSH show compromised steroidogenesis and oocyte developmental ability (Damiani et al., 1996). Another consideration with regard to FSH is the FSH isoform composition of FSH preparations used in GnRH-immunised or GnRH analogue treated heifers. The glycosylation status of FSH alters its half-life and biological activity (Cooke et al., 1995), and thus may alter antral follicle responses to similar amounts of circulating FSH. No differences in FSH isoforms, however, were seen during the transient rises in a heifer cycle or the early postpartum period, again indicating how similar follicle wave growth is in different reproductive states (Cooke et al., 1997a; Crowe et al., 1998). The transient FSH rise stimulates all antral follicles present at the time that are at the end of their first ‘slow’ growth phase; they not only respond to but now depend on elevated FSH for continued cell proliferation and enhanced steroidogenesis. Whether the cohort follicles that emerge in response to a transient FSH rise also completed their first growth phase

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Fig. 2. The effects of two doses of steroid-free bovine follicular fluid (bFF) given to heifers at the peak of the first transient FSH rise of the cycle on (a) inhibin-A, (b) FSH, and (c) dominant follicle growth; despite differences in inhibin-A concentrations achieved by the two doses, FSH suppression and delay in follicle wave emergence were similar (from Bleach et al., 2001). Values are means ± S.E.M. (n = 3–4); ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001 compared to control group.

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together, i.e. pre-emergence growth occurs in a wave-like fashion, is not known. If this was the case, then there may be times when antral follicles ready to emerge are not present. Yet during the oestrous cycle ablation of the DF or follicles from 5 mm always causes a new wave emergence linked to the induced rise in FSH concentrations (Bergfelt et al., 1994b; Bodensteiner et al., 1996). In addition, our own observations in GnRH-immunised heifers did not confirm a wave-like growth pattern of antral follicles less than 5 mm in diameter. The onset of the second growth phase of antral follicles and subsequent cohort growth are absolutely dependent on elevated FSH concentrations. When FSH concentrations decline, follicles begin to show characteristic changes such as reduced oestrogen-activity, reduced levels of higher molecular weight (MW) inhibins and increased amounts of lower MW insulin-like growth factor (IGF)-binding proteins culminating in granulosa cell apoptosis (Sunderland et al., 1996; Mihm et al., 1997; Austin et al., 2001). Prevention of this decline by administration of physiological amounts of FSH also prevents subordinate follicle atresia and associated changes in intrafollicular oestradiol, inhibins and IGF-binding proteins (Fig. 3; Adams et al., 1993; Mihm et al., 1997; Austin et al., 2002). Only the DF is able to maintain follicular cell proliferation, follicular fluid accumulation and enhance its steroidogenesis despite declining and nadir FSH. If FSH-induced follicular functions

Fig. 3. Administration of recombinant bovine FSH from the peak of the first transient FSH rise of the heifer oestrous cycle prevents subordinate atresia and delays selection of the DF when compared to saline-treated control cycles (from Mihm et al., 1997). DF1: first dominant follicle of the cycle. Sub. F.: subordinate follicles.

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are crucial to attain this relative FSH-independence, then this follicle must have the highest FSH response and thus the lowest FSH requirement before it passes the 8.5 mm size threshold. So far, higher levels of FSH binding and FSH mRNA expression have only been detected in oestrogen-active versus – inactive follicles on day 5 of the cycle, or in the DF 48 h after emergence of the first follicle wave compared to 12 h, i.e. after DF selection (Ireland and Roche, 1983; Xu et al., 1995; Bao et al., 1997). In addition, there are multiple spliced variants of FSH receptor mRNA encoding the extracellular domains in bovine granulosa cells with possible consequences for FSH binding and receptor signalling (Rajapaksha et al., 1996). Also, two further spliced variants have been identified in the sheep and mouse which are predicted to alter intracellular signalling pathways thus causing differential FSH response (Sairam et al., 1996, 1997; Babu et al., 2001). Our preliminary data on expression of the new end sequence mRNA which characterises both new FSH receptor variants suggests that bovine granulosa cells from antral follicles may also utilise different FSH signalling pathways, and it remains to be investigated whether these are differentially employed within the cohort. As a sign of greatest FSH-independence within the cohort, the DF itself prevents its closest competitor from continued growth by causing a final reduction in FSH at the last stage of DF selection (Ginther et al., 1999, 2000a,b). Thus, DF selection is a systemic process simultaneously affecting cohort growth on both ovaries via reductions in FSH following a transient rise (Adams et al., 1993; Mihm et al., 1997). 2.2. LH pulsatile release and the cohort LH stimulation of theca cells is essential for androgen synthesis acting as precursors for oestradiol, the enhanced synthesis of which is always associated with success within the cohort and continued progress during follicle wave growth (Austin et al., 2001). When follicles within the emerging cohort were maintained with exogenous FSH and subordinate atresia was prevented, no selected DF could be identified, and maintained cohort follicles showed a reduction in thecal LH receptor and steroidogenic enzyme mRNA levels compared to a DF (Mihm et al., 1997, 2000a). Only when LH pulses were administered concomitantly, the steroidogenic potential of FSH-maintained cohort follicles reached levels seen in the DF (Crowe et al., 2000). Similarly, aromatase activity of FSH-maintained cohort follicles in the GnRH-immunised model was induced by additional LH pulses (Crowe et al., 2001). Thus, LH responsiveness appears to be essential for oestradiol synthesis in growing cohort follicles. In fact, acquisition of LH receptors on granulosa cells is proposed to differentiate the follicle destined to become dominant from other cohort members (Bao et al., 1997), although other studies demonstrate that gene expression and translation into a functional LH receptor protein do not diverge in dominant versus subordinate follicles until after DF selection (Stewart et al., 1996; Evans and Fortune, 1997). Additional LH pulses administered to the emerging first follicle wave did not prolong cohort survival thus delaying DF selection or alter steroidogenic ability of medium (cohort) follicles (Crowe et al., 2000). In the converse situation, when LH pulses are completely abolished following a chronic GnRH-agonist treatment, or when LH pulses only occur very infrequently in the early postpartum period, follicle wave growth still occurs (Gong et al., 1996; Stagg et al., 1998). Similarly, steroid treatments aimed to reduce or even abolish LH

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pulses after emergence of the first follicle wave of the cycle or the transient LH rise seen at deviation, do not affect the timing of selection of the first DF or the size of the DF at the end of selection (Adams et al., 1992b; Burke et al., 1994; Kulick et al., 1999; Ginther et al., 2001). Although this suggests that FSH-dependent antral follicle growth before DF selection is not dependent on LH, cohort follicle functions are subtly affected in relation to intrafollicular oestradiol, inhibins, free IGF-I and lower MW IGF-binding proteins when LH pulses are reduced or completely abolished using steroid treatments (Ginther et al., 2001; Austin et al., 2002). Also, any pre-selection reduction in LH causes reduced DF growth and lifespan following its selection (Burke et al., 1994; Bo et al., 1995; Ginther et al., 2001). In fact, gonadotrophin administration in GnRH-agonist treated heifers led to the conclusion that LH is essential to stimulate antral follicles to grow beyond 9 mm in diameter (Gong et al., 1996) when a shift from FSH- to LH-dependency has taken place. 2.3. Ovarian secretions regulate cohort growth and DF selection In cattle of most reproductive states, cyclical FSH rises are responsible for the regular emergence of follicle waves followed by DF selection. The rate of reduction in FSH concentrations is directly related to the number of growing cohort follicles, most rapidly occurring when the complete wave is allowed to progress and select a DF, while the FSH decline is inhibited by continuous aspiration of cohort follicles following their emergence (Gibbons et al., 1999). Thus, cohort secretions into the systemic circulation must be responsible for declining FSH, indirectly causing their own atresia and DF selection. During cohort growth following its emergence inhibin-A increased coincident with systemic oestradiol, while FSH concentrations were reduced by approximately 50% (Fig. 4; Bleach et al., 2001). This pattern reflects the acquisition and subsequent maintenance of the ability to synthesise increased amounts of oestradiol and higher MW inhibins by successful cohort follicles 33 and 53 h after the FSH maximum (again when FSH has declined to ca. 50% of its maximum concentrations; Austin et al., 2001). Follicular secretions other than oestradiol and inhibin-A are thought to be involved in the FSH decline during cohort growth, as growing cohort follicles produce follistatin (Mihm et al., 1997; Austin et al., 2001), and steroid-free bovine follicular fluid treatment to suppress the peri-ovulatory FSH rise and follicle wave emergence is still effective in inhibin-immunised heifers (Wood et al., 1993; see also Fig. 2). Indirect evidence for the conclusion that inhibin-A secretion into circulation by the growing cohort is mostly responsible for the FSH decline and thus indirectly for DF selection, comes from a study in which growing cohort follicles were made atretic using exogenous steroid treatments causing an immediate decline in inhibin-A, which was followed by a rise in FSH concentrations despite high oestradiol (Mihm et al., 2001). During the dominance period antral follicles completing their first ‘slow’ growth phase are prevented from embarking on their second FSH-dependent growth phase by the DF. Loss of dominance during the luteal phase or induced atresia of a DF that was artificially maintained causes an increase in FSH concentrations and emergence of a new follicle wave (Sunderland et al., 1994; Manikkam and Rajamahendran, 1997). Removal of the selected DF using ultrasound-guided ablation causes a very rapid FSH rise and decline following emergence of a new follicle wave within 2 days of ablation (Fig. 5; Bodensteiner et al., 1996; Ginther et al., 1999). Ablation of the DF causes a rapid reduction in systemic oestradiol

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Fig. 4. Mean concentrations of gonadotrophins, steroids and inhibin-A during prostaglandin F2␣ (PG)synchronised cycles in heifers; hormone concentrations are aligned to the LH surge (from Bleach et al., 2001).

and inhibin-A in conjunction with the rapid FSH rise (Fig. 5), and both DF secretions are considered to be responsible for maintaining FSH at basal levels during the dominance period. The relative importance of oestradiol or inhibin-A in FSH suppression during a dominance period is difficult to ascertain, but exogenous oestradiol only exerts a transient inhibitory effect on pituitary FSH secretion (Cooke et al., 1997b; O’Rourke et al., 2000),

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Fig. 5. The effect of ablation of the first dominant follicle (DF) of the oestrous cycle in one cow on systemic ) hormone concentrations and follicle wave growth. The time of DF ablation is indicated by a dashed line. ( FSH; ( ) oestradiol or inhibin-A.

while immunoneutralisation of endogenous inhibin during the early and mid-luteal phases of the bovine oestrous cycle results in a marked and selective FSH rise (Kaneko et al., 1993; Glencross et al., 1994; Kaneko et al., 1997). In addition, during ‘physiological’ loss of dominance in the luteal phase of the oestrous cycle, oestradiol secretion from the first wave DF can be reduced from day 6 of the cycle, while FSH concentrations do not rise until days 7–9 (Sunderland et al., 1994). The fact that inhibin-A in serum declines slowly to

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reach nadir concentrations at exactly the time of the next FSH maximum (Bleach et al., 2001; Mihm et al., 2001), gives weight to the conclusion, that follicular inhibin may be the more important factor in the regulation of FSH secretion during dominance of a DF. Are there any direct systemic effects of ovarian secretions on antral follicles as they reach the FSH-dependent stage of development? Although one study reports that exogenous FSH can cause new wave emergence in animals treated with bovine follicular fluid to prevent the endogenous FSH rise (Bergfelt et al., 1994a), administration of FSH during the dominance period of the first DF does not consistently lead to advanced emergence of the next follicle wave (Adams et al., 1993; Mihm et al., 1995; Bodensteiner et al., 1996; Ginther et al., 2002). In accordance with this, several studies report reduced superovulatory responses of animals given exogenous FSH during a dominance period (Bungartz and Niemann, 1994). New follicle growth from 4 mm induced by exogenous FSH can be severely suppressed when systemic oestradiol concentrations are maintained at 2–3 times follicular phase concentrations following induction of atresia of the first follicle wave (Cooke et al., 1997b). This may be due to direct inhibitory effects of oestradiol or secretions from follicles undergoing atresia, which may diminish the FSH response in antral follicles as they acquire FSH-dependence. Lack of FSH-stimulated growth was not thought to be due to an inhibition of LH pulses or an inadequate FSH isoform profile, as similar doses of FSH induce follicle growth in GnRH-immunised heifers (Crowe et al., 2001). 2.4. Metabolic hormones affect the emerging cohort directly Metabolic states of animals due to negative energy balance clearly affect a variety of circulating hormones such as growth hormone, IGF-I, insulin, leptin, cortisol or thyroxine, all of which have been found to affect bovine follicular cell proliferation or steroidogenesis in vitro (Gong et al., 1993, 1994; Spicer et al., 1993; Spicer and Stewart, 1996a; Gutierrez et al., 1997a,b; Spicer and Chamberlain, 1998; Glister et al., 2001; Spicer et al., 2000a, 2002; Jimenez-Krassel and Ireland, 2002). In fact, some of these metabolic mediators such as IGFs and IGF-binding proteins are themselves synthesised in follicular cells (Armstrong et al., 1998, 2000) and act within paracrine or autocrine regulatory systems considered to be essential for follicle wave growth and DF selection. It is very difficult to differentiate the effects of various metabolic hormones from each other, as changes occur simultaneously when nutrition is compromised (Gutierrez et al., 1997c; Gong, 2002). The relative contributions of indirect effects exerted by metabolic hormones via gonadotrophins versus direct ovarian effects on follicular growth may also be difficult to determine, as any change in ovarian function will in turn affect gonadotrophin release patterns. It is remarkable that most of the second ‘fast’ phase of antral follicle growth, specifically cohort growth and DF selection, is very difficult to perturb and occurs in all reproductive and nutritional states, even during late pregnancy (Ginther et al., 1996) or following cessation of cyclicity in severe chronic undernutrition (Rhodes et al., 1995; Bossis et al., 1999). DF turnover was maintained during acute or chronic negative energy balance which reduced systemic concentrations of metabolic hormones (IGF-1, insulin), DF sizes and DF ovulatory ability, and in the case of chronic deficits affected DF oestradiol secretion; gonadotrophin secretion showed alterations which depended on the gonadotrophin and the duration of the

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negative energy balance (Spicer et al., 1992; Rhodes et al., 1995; Stagg et al., 1998; Bossis et al., 1999, 2000; Mackey et al., 1999, 2000). While this implies that the transient FSH rise and growth of FSH-dependent antral follicles are largely unaffected, follicles and particularly oocytes express growth hormone receptors from very early stages of development (Kölle et al., 1998) and their subsequent functions and developmental ability may be subtly compromised as a result of earlier interference (Cushman et al., 2001). Immunisation against growth hormone-releasing factor provides a model to study influences of the growth hormone/IGF/IGF-binding protein system on antral follicular growth and its interaction with gondotrophins. While follicular development in immunised heifer calves showing much reduced weight gain and delayed puberty is compromised due to both central effects on LH and ovarian effects via the IGF-I/IGF-binding protein system (Cohick et al., 1996), primi- and multi-parous beef cows show no alterations in cyclicity or DF selection despite marked changes in serum IGF-I and IGF-binding protein 2 (Stanko et al., 1994). Supplementation with growth hormone in cyclic heifers accompanied by raised circulating levels of IGF-I and insulin but no changes in gonadotrophins, increases the population of 2–5 mm follices (these are, presumably, antral follicles at the end of their first ‘slow’ growth phase), but does not interfere with the DF selection process (Gong et al., 1991, 1997). Similar effects on small antral follicles were seen in heifers with increased dietary intake associated with elevated insulin but reduced growth hormone and no change in IGF-I (Gutierrez et al., 1997c). The lack of alterations in growth hormone, insulin and IGF-I on DF selection is surprising, as enhanced FSH response of the cohort follicle destined to become the DF is related to increased bioavailability of IGFs (Mihm et al., 2000b), IGF-binding protein 2 is lower in the DF (Armstrong et al., 1998), and growth hormone treatment has been shown to increase follicular fluid IGF-I and decrease IGF-binding protein 2 in dominant and subordinate follicles (Stanko et al., 1994). Thus, growth hormone via systemic IGF-I or insulin may act to stimulate antral follicles during their first, gonadotrophin independent, growth phase, enabling more follicles to reach the FSH-dependent stage of development with possible effects on oocyte quality (Cushman et al., 2001; Roth et al., 2002). During the subsequent FSH-dependent antral growth phase, IGF-I concentrations may have to remain elevated to enhance follicular response to FSH, thus increasing follicular oestradiol secretion (Jimenez-Krassel et al., 1999). Cows with a high incidence of twinning show distinct transient FSH rises coupled with raised systemic IGF-I concentrations as well as disrupted DF selection, while higher FSH rises or higher IGF-I concentrations on their own lead to normal (single) DF selection (Alvarez et al., 2000; Echternkamp et al., 1990; Echternkamp, 2000). Elevated growth hormone may also have some direct inhibitory effects on gonadotrophin- and insulin-induced steroidogenesis in follicle cells (Spicer and Stewart, 1996b; Jimenez-Krassel and Ireland, 2002). These inhibitory effects may become apparent in situations where systemic IGF-I and insulin are reduced due to nutritional deprivation, and contribute to the reduction in follicular oestradiol release seen (Bossis et al., 1999). While effects of diminished follicular function on circulating gonadotrophins, particularly FSH, are predicted, increases in FSH were seen not only in cyclic but also in ovariectomised heifers under acute nutritional deprivation (Mackey et al., 2000), again illustrating that nutritional disturbances can act both centrally and at the ovarian level.

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3. Endocrine regulation of the fate of the selected DF 3.1. FSH and the DF The selected DF is relatively FSH independent and during a normal or prolonged dominance period maintains FSH at basal concentrations (Sunderland et al., 1994; Cooke et al., 1997a; Mihm et al., 1999). Exogenous FSH administered to the newly selected first DF does not affect its growth, oestrogenic activity or intrafollicular amounts of the smallest inhibin dimer (Adams et al., 1993; Mihm et al., 1995; Ginther et al., 2002). However, basal FSH concentrations are still essential to continued survival of the first DF of the cycle, and suppression of FSH below normal basal levels using bovine follicular fluid or oestradiol predisposes the DF to atresia (Adams et al., 1992a; Turzillo and Fortune, 1993; Bergfelt et al., 2000; Ginther et al., 2000a). However, suppression of FSH during a dominance period has only been achieved by administering bovine follicular fluid or oestradiol, which themselves may influence DF growth, and, therefore, absolute FSH requirements by the DF are not known. Oestrogen-active follicles after DF selection show high FSH binding and the DF itself expresses FSH receptors, which speaks for a role of FSH in continued growth and steroidogenesis of the DF (Ireland and Roche, 1983; Xu et al., 1995; Rajapaksha et al., 1996). Baseline FSH during a dominance period does not differ in its isoform profile from the profile seen during transient FSH rises, and thus is not considered to be more bioactive than elevated FSH that stimulates cohort emergence (Cooke et al., 1997a). Because the DF maintains several follicular functions induced by elevated FSH, such as aromatase activity, IGF, activin or inhibin synthesis (Badinga et al., 1992; Mihm et al., 1997; Austin et al., 2001), compared to cohort follicles it may have a very much enhanced FSH response or be uniquely able to amplify all FSH-stimulated granulosa cell functions, for example by using intrafollicular IGFs (Glister et al., 2001; Spicer et al., 2002). It is therefore surprising that additional FSH enhances some proliferative responses, but does not seem to influence DF differentiation in terms of steroidogenesis or the onset of DF atresia (Mihm et al., 1995). 3.2. LH and the DF Following its selection, DF growth, oestrogen activity and lifespan are controlled by the LH pulse pattern. Administration of LH pulses during the luteal phase prolongs the dominance phase of the first wave DF (Taft et al., 1996), while treatment with an GnRH antagonist to abolish LH pulses during growth of the first follicle wave reduces maximum sizes and dominance periods of the first and second DFs (Fike et al., 1997). Administration of LH pulses to the first DF postpartum in beef cows, which would not ovulate normally, causes increased oestradiol secretion, which in turn induces the gonadotrophin surge and ovulation (Duffy et al., 2000). Increased LH pulse frequencies seen following progestagen treatments will prolong the period of dominance of DFs from 2 to 7 days to more than 14 days (Savio et al., 1993; Stock and Fortune, 1993; Mihm et al., 1999). Conversely, DF atresia via apoptosis can be induced by an acute decrease in LH pulse frequency using exogenous progesterone (Savio et al., 1993; Rajamahendran and Manikkam, 1994), GnRH antagonist (Manikkam et al., 1995) or oestrogen (Yelich et al., 1997). Thus, the selected DF may have overcome FSH dependency, but is now extremely sensitive to LH pulsatility, with thecal

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gene expression for LH receptors and steroidogenic enzymes, and LH-induced androgen production (enhanced by high amounts of inhibin) crucial to granulosa cell aromatase gene expression, oestradiol synthesis and continued survival (Wrathall and Knight, 1995; Mihm et al., 2000a; Price and Hamel, 2002). Different nutritional and reproductive states affect GnRH and thus LH release during the postpartum period in dairy cows experiencing negative energy balance (Canfield and Butler, 1990; Beam and Butler, 1997), in beef suckler cows calving in low body condition (Stagg et al., 1998), before puberty (Evans et al., 1994), and in beef heifers experiencing nutritional anoestrus (Rhodes et al., 1995; Stagg et al., 1995; Bossis et al., 1999). Leptin is being discussed as one of the central mediators of body condition, and not only indicates body fat status, but also changes acutely with meal intake in heifers and cows (Amstalden et al., 2000; Delavaud et al., 2002). Leptin may be one of the nutritional regulators of LH release in the bovine in vivo. However, reductions in leptin following acute feed withdrawal are usually accompanied by reductions in IGF-I and insulin, while leptin administration increases insulin (Amstalden et al., 2000, 2002a), which may alter glucose centrally if not systemically altering GnRH pulsatility. Evidence for a role of leptin at the level of pituitary LH release comes from an ovariectomised beef cow model, where in animals fasted for 60–72 h intracerebroventricular infusions of leptin increase mean LH in a dose-dependent manner, and leptin treatment of adenohypophyseal explants increases basal and GnRH-stimulated LH release (Amstalden et al., 2002a,b; Zieba et al., 2002). It is not known whether sudden reductions in leptin or alterations in other metabolic mediators caused by acute feed withdrawal are responsible for the inhibition of the gonadotrophin surge seen in some synchronised beef heifers (Mackey et al., 1999, 2000). 3.3. Metabolic hormones may regulate DF functions directly Acute nutritional deficits can influence growth and oestradiol synthesis of the first-wave or preovulatory DF without affecting LH pulsatility (Mackey et al., 1999). As nutritional restriction may increase growth hormone, but decrease IGF-I and insulin, it is probable that LH-dependent growth and oestradiol synthesis of the DF is still dependent on high amounts of bioavailable or ‘free’ IGFs, and responds to alterations in systemic growth hormone or insulin (Jimenez-Krassel et al., 1999; Jimenez-Krassel and Ireland, 2002). In addition, changes in circulating thyroxine due to nutritional deficits may further reduce follicular steroidogenesis already limited by reduced IGF-I and insulin (Spicer et al., 2001, 2002). Recently, Gong et al. (2001, 2002) report beneficial effects of dietary-induced increases in circulating insulin in postpartum dairy cows of different genetic merit on fertility parameters, despite the absence of any effects on gonadotrophins, DF growth and DF turnover. Two in vivo studies demonstrate clearly, that the two metabolic mediators insulin and IGF-I can act directly on some antral follicle populations increasing growth and oestradiol synthesis in small first-wave and in large FSH-stimulated follicles (Simpson et al., 1994; Spicer et al., 2000b). Finally, direct ovarian effects of circulating leptin have been proposed, as leptin receptors are expressed in the ovary (Brannian and Hansen, 2002), and leptin appears to influence gonadotrophin-, insulin- and IGF-I-induced thecal androgen and possibly granulosal progesterone synthesis in vitro, although actual effects are equivocal (Spicer and Francisco, 1997; Glister and Knight, 2000; Spicer et al., 2000a; Richards and Knight,

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2002). Very recently, preliminary information was given on a study performed in ewes with autotransplanted ovaries, where direct ovarian leptin administration reduced oestradiol secretion from the preovulatory follicle (Kendall et al., 2002), although central effects cannot be excluded. Clearly, it is difficult to dissociate central effects of metabolic mediators from direct effects on follicles undergoing their second antral growth phase, especially as altered ovarian functions before and after ovulation may in turn influence gonadotrophins. As increased conception rates have been seen following the high insulin diet in postpartum dairy cows (Gong, 2002), influences of metabolic hormones may be exerted during the first ‘slow’ growth phase of antral follicles on both follicle and oocyte, altering their subsequent gonadotrophin-dependent growth phase and oocyte developmental competence.

4. Conclusions Examination of the differential roles of the two gonadotrophins particularly in follicle wave growth (the second ‘fast’ growth phase of antral follicle development) in the bovine led to the following findings: Transient rises in FSH concentrations are responsible for antral follicle growth beyond 4–5 mm in diameter, and the decline in FSH concentrations is responsible for cohort atresia as well as DF selection. Thus, the selected DF is the only follicle able to maintain and enhance all follicular functions induced by elevated FSH despite declining and nadir FSH, and free IGFs appear to play a very important role in these processes. Secretions from the growing cohort and the selected DF, particularly oestradiol and inhibin-A, are thought to be responsible for the FSH fluctuations responsible for DF selection (FSH decline) and emergence of the next follicle wave (transient FSH rise). The LH pulse environment is not crucial for cohort growth and DF selection, but an acute reduction will affect cohort steroidogenesis and have subsequent effects on lifespan, growth and steroidogenesis of the selected DF. Following its selection, DF gonadotrophindependency has shifted from FSH to LH, with atresia occurring when LH pulse frequencies are lower than 1 pulse every 2 h. Whether acquisition of LH receptors on granulosa cells are crucial to this shift towards LH-dependency, and what the mechanisms are that allow LH to stimulate and enhance follicular functions previously induced by FSH has yet to be resolved. Acute and chronic nutritional deprivation cause deficits in mostly DF growth and oestradiol production, but not usually in DF selection. Some direct effects of the metabolic hormones belonging to the growth hormone–insulin–IGF-I axis as well as leptin, thyroxin and cortisol have been demonstrated in vitro and in vivo, but which of the metabolic hormones is most essential for ovarian function may be very difficult to determine. Reasons for this may be that absence or oversupply of some metabolic hormones compromise animal health, hormones act on ovaries indirectly through other metabolic mediators and via central effects, effects may depend on the duration and extent of hormonal changes experienced, and the multitude of hormonal effectors almost implies redundancy in the system. Increasing growth hormone or its mediators IGF-I and insulin possibly allows more early antral follicles than normal to proceed to the FSH-dependent stage, yet subsequent DF selection is never compromised. It is proposed that mediators such as IGF-I may have to be chronically elevated in the presence of pronounced FSH elevations to enable more than one cohort

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member to survive declining FSH causing twin ovulations (Echternkamp, 2000). However, any long-term alterations in the growth hormone axis may be able to influence not only early antral follicular but also oocyte development with possible subsequent effects on fertility. Following DF selection, metabolic mediators may affect subsequent DF growth and steroidogenesis via effects on the LH secretory profile, particularly in situations of chronic nutritional deficits where LH pulsatility is reduced before anovulation ensues. Whether central or direct ovarian effects of metabolic mediators prevail, may be decided by the nutritional or reproductive state of the animal, i.e. presence of gonadotrophins and other metabolic hormones: when animals are overfed leptin may have to directly suppress follicular oestradiol secretion ‘over-induced’ by raised metabolic mediators and gonadotrophins (Spicer, 2001), while during re-alimentation following severe nutritional deprivation or during a prolonged postpartum period increasing leptin may be involved in the increases in LH pulsatility demonstrated (Stagg et al., 1998; Bossis et al., 2000). Further studies at the granulosa and thecal cell level of gonadotrophin and metabolic hormone response systems and the modulation by ovarian growth factors will be greatly enhanced by the increasing availability of genomic and proteomic bovine databases.

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