Reproduction in Domestic Animals

226 FX Donadeu and HG PedersenRegulation of Follicular Wave DevelopmentEmergence of a follicular wave and subsequent selectionof a dominant follicle are under finely-tuned regulationby systemic mechanisms involving changes in gonadotropinlevels and local mechanisms that involve changesin follicular factor levels.Systemic regulation of follicular wave development.Unlike pre-antral follicles, antral follicles cannotdevelop without adequate gonadotropin stimulation andthis has been experimentally shown in the mare(Pedersen et al. 2002; Imboden et al. 2006).Follicular waves in the mare, as in other species, aretemporally preceded by a stimulatory surge in circulatingFSH (Ginther et al. 2003a). The acute dependence offollicular waves on FSH has been shown in mares by theinability of follicles to grow beyond a diameter of 15 mmafter suppression of circulating FSH by systemic injectionof follicular fluid (Bergfelt and Ginther 1985). Closefunctional relationships between FSH surges and follicularwaves involve not only positive effects of FSH onfollicles but also negative effects of follicles on FSH. Thewave-associated FSH surge reaches a peak when thelargest follicle is approximately 13 mm in diameter(Gastal et al. 1997; Donadeu and Ginther 2001). Thefollowing decline in FSH results from an increase incirculating inhibin, presumably inhibin-A (Watson andAl-zi’abi 2002), contributed mainly by the three largestfollicles of the wave as they grow above 13 mm(Donadeu and Ginther 2001). The declining FSHconcentrations continue to support growth of thefollicles of the wave until the largest (future dominant)follicle reaches the expected diameter at the beginning ofdeviation (approximately 22 mm). At that time, circulatingFSH levels become too low to maintain thegrowth of the follicles of the wave. The low FSH, yet,does not restrict the growth of the future dominantfollicle which by that time has acquired the ability tomore efficiently use circulating gonadotropins forgrowth (Ginther et al. 2003a). The differential responsesof the largest and smaller follicles of a wave togonadotropins result in the initiation of diameterdeviation. Continuous suppression of FSH throughoutdeviation ensures the morphological and functionaldemise of subordinate follicles and is attributable toproduction of high levels of inhibin and oestradiol bythe dominant follicle (Gastal et al. 1999; Donadeu andGinther 2001). The critical role of low FSH levels in thedeviation mechanism in mares is illustrated by thedisruption of the deviation mechanism after administrationof FSH (Squires 2006) or immunization againstinhibin (McCue et al. 1992) leading to the developmentof multiple ovulatory follicles.While FSH is particularly important for folliculargrowth before deviation, LH becomes more criticalduring deviation. This has been demonstrated by studiesshowing that experimental suppression of LH in cyclingmares leads to the regression of the dominant follicleearly during its development (Bergfelt et al. 2001), and isconsistent with an increase in circulating LH before thebeginning of deviation (Bergfelt et al. 2001). The studyof LH–follicle interrelationships during the anovulatoryseason has revealed a direct temporal relationshipbetween an increase in circulating LH, but not FSH,and the development of major waves, further indicatingthat an increase in LH plays a major role in stimulatingthe development of dominant follicles (reviewed inDonadeu and Watson 2007). An additional conclusionwas that circulating LH concentrations above thoserequired for growth of the dominant follicle are requiredfor the development of ovulatory competence, i.e. forthe dominant follicle to become fully responsive to anLH surge (Donadeu and Watson 2007).Studies in cattle have shown that LH receptorexpression differentially increases in granulosa and thecacells of the early dominant follicle (Bao and Garverick1998; Beg and Ginther 2006). These findings areconsistent with those in other species (Richards 2001).Although not critically examined in relation to thebeginning of deviation, higher LH receptor levels havebeen reported in dominant-size follicles than in smallerfollicles in the horse (Fay and Douglas 1987; Goudetet al. 1999). Taken together, the findings on LH levelsand LH receptor expression during a follicular wave inmares are consistent with the conclusion that deviationinvolves a critical increase in the dependence of thedominant follicle on LH.Limited data exist on the involvement of substancesother than gonadotropins in the endocrine regulation ofantral follicles in mares. Based on observed direct effectson follicle growth or on the presence of specific receptorsin equine ovaries, positive roles on follicle growth havebeen suggested for circulating levels of substancesincluding growth hormone (Cochran et al. 1999), dopamine(King et al. 2005) and prolactin (Thompson et al.1997).Although follicular insulin-like growth factor-1(IGF-1) in mares largely derives from the systemiccirculation, its bioactivity is regulated mostly throughlocal mechanisms (Watson et al. 2004) and the role ofIGF-1 is therefore considered in the next section.Local regulation of follicular wave development. Localregulation of follicle development in monovular specieshas been studied extensively in relation to follicleselection (reviewed in Fortune et al. 2004; Beg andGinther 2006; Knight and Glister 2006). A variety ofprotein and steroid factors including members of theIGF family, oestradiol, inhibins and activins, follistatinand vascular endothelial growth factor (VEGF) areinvolved. In general, these factors act, often in aparacrine manner, to either enhance or diminish thetrophic effects of gonadotropins on follicular cellsthrough a variety of mechanisms. Differential changesin the levels of specific factors between follicles thusensure the continuous development of the dominantfollicle and the regression of subordinate follicles duringdeviation.A differential increase in the levels of oestradiol, IGF-1,activin-A and inhibin-A in the future dominant folliclewas associated with the beginning of deviation in mares,whereas differentially elevated levels of progesteroneand inhibin-B occurred later during the development ofthe dominant follicle (Donadeu and Ginther 2002a).Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag