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Contents
The mare provides a unique experimental model for studying follicle development in monovular species. Development of antral follicles in horses is characterized by the periodic growth of follicular waves which often involve the selection of a single dominant follicle. If properly stimulated, the dominant follicle will complete development and eventually ovulate a fertile oocyte. Regulation of follicular wave emergence and follicle selection involves an interplay between circulating gonadotropins and follicular factors that ensures that individual follicles are properly stimulated to grow (or to regress) at any given stage of follicular wave development. Periodic development of follicular waves continuously occurs during most of post-natal life in the mare and is inuenced by factors such as stage of oestrous cycle, season, pregnancy, age, breed and individual so that dierent types of follicular waves (minor or major, ovulatory or anovulatory) and dierent levels of activity within waves may develop under dierent physiological conditions. Changes in gonadotropin levels and or in the sensitivity of follicles to circulating gonadotropins seem to account largely for these physiological variations in follicle development.
This review summarizes current knowledge on equine follicle development. Information on pre-antral and early antral follicles is particularly scarce in the horse; therefore, relatively more focus has been placed on the late stages of antral follicle development up to the preovulatory stage. Details on physiological and practical aspects of the ovulatory process and subsequent formation of the corpus luteum can be found elsewhere (Ginther 1992; Boerboom and Sirois 2001; Squires 2006).
Introduction
Although scientic interest in equine follicles existed by the 1920s (Seaborne 1925), detailed studies on equine follicle dynamics did not begin until 50 years later under the pioneering lead of OJ Ginther at the University of Wisconsin (reviewed in Ginther 1979). During the early 1980s, ultrasonography became available for equine theriogenology (Palmer and Driancourt 1980). Transrectal ultrasonography combined with systemic hormone measurements were subsequently used extensively to understand equine follicle dynamics. The more recent introduction (mid-1990s) of the technique of ultrasoundguided transvaginal ovarian puncture provided scientists unprecedented access to the live equine ovary and allowed the targeting of individual follicles for collection of follicle samples, injection of test substances or experimental manipulation of follicles (Gastal et al. 1997; Gerard and Monget 1998; Donadeu and Ginther 2001; Martoriati et al. 2003). The experimental use of these procedures has led to extraordinary advances in the knowledge of equine ovarian physiology during the last 15 years (reviewed in Beg and Ginther 2006; Donadeu and Watson 2007). Two important outcomes of this knowledge have been an improvement of reproductive eciency in mares (Squires 2006) and a greater understanding of follicular physiology in monovular species in general. In regard to the latter, consideration of the mare as a useful model for studying ovarian processes during human health and disease has recently increased (Ginther et al. 2004c; Carnevale 2008).
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1982). Similar to pre-antral stages, little is known on the development of antral follicles before they reach approximately 2 mm, the smallest diameter that can usually be detected by transrectal ultrasonography. It has been reported that the growth of an equine follicle from 0.1 to 1 mm takes approximately two oestrous cycles (Driancourt 1979) and that atresia during this early phase of antral development is rare (Ginther 1992). As in other farm species and humans, the development of antral follicles in the horse is characterized by the periodic growth of cohorts of follicles or follicular waves (Sirois et al. 1989; Bergfelt and Ginther 1993). Characterization of follicular waves has involved the ultrasonic day-to-day identication of individual follicles (Bergfelt and Ginther 1993; Gastal et al. 1997) and the use of a statistical method that avoids the need to maintain the identities of individual follicles during serial ultrasound examinations (Ginther and Bergfelt 1992; Donadeu and Ginther 2002b). Follicular waves in the horse can be identied in relation to follicles 2 mm in diameter and larger; however, it is not known whether earlier antral and pre-antral stages are also characterized by wave-like patterns of growth, a question that has also not been claried in other species (Mizunuma et al. 1999; McGee and Hsueh 2000). Follicular waves and their regulation with an emphasis on normal oestrous cycles will be described in this and the next section. Follicular wave patterns characteristic of other reproductive states will be described in a separate section. Characteristics of a follicular wave. Follicular wave emergence has been normally dened for experimental purposes as occurring when the largest follicle reaches 6 or 13 mm, depending on the study (Ginther et al. 2003a). Identication of wave emergence often requires day-to-day ultrasonic evaluation of the ovary usually after aspiration of all follicles from previous waves. A follicular wave initially involves the simultaneous growth of a variable number of follicles at a common rate of between 2 and 3 mm day. A recent study involving ablation of all follicles during the middle of an oestrous cycle in pony mares reported a mean of approximately 12 follicles emerging during the common growth phase of the ablation-induced wave (Gastal et al. 2004). Approximately two follicles emerged each day during the rst 4 days after wave emergence with a progressive decrease in the numbers of follicles emerging thereafter. The exact number of follicles emerging within waves is aected by factors such as season (Donadeu and Ginther 2003). The phase of common follicle growth is followed by the selection of a single follicle (occasionally two follicles) which is manifested as a deviation in diameter between the two largest follicles of the wave beginning when the largest follicle reaches approximately 22 mm (Ginther et al. 2003a). Deviation begins a mean of 7 days before ovulation and is characterized by the continuous growth (at an unchanged rate) of the largest (selected) follicle as a dominant follicle and the simultaneous cease in growth and subsequent regression of smaller, subordinate follicles. Once it grows to
approximately 3545 mm, the dominant follicle normally either ovulates or ceases to grow and begins to regress, depending on whether an ovulatory LH surge occurs. The establishment of dominance is mediated by a dierential increase in trophic support to the largest follicle of a wave by mechanisms that will be explained in more detail in the next section. This leads to profound changes in follicular cell function that are necessary for the eventual full maturation of the follicle to an ovulatory-competent state and that are reected in dramatic changes in global gene expression, changes that have begun to be characterized in other species, most notably cattle (Sisco et al. 2003; Fayad et al. 2004; Mihm et al. 2008). Dominance does not seem to be a pre-determined trait among the follicles growing in a wave because follicle ablation studies have demonstrated that all follicles have similar capacity to become dominant, a capacity that in subordinate follicles is lost within approximately 48 h after the beginning of deviation (Gastal et al. 2004). The same studies showed that in approximately 61% of waves the rst follicle to emerge at 6 mm maintains its size advantage over smaller follicles through the common growth phase and becomes dominant. The likelihood of the largest follicle becoming dominant increases as it approaches the expected diameter at the beginning of deviation (Gastal et al. 2004). In a few instances, yet, the largest follicle ceases or slows down its growth during the common growth phase and is replaced by the second largest follicle (or sometimes even a smaller follicle) which then becomes the dominant follicle. Types of follicular waves. Follicular waves have been classied as major waves (referred to in the literature and throughout this review simply as follicular waves) or minor waves, depending on whether they involve the development of a readily identiable dominant follicle or they produce only smaller follicles, respectively (Ginther 1993; Donadeu and Ginther 2002b). The number of follicular waves during an oestrous cycle varies between species. In the horse, as in humans, only one or two major follicular waves develop during each cycle (Ginther et al. 2004c). A major wave (named primary wave) always emerges during the middle of the equine oestrous cycle and produces the ovulatory follicle. Approximately 25% of interovulatory intervals involve an additional major wave (secondary wave) that develops during the rst half of the cycle (Sirois et al. 1989; Bergfelt and Ginther 1993). The incidence of secondary waves is signicantly higher in some breeds such as Thoroughbreds, and some of these waves may produce ovulations. The ability to ovulate in the presence of high progesterone levels during dioestrus seems to be unique to the horse (Ginther 1992). Minor waves (largest follicle usually <30 mm) have been identied at dierent stages of the oestrous cycle and their incidence has been reported to be low, 25% or less of oestrous cycles (Bergfelt and Ginther 1993; Ginther 1993). Yet, a study considering follicles as small as 2 mm concluded that relatively high levels of underlying activity may involve the smallest follicles of a wave (Ginther and Bergfelt 1993).
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season has revealed a direct temporal relationship between an increase in circulating LH, but not FSH, and the development of major waves, further indicating that an increase in LH plays a major role in stimulating the development of dominant follicles (reviewed in Donadeu and Watson 2007). An additional conclusion was that circulating LH concentrations above those required for growth of the dominant follicle are required for the development of ovulatory competence, i.e. for the dominant follicle to become fully responsive to an LH surge (Donadeu and Watson 2007). Studies in cattle have shown that LH receptor expression dierentially increases in granulosa and theca cells of the early dominant follicle (Bao and Garverick 1998; Beg and Ginther 2006). These ndings are consistent with those in other species (Richards 2001). Although not critically examined in relation to the beginning of deviation, higher LH receptor levels have been reported in dominant-size follicles than in smaller follicles in the horse (Fay and Douglas 1987; Goudet et al. 1999). Taken together, the ndings on LH levels and LH receptor expression during a follicular wave in mares are consistent with the conclusion that deviation involves a critical increase in the dependence of the dominant follicle on LH. Limited data exist on the involvement of substances other than gonadotropins in the endocrine regulation of antral follicles in mares. Based on observed direct eects on follicle growth or on the presence of specic receptors in equine ovaries, positive roles on follicle growth have been suggested for circulating levels of substances including 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 systemic circulation, its bioactivity is regulated mostly through local mechanisms (Watson et al. 2004) and the role of IGF-1 is therefore considered in the next section. Local regulation of follicular wave development. Local regulation of follicle development in monovular species has been studied extensively in relation to follicle selection (reviewed in Fortune et al. 2004; Beg and Ginther 2006; Knight and Glister 2006). A variety of protein and steroid factors including members of the IGF family, oestradiol, inhibins and activins, follistatin and vascular endothelial growth factor (VEGF) are involved. In general, these factors act, often in a paracrine manner, to either enhance or diminish the trophic eects of gonadotropins on follicular cells through a variety of mechanisms. Dierential changes in the levels of specic factors between follicles thus ensure the continuous development of the dominant follicle and the regression of subordinate follicles during deviation. A dierential increase in the levels of oestradiol, IGF-1, activin-A and inhibin-A in the future dominant follicle was associated with the beginning of deviation in mares, whereas dierentially elevated levels of progesterone and inhibin-B occurred later during the development of the dominant follicle (Donadeu and Ginther 2002a).
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Studies involving intrafollicular factor injection in mares have provided insight into the complex interrelationships between these factors during follicle deviation (Ginther et al. 2005). It has been concluded that although all these factors are likely involved in the development of the dominant follicle after the beginning of deviation, only IGF-1 is involved in the initiation of deviation by, among other actions, regulating the levels of other growth factors in the dominant follicle (Beg and Ginther 2006). This is consistent with the particularly important role of the IGF-1 system in follicle selection in other species (Mazerbourg et al. 2003). Results from a series of in vivo experiments have convincingly conrmed the critical role of the IGF system in follicle selection in mares. Injection of IGF-1 into the second largest or a smaller follicle at the beginning of deviation changed its fate from subordinate to co-dominant resulting in the development of multiple ovulatory follicles (Ginther et al. 2004a; b; Gastal et al. 2007). Conversely, injection of IGF binding protein (IGFBP)-3 into the largest follicle at the beginning of deviation resulted in the follicle regressing and being replaced by the second largest follicle which became dominant (Ginther et al. 2004a). At least four types of IGFBPs (IGFBP-2, 3, 4 and 5), which negatively regulate IGF activity, have been identied in equine follicles and the concentrations of three of these (IGFBP-2, 4 and 5) are correlated negatively with those of IGF-1 during follicle development (Gerard and Monget 1998; Bridges et al. 2002). Consistent with the stimulatory role of IGF-1 in the development of ovulatory follicles, reduced levels of bioactive IGF-1 are thought to be involved in the developmental deciencies of dominant follicles during the spring transition that prevent them from acquiring ovulatory competence (Acosta et al. 2004; Watson et al. 2004). An additional factor that has begun to be explored in relation to follicle selection in horses is VEGF. This angiogenic factor has been shown to be necessary for follicle development in other species (Fraser and Wul 2001). VEGF levels dierentially increase in the dominant follicle in horses (Ginther et al. 2004b), and this increase is thought to be mediated, at least partly, by IGF-1. VEGF is likely involved in the reported increase in vascularization of the future dominant follicle before the beginning of deviation (Acosta et al. 2004) which presumably increases the availability of circulating gonadotropins to the follicle. The reduced levels of follicular VEGF and low vascularity of the wall of dominant follicles during the spring transition relative to the ovulatory season (Watson and Al-ziabi 2002) underscore the critical role of VEGF in the development of the ovulatory follicle in horses.
Studies in pony mares using follicle ablation to facilitate the identication of individual follicular waves revealed that, as during the ovulatory season, follicular waves periodically occur during the anovulatory season despite the reduced levels of follicle development (Donadeu and Ginther 2002b, 2003; Ginther et al. 2003b). Only minor waves (largest follicle <21 mm) occurred during the middle of the anovulatory season or deep anoestrus, whereas major waves were often detected during the rst 2 months (fall transition) and the last 2 months (spring transition) of the anovulatory season, in agreement with previous studies (Ginther 1990; Watson et al. 2002). The onset of the spring transitional period involved an abrupt increase in follicular activity from the low activity typical of deep anoestrus which was reected in a distinct increase in the diameter of follicles and, most notably, a fourfold increase in the numbers of follicles > mm within waves (means of 3.2 and 11.5 12 follicles in waves developing during deep anoestrous and the early spring transition, respectively). Although dominant follicles during transition may not grow to the diameters typical of ovulatory follicles, in the same study transitional waves produced more follicles than waves developing during the ovulatory season (means of 11.5 and 6.0 follicles > mm, respectively) attesting to 12 the high levels of follicular activity even in the absence of ovulation in transitional mares (Donadeu and Ginther 2003). Based on consistent temporal relationships between follicles and circulating hormones, it has been concluded that the dierences in follicle development between dierent periods of the anovulatory season as well as the decient development of dominant follicles during the spring transition relative to the ovulatoy season are not attributable to decient circulating FSH levels but rather to changes in LH and, possibly, dierences in follicular sensitivity to gonadotropins (reviewed in Donadeu and Watson 2007). Season-related eects on follicular activity have also been reported between the two halves of the ovulatory season, with higher levels of activity during the rst half of the season due to higher incidence of both secondary waves and minor waves associated with higher gonadotropin levels (Ginther 1992, 1993). Eects of pregnancy and parturition. Considerable research work is needed to better characterize follicular dynamics and associated regulatory mechanisms during and following pregnancy in the mare. Based on combined data from ultrasound and rectal palpation studies, follicular dynamics during the rst half of pregnancy are similar to those occurring during the rst half of the anovulatory season, with an initial period of variable activity (between days 11 and 40 of pregnancy) characterized by the periodic development of major waves or, more commonly, development of sporadic major waves or only minor waves (Ginther and Bergfelt 1992), followed by a pronounced decrease in follicular activity in all mares between days 50 and 140 of pregnancy so that the diameter of the largest follicle does not exceed 15 mm by day 140 (Squires et al. 1974). A decrease in follicular activity has also been reported after the rst one-third of pregnancy in cattle (Ginther et al. 1996).
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Based on reported hormonefollicle associations, decient FSH levels do not seem to be responsible for the reduction in follicular growth in some mares between days 11 and 40 of pregnancy (Ginther and Bergfelt 1992), an eect that may instead be accounted for by reduced levels of LH (due to persistent progesterone negative feedback), similar to the eects of the seasonal reduction in circulating LH on follicle growth during the fall transitional period (Ginther et al. 2003b). The mechanisms responsible for the dramatic reduction in follicular growth during mid and late pregnancy in mares have not been claried but likely involves a temporally associated decrease in circulating FSH (reviewed in Ginther 1992). This is dierent from the anovulatory season during which changes in FSH levels do not seem to play a major role in the decrease in follicle growth during deep anoestrus (Donadeu and Watson 2007). Reduced follicle numbers during midpregnancy are also likely attributable to ovulation or luteinization of follicles into accessory corpora lutea under the inuence of chorionic gonadotropin (Ginther 1992). Further complexity into the regulation of follicle growth during pregnancy is provided by the observation that the eects of season on hormones and follicles continue to occur during pregnancy (Ginther 1992). The natural pressure to produce a foal each year in a species with an 11-month-long pregnancy is reected in an early post-partum ovulation in the mare (foal heat, typically within 2 weeks of parturition). A steady increase in the diameter of the largest follicle and in the numbers of follicles after parturition resulting in ovulation 14 days later was recently shown in Arabian mares (Gunduz et al. 2008). The post-partum increase in follicular growth is induced by an increase in gonadotropin secretion at the time of parturition (Hines et al. 1987; Ginther et al. 1994). Studies have shown that the follicular response to parturition may vary in individual horses or dierent types of horses, and may not readily occur in primiparous mares (Nagy et al. 1998), in the presence of a nursing foal (Ginther 1992) or during the winter, when the negative eects of season may prevail over the positive eects of parturition (Ginther et al. 1994). Follicle development before puberty. Follicle development in spring-born pre-puberal pony llies has recently been studied in detail (Nogueira and Ginther 2004), adding to limited information on follicle proles from earlier studies (reviewed in Ginther 1992). Follicular activity during 210 months of life was characterized by a progressive increase in mean follicle diameter (from approximately 6 to 10 mm) and mean follicle numbers (from 3 to 17 follicles) between 2 and 5 months of age, a short plateau in activity coinciding with the winter months and a re-initiation of follicle growth after 7 months of age leading to the onset of the rst ovulatory season in spring (Nogueira and Ginther 2004). Changes in follicle activity during the rst year of life were positively correlated with changes in circulating gonadotropins, consistent with a regulatory role of season on gonadotropin and follicular activity beginning early during life in mares. Follicular growth before puberty was characterized by the development of
(minor) follicular waves. Remarkably, these waves were not temporally associated with statistically signicant circulating FSH surges, an observation that warrants further investigation. Eects of aging on follicular activity. As highlighted in a recent review, many age-related changes in follicular activity in the horse resemble those occurring in humans (Carnevale 2008). Follicular activity during oestrous cycles begins to decrease in mares 20 years of age or older eventually leading to a cease in ovarian activity (Carnevale et al. 1993, 1994). Interovulatory intervals rst become longer in these mares due to longer follicular phases associated with a primary follicular wave that emerges later and contains less follicles. In addition, the ovulatory LH surge is less pronounced in the older mares, and there is a higher incidence of ultrasonically atypical ovulations characterized by a central hypoechogenic area at the ovulatory site. The reduction in follicular activity and frequency of ovulation in mares 20 years old is associated with an overall elevation in concentrations of FSH and LH during the follicular phase, a phenomenon that also occurs during the peri-menopausal period in women. This is eventually associated with persistent ovarian inactivity with follicles <5 mm and no ovulations in the presence of continuously elevated concentrations of FSH and LH. Reportedly, approximately 40% of horses 24 years or older have no ovarian activity (Vanderwall 1990) whereas 50% of ponies 20 years or older have irregular or absent ovulations (Carnevale et al. 1994). It has been suggested that an age-related elevation in FSH concentrations may hasten the eventual depletion of the primordial follicle pool in older mares, similar to what occurs in women (Carnevale 2008). Age-related dierences in follicular activity have also been reported in mares during the period of transition into the ovulatory season during which progressively lower follicle diameters and numbers of follicles were found in mares 37, 1719 and 20 years old (Carnevale et al. 1997).
Conclusions
The possibility of experimentally targeting equine follicles at very precise stages of development in vivo using a relatively noninvasive ultrasound-guided technique makes the horse a very attractive model to study in detail the dynamics of antral follicles. In addition, the seasonal nature of ovarian activity in mares oers a unique model to study the factors naturally regulating follicle development in a monovular species. As in other monovular species, the development of antral follicles in horses is characterized by the periodic emergence of follicular waves and the selection of usually a single dominant follicle that under the appropriate hormonal milieu will ovulate a fertile oocyte. Follicular wave emergence and follicle selection are driven by systemic changes in levels of FSH (wave emergence and follicle selection) and LH (follicle selection), and by local changes in follicular factors that, through a variety of mechanisms, are responsible for ne-tuning the response of follicular cells to gonadotropin stimuli to ensure the continuous growth of the
229 Cochran RA, Leonardi-Cattolica AA, Sullivan MR, Kincaid LA, Leise BS, Thompson DL Jr, Godke RA, 1999: The eects of equine somatotropin (eST) on follicular development and circulating plasma hormone proles in cyclic mares treated during dierent stages of the estrous cycle. Domest Anim Endocrinol 16, 5767. Deanesly R, 1975: Germ cell development and the meiotic prophase in the fetal horse ovary. J Reprod Fertil Suppl 23, 547552. Donadeu FX, Ginther OJ, 2001: Eect of number and diameter of follicles on plasma concentrations of inhibin and FSH in mares. Reproduction 121, 897903. Donadeu FX, Ginther OJ, 2002a: Changes in Concentrations of follicular uid factors during follicle selection in mares. Biol Reprod 66, 11111118. Donadeu FX, Ginther OJ, 2002b: Follicular waves and circulating concentrations of gonadotrophins, inhibin and oestradiol during the anovulatory season in mares. Reproduction 124, 875885. Donadeu FX, Ginther OJ, 2003: Interactions of follicular factors and season in the regulation of circulating concentrations of gonadotrophins in mares. Reproduction 125, 743750. Donadeu FX, Watson ED, 2007: Seasonal changes in ovarian activity: lessons learnt from the horse. Anim Reprod Sci 100, 225242. Driancourt MA, 1979: Follicular kinetics in the mare ovary. Ann Biol Anim Biochim Biophys 19, 14431453. Driancourt MA, Paris A, Roux C, Mariana JC, Palmer E, 1982: Ovarian follicular populations in pony and saddletype mares. Reprod Nutr Dev 22, 10351047. Driancourt MA, Prunier A, Palmer E, Mariana J, 1983: Seasonal eects on ovarian follicular development in pony mares. Reprod Nutr Dev 23, 207215. Fay JE, Douglas RH, 1987: Changes in thecal and granulosa cell LH and FSH receptor content associated with follicular uid and peripheral plasma gonadotrophin and steroid hormone concentrations in preovulatory follicles of mares. J Reprod Fertil Suppl 35, 169181. Fayad T, Levesque V, Sirois J, Silversides DW, Lussier JG, 2004: Gene expression proling of dierentially expressed genes in granulosa cells of bovine dominant follicles using suppression subtractive hybridization. Biol Reprod 70, 523533. Fortune JE, Rivera GM, Yang MY, 2004: Follicular development: the role of the follicular microenvironment in selection of the dominant follicle. Anim Reprod Sci 8283, 109126. Fraser HM, Wul C, 2001: Angiogenesis in the primate ovary. Reprod Fertil Dev 13, 557566. Gastal EL, Gastal MO, Bergfelt DR, Ginther OJ, 1997: Role of diameter dierences among follicles in selection of a future dominant follicle in mares. Biol Reprod 57, 1320 1327. Gastal EL, Donadeu FX, Gastal MO, Ginther OJ, 1999: Echotextural changes in the follicular wall during follicle deviation in mares. Theriogenology 52, 803814. Gastal EL, Gastal MO, Beg MA, Ginther OJ, 2004: Interrelationships among follicles during the common-growth phase of a follicular wave and capacity of individual follicles for dominance in mares. Reproduction 128, 417422. Gastal EL, Gastal MO, Donadeu FX, Acosta TJ, Beg MA, Ginther OJ, 2007: Temporal relationships among LH, estradiol, and follicle vascularization preceding the rst compared with later ovulations during the year in mares. Anim Reprod Sci 102, 314321. Gerard N, Monget P, 1998: Intrafollicular insulin-like growth factor-binding protein levels in equine ovarian follicles during preovulatory maturation and regression. Biol Reprod 58, 15081514.
dominant follicles and the simultaneous regression of subordinate follicles during follicle deviation. Follicular waves occur throughout post-natal life in the horse until follicles irreversibly cease to grow at approximately 20 years of age. The levels of follicular activity are aected by factors such as stage of the oestrous cycle, season, pregnancy, age, breed and individual. This results in variations in follicular wave patterns that most notably include the production or absence of a dominant follicle (major or minor waves) and the development of ovulatory-competent or ovulatory-incompetent dominant follicles. Available information indicates that these physiological variations in follicular wave patterns are driven by changes in circulating levels of FSH and or LH and by local changes in responsiveness of follicles to gonadotropins. Yet, considerable work is needed to better understand the mechanisms by which follicle development is regulated during dierent physiological conditions outside the oestrous cycle in mares.
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Authors address (for correspondence): FX Donadeu, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. E-mail: xavier.donadeu@ed.ac.uk Conict of interest: All authors declare no conict of interests.