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Historical Perspective of Turnover of Dominant FolliclesDuring the Bovine Estrous Cycle: Key Concepts, Studies,Advancements, and Terms

J. J. Ireland,* M. Mihm,† E. Austin,‡ M. G. Diskin,§ and J. F. Roche‡*Molecular Reproductive Endocrinology Laboratory,

Department of Animal Science, Michigan State University†Department of Veterinary Preclinical Studies,

University of Glasgow Veterinary School, Glasgow, UK‡Faculty of Veterinary Medicine,

University College Dublin, Ballsbridge, Dublin 4, Ireland§Teagasc, Athenry, Co. Galway, Ireland

ABSTRACT

This review chronicles the key concepts, studies, ad-vancements and terms that have led to our currentunderstanding of turnover of dominant follicles (growthand atresia) during the bovine estrous cycle. The “two-wave” concept of follicular development was first pro-posed in 1960, but remained controversial for the next28 yr. The concept of the “dominant” follicle wasadapted to cattle in 1987. By 1988, ultrasound analysisof individual follicles had demonstrated that heifersusually had two or three distinct waves of turnover ofdominant follicles during an estrous cycle. From 1992to 1993, it was established that a transient rise in serumconcentrations of FSH initiated each follicular wave,and a decreased episodic secretion of LH was associatedwith loss of dominance and the end of a nonovulatoryfollicular wave. In the past decade, numerous intrafolli-cular growth factors, such as inhibins, activins, andinsulin-like growth factors and their binding proteins,have been identified in follicular fluid of individual bo-vine follicles. In addition, in vitro studies demonstratethat these growth factors could have endocrine, auto-crine, or paracrine actions that modify gonadotropin-stimulated follicular growth and differentiation. How-ever, the precise role of intrafollicular growth factorsin turnover of dominant follicles has not been defined.We concluded that two or three FSH-stimulated wavesof follicular growth usually occur during the bovineestrous cycle, and each follicular wave culminates indevelopment of a single nonovulatory or ovulatory dom-inant follicle.(Key words: dominant follicles, follicular waves, bo-vine estrous cycle, key concepts)

Abbreviation key: RIA = radioimmunoassay.

1Received November 12, 1999.Accepted March 10, 2000.Corresponding author: J. J. Ireland; e-mail: Ireland@pi-

lot.msu.edu.

2000 J Dairy Sci 83:1648–1658 1648

INTRODUCTION

Numerous procedures to artificially manipulate thelength of estrous cycles, time of ovulation, or numbersof follicles that grow and ovulate in cattle have beendeveloped (80). However, none have consistently im-proved fertility or removed the considerable variationin number of follicles or in oocyte quality after superovu-lation. Further progress in development of more reli-able procedures to control follicular development mayhave been hindered because the physiological conceptof a “dominant” follicle (one that prevents growth ofother follicles during the bovine estrous cycle) has onlyrelatively recently been recognized by animal scien-tists. Indeed, the idea that turnover (growth and atre-sia) of antral follicles during the bovine estrous cycleis a continuous process without distinct patterns per-sisted in the literature from 1927 to 1986 (8, 57, 90).However, the development and adaptation of ultraso-nography as a noninvasive means to monitor turnoverof follicles on consecutive days in the same animalfirmly establishes that ovarian antral follicles grow indistinct patterns or “waves” throughout most of theheifer’s life.

A large number of excellent recent reviews have ad-dressed the topic of regulation of turnover of dominantfollicles in cattle, including the interaction of gonadotro-pins with intrafollicular growth factors (5, 6, 19, 22,23, 25, 30, 41, 43, 50, 53, 61, 62, 78, 80, 90, 98, 99).Consequently, the purpose of the present review is todescribe, in chronological order, the key concepts, stud-ies, advancements, and terms that have led to our cur-rent understanding of turnover of dominant folliclesduring the bovine estrous cycle.

KEY CONCEPTS, STUDIES, ADVANCEMENTS,AND TERMS

1960: The two-wave concept for follicular growthduring the bovine estrous cycle is proposed. Animal

SYMPOSIUM: FOLLICULOGENESIS IN THE BOVINE OVARY 1649

reproductive scientists were aware before 1960 thatpreovulatory size follicles existed during the middle ofthe estrous cycle in cattle (9, 14, 38, 39, 57). In 1960,however, Rajakoski (76) reported results of a 3-yr studyof bovine ovaries obtained after slaughter of one to threesexually mature Swedish Red-and-White Breed heifers(usually 1) on each day of the estrous cycle. Follicles≥1 mm in diameter were counted, and histological anal-ysis of each sectioned ovary was performed. Based pri-marily on qualitative analysis, Rajakoski stated that“One interpretation for these results” is “that follicles≥5 mm show two growth waves during an oestrus cycle.The first of these occurs between the third and thefourth days and the other between the twelfth and four-teenth. Both result in a follicle of preovulatory size. Thelarge follicle of the first wave undergoes atresia fromthe twelfth day to leave the large atretic follicle whichis present in one of the ovaries from the twelfth to theseventeenth days. The large follicle of the second waveovulates after final maturation during oestrus” (76).Thus, Rajakoski was the first to propose the two-waveconcept of follicular turnover during the bovine estrouscycle. Nevertheless, over the next 28 yr, his study re-mained controversial because investigators reportedthat their results either supported (37, 44, 67, 93) orrefuted the two-wave hypothesis (8, 16, 17, 48, 54, 56,72, 90).

1972 and 1981: Lifespan and fate of individualfollicles during the estrous cycle of heifers is di-rectly examined. Dufour et al. (17) and Matton et al.(56) were the first to devise a method to follow changesin size of individual antral follicles on the surface ofbovine ovaries. In their studies, groups of heifers fromdifferent days of the estrous cycle underwent surgery.They injected dots of India ink at different locationsinto the stromal tissue surrounding the periphery ofeither the largest follicle per pair of ovaries (17) or thetwo largest follicles for each ovary (56). Three to fivedays after marking, each heifer was subjected to ovari-ectomy, and the size and fate of each marked folliclewas determined. Their results demonstrated that oneof the largest follicles on each ovary persists from d 3to 13 of the estrous cycle, then undergoes atresia (56).This finding directly supported the existence of the firstwave of Rajakoski’s two-wave hypothesis (76). How-ever, neither of the two largest follicles marked on eachovary between d 13 to 18 of the estrous cycle ovulated(56). Thus, this finding refuted Rajakoski’s two-wavehypothesis (76).

1982–1983: Growth and differentiation of estro-gen-active and -inactive follicles during the es-trous cycle is characterized. Before 1982, the healthstatus of an antral follicle (growing or atretic) in cattlewas determined by traditional histological methods (8,

Journal of Dairy Science Vol. 83, No. 7, 2000

18, 55, 72, 76). In vitro studies in sheep, however, dem-onstrated that healthy antral follicles produce moreestradiol than androgens compared with atretic follicles(7, 63). In contrast, atretic follicles produce more andro-gens than estradiol compared with healthy follicles (7,63). Ireland and Roche (47, 48, 49) were the first toclassify individual antral follicles (≥ 6 mm in diameter)in heifers as estrogen-active or estrogen-inactive basedon the intrafollicular ratio of concentrations of estradiolto progesterone or androgens in follicular fluid. Estro-gen-active follicles (estradiol > progesterone and andro-gens) have biochemical characteristics of healthy grow-ing follicles, but estrogen-inactive follicles (progester-one or androgens > estradiol) have characteristics ofatretic follicles or follicles destined to become atretic(47, 48, 49).

In a series of studies (47, 48, 49), ovaries were re-moved from groups of heifers at 2-d intervals during d3 to 13 of the estrous cycle, or at different times during aspontaneous or prostaglandin-induced follicular phase.Each follicle (≥6 mm in diameter) per pair of ovarieswas classified as estrogen-active or -inactive. Resultsof these studies established that growth of estrogen-active follicles is associated with an enhanced numberof granulosa cells and an increased intrafollicular con-centration of estradiol and number of binding sites forLH in granulosa and theca cells both during the follicu-lar phase, and during d 3 to 7 of the luteal phase of theestrous cycle (47, 48, 49). In contrast, the number ofbinding sites for FSH in granulosa cells decreases. Dur-ing the follicular phase, but after the preovulatory go-nadotropin surge, or during d 9 to 11 of the luteal phase,the largest follicle is estrogen-inactive. Compared withestrogen-active follicles, the estrogen-inactive follicleshave a reduced intrafollicular concentration of estradioland a diminished number of gonadotropin receptor sitesin granulosa and theca cells. These studies demonstratethat estrogen-active follicles switch from FSH- to LH-responsiveness as they develop, and that a decreasednumber of gonadotropin receptors in granulosal andthecal cells are associated with loss of capacity of estro-gen-active follicles to produce estradiol.

1984: Ultrasound was used to monitor sizes offollicles during the estrous cycle of heifers. Studieson the dynamics of follicular turnover during the es-trous cycle were hindered before 1984 primarily be-cause morphological observations were based on single,point-in-time analysis of ovaries obtained after slaugh-ter (8, 9, 14, 38, 39, 44, 55, 57, 72, 76) or ovariectomy(47, 48, 49) of cattle. In addition, heifers were subjectedto surgery at least twice when sequential developmentof follicles was examined (16, 17, 56, 86). In 1984, twolaboratories reported visualization of ovarian struc-tures in a cow (77) or heifers (65) with a linear-array

IRELAND ET AL.1650

ultrasound scanner. Pierson and Ginther (65), however,were the first to use ultrasonography to monitor diame-ter of follicles throughout the estrous cycle of heifers.The reported diameter of a follicle usually refers to thewidth of the nonechogenic antrum of a follicle, whichcontains follicular fluid (69, 74). Thus, diameters of folli-cles subjected to ultrasound are 2 to 3 mm smallerthan diameter of the same follicles after dissection (74).Pierson and Ginther (65) characterized follicle growthas follows: “1) growth of a large follicle to an ostensiblyovulatory size followed by regression at approximatelymid-cycle, 2) selective accelerated growth of the follicledestined to ovulate approximately 3 d before ovulation,and 3) regression a few days before ovulation of thelarger follicles that were not destined to ovulate”. Theseultrasound results (65), coupled with those of later stud-ies (66, 67, 68), clearly show a bimodal distribution innumbers and sizes of follicles during the estrous cycleof heifers. In a more extensive followup study in heifers,Pierson and Ginther (67) stated that their results “sup-port the postulate of two waves of follicular growthduring the estrous cycle”.

1987: The concept of a dominant follicle as ob-served in primates is applied to cattle, and thethree-wave hypothesis for development of domi-nant follicles during the estrous cycle is proposed.Hodgen et al. (34) proposed the concept of dominance in1977 to explain why follicle growth during the primatemenstrual cycle is attenuated in the presence of theovulatory follicle or corpus luteum. Because of markeddifferences in size between the largest and next largestfollicle, two groups postulated that the largest folliclein heifers is “dominating or dominant” (44, 56). How-ever, the morphological, histological, hormonal, andbiochemical evidence supporting the presence of domi-nant follicles during the bovine estrous cycle was notdescribed until 1987 (43, 50). In reviews (43, 50), it wasargued that a single estrogen-active follicle becomesthe largest follicle during three different periods of theestrous cycle. In addition, increased serum concentra-tions of estradiol in one of the two utero-ovarian veins isassociated with enhanced intrafollicular concentrationsof estradiol in the largest estrogen-active follicle duringthe same periods of the estrous cycle (24, 46, 47, 48,49). Based primarily on these results and coupled withthe earlier findings from the India-ink marking studiesof Dufour et al. (17) and Matton et al. (56), Ireland andRoche (50) concluded that “three cycles of developmentof dominant follicles occur during a bovine estrous cycle.Each cycle of development of a dominant follicle goesthrough a selection, dominance and atresia or ovulationphase similar to that described for dominant ovulatoryfollicles during a primate menstrual cycle”.


1988: Ultrasound analysis and ovarian mapsare used to track growth and atresia of individualfollicles throughout the estrous cycle of heifers. In1988, three different groups of investigators were thefirst to publish results of four similarly designed ultra-sonography studies. Each study used daily ultrasoundanalysis to monitor growth of individual folliclesthroughout the estrous cycle of heifers (26, 69, 81, 88).These studies were distinguished from the previous ul-trasound reports (65, 66, 67, 68) because location (rela-tive to the anterior and posterior poles, greater curva-ture and hilus of each ovary, and (or) corpus luteum)and diameter of each follicle ≥5mm on each ovary wereboth established during each ultrasound session. In ad-dition, the location and diameter for each follicle wassketched on a diagram or map for each ovary. Resultsof daily ultrasound analysis and mapping, therefore,established the patterns of growth and regression ofeach “mapped” follicle. Of 46 estrous cycles examinedfor 33 heifers in three separate studies (26, 81, 88), 1estrous cycle had one follicle wave, 8 cycles had twowaves, 35 cycles had three waves, and 2 cycles had fourwaves of follicular development. These findings showthat three waves of dominant follicles per estrous cycleis the most common pattern observed in heifers, whichconfirmed the three-wave hypothesis (43, 50). In con-trast, visual inspection of graphs of ultrasound resultsfor heifers in another study (69) showed predominantlytwo waves during an estrous cycle, which supported thetwo-wave hypothesis (76). Taken together, ultrasoundanalysis shows that cattle usually have two or threewaves of follicular development during their estrouscycle. Thus, both the two-wave (76) and three-wave (43,48, 50) hypotheses are correct.

The dynamics of follicular turnover, including maxi-mum diameter, rate of growth or atresia, day of appear-ance of follicles ≥5 mm in diameter, and persistence orduration of detection of follicles, were also first de-scribed for dominant and nondominant or secondaryfollicles in the aforementioned studies (26, 81, 88). Inbrief, the beginning of a wave (also called emergence)is defined as the first day of the estrous cycle a growingfollicle ≥5 mm in diameter in a new wave is detectedby ultrasound. With this definition, the average day ofthe estrous cycle (for heifers with three waves) eachwave begins is d 1.9 (range = 1 to 3), 9.4 (8 to 11), and16.1 (14 to 19) (26, 88). For the first, second, and thirdwaves, the maximum size of each dominant follicle is12.3 to 15.5, 10.2 to 15.9, and 12.8 to 18.8 mm. Maxi-mum size is reached on d 6 to 6.4, 14.2 to 16, and 21of the estrous cycle (26, 81, 88). Persistence or durationof detection of a dominant nonovulatory follicle, definedas the interval between its appearance and disappear-ance, is 11.4 to 17 versus 7.4 to 13.1 d for the first and


second wave (26, 81, 88). In contrast, the dominantovulatory follicle of the third wave persists about 6 dbefore ovulation (26, 81, 88). The number of nondomi-nant follicles ≥5 mm for each wave averages 5.3, 3.9,and 4.7, and these follicles persist for about 6 d. Themaximum diameter of nondominant follicles is usually≤8 mm (26). For heifers that had two waves per estrouscycle, the first and second (ovulatory) waves commenceon d 2 to 4 and 10 to 11, and reach maximum diametersof about 13 mm on d 6 and 19, respectively (81, 88).The ovulatory follicle is detected 10 d before ovulation(88). It is not known why there is great variabilityamong heifers (with three follicle waves) in emergenceof each wave during an estrous cycle, maximum size ofthe dominant follicle during each wave, and persistenceof a dominant follicle.

The following list defines the terms currently used todescribe the physiological phenomenon and dynamicsassociated with turnover of dominant follicles in cattle(Figure 1).

Cohort: A group of nearly synchronously growingfollicles ([33]; Figure 1).

Recruitment: The process whereby a cohort of pri-mordial follicles (primordial follicle = oocyte surroundedby a single layer of squamous pregranulosal cells) be-gins growth or enters into a trajectory of growth (87),and, thereafter, becomes dependent on gonadotropinsfor its continued development to ovulatory size ([33],not depicted in Figure 1). After hypophysectomy of labo-ratory species or sheep, recruitment of primordial folli-cles and limited growth of a reduced number of prean-tral follicles occurs (35). This finding implies that go-nadotropins are not required for recruitment or earlyfollicle growth. However, gonadotropin treatment of hy-pophysectomized animals markedly enhances both re-cruitment and subsequent growth of preantral follicles(35). Thus, gonadotropins are very likely to have animportant role both in the recruitment process and rateof follicle growth. Nevertheless, the factor(s) that initi-ates recruitment has not been defined.

Wave: The cyclic pattern of growth of antral follicles.A follicular wave in heifers is usually characterized bygrowth of a cohort of ∼24 antral follicles ∼3 mm indiameter, and atresia of all but a single dominant folli-cle that continues to grow until it reaches ovulatorysize (30). A wave ends in either ovulation or atresia ofthe dominant follicle.

Selection: The process that results in the reductionof the number of follicles in a growing cohort to thespecies-specific ovulatory quota (33). Selection is com-plete when the number of healthy follicles in a growingcohort equals the number of follicles that ovulated ((33),Figure 1). As originally defined by Hodgen (42), selec-tion begins coincident with recruitment of a cohort of


Figure 1. A model explaining the physiological terms associatedwith each wave of follicular development during the estrous cycle ofheifers. Based on ultrasound analysis, most heifers have one (Firstwave) or two waves (First wave, Second wave) of follicular develop-ment during the luteal phase and a single wave of development (Ovu-latory wave) during the follicular phase. Cohort refers to a groupof similar sized nearly synchronously growing follicles. Emergencemarks the beginning of a wave and is the first day a 4- or 5-mmfollicle is the largest in a new wave. The beginning of selection cannotbe determined by ultrasonography. However, the end of selectionoccurs coincident with onset of dominance. Deviation is when growthrates between the dominant and largest subordinate follicle begin todiffer. Dominance occurs when the largest follicle in a wave is 1 to 2mm larger than the next largest follicle and growth of all subordinatefollicles ceases. Subordinate follicles are all nondominant follicles ina wave. Loss of dominance marks the end of a wave and is detectedat emergence of the next wave. The growing phase for a follicle beginson the day of the estrous cycle of its emergence and ends the daydiameter of the follicle ceases to increase. The static phase is fromthe day follicle diameter ceases to increase (end of growing phase)until the day follicle diameter decreases minus one day. The re-gressing phase is the last day of the static phase until the follicle isno longer detectable, which is usually when it reaches 4 to 5 mmin diameter.

primordial follicles. Thus, ultrasound has insufficientresolution to identify the beginning of a selection phase.However, the end of the selection phase for a wave,which can be detected by ultrasound, occurs coincidentwith the onset of dominance (defined below). Unravel-ing the selection process, or more specifically, why one(the “selected”) follicle of a cohort develops to ovulatorysize as the others undergo atresia is an area of intenseresearch, rich in both elegant models and intriguinghypotheses (5, 6, 19, 22, 23, 25, 30, 33, 35, 36, 41, 43,50, 61, 62, 78, 80, 83, 99).

Emergence: The first day during growth of a cohortof follicles in a wave that the largest follicle detectedby ultrasound is 4 (27) or 5 mm in diameter ((26), Figure1). Thus, emergence, as detected by ultrasound, marksthe beginning of a wave. Whether to use 4 or 5 mm asa criterion for emergence depends both on the skill ofthe ultrasound user and the resolution of the scanner.

IRELAND ET AL.1652

Because of variability in time of emergence for the dif-ferent waves during an estrous cycle, as mentioned ear-lier, day of emergence is a useful marker for aligningwaves among groups of cattle. The interval from emer-gence of one wave to emergence of the next wave estab-lishs the length of a wave (Figure 1, vertical arrows).Note, however, that ultrasound cannot be used to estab-lish when recruitment begins, as mentioned above.Thus, the precise length of time required for a primor-dial follicle after its recruitment to become dominantin a wave cannot be established with ultrasound.

Dominance: The process whereby a follicle preventsgrowth of other follicles, or grows in a hormonal milieuunfit for growth of other follicles (42). Based on thisdefinition, onset of dominance is best defined by ultra-sound as the first day of the estrous cycle that: 1) thedominant follicle in a wave is at least 1 to 2 mm largerthan the next largest follicle, and 2) growth of all subor-dinate follicles in the same wave ceases ([59], Figure1, solid lines at top). It may be possible, based on retro-spective ultrasound or biochemical analyses, to identifythe follicle that is destined to become dominant, but thispredestined dominant follicle should not be considereddominant until growth of all subordinates in the waveceases. Loss or end of dominance (Figure 1, top, arrows)by the dominant follicle of a wave is defined morphologi-cally by ultrasound as occurring on the day of emer-gence of the subsequent wave.

Subordinate follicles: The remaining follicles (usu-ally 2 to 5) in a wave after identification of the dominantfollicle by ultrasound (28) (Figure 1).

Dynamics of follicular growth: Based on ultra-sound determination of diameter, each dominant orsubordinate follicle progresses through a growing,static, and regressing period (depicted for dominantfollicle in Figure 1, [27]). Some of these periods extendinto other waves, especially the regressing phase (Fig-ure 1). Consequently, precise ovarian maps are criticalto track turnover of individual follicles and to assignfollicles to the appropriate wave. The growing phasefor a follicle begins on the day of the estrous cycle ofits emergence and ends the day the diameter of thefollicle ceases to increase. The static phase is from theday follicle diameter ceases to increase (end of growingphase) until the day follicle diameter decreases minus1 d. The regressing phase is the last day of the staticphase until the follicle is no longer detectable, whichis usually when it reaches 4 to 5 mm in diameter (27).

Deviation: The divergence of growth rates betweenthe two largest follicles (Figure 1, thick arrows) withina wave, which is retrospectively determined by ultra-sound (30). Deviation, however, should not be confusedwith selection because selection refers to the phenome-non associated with reduction in number of the origi-


nally recruited follicles in a wave to the ovulatory quota(33). However, deviation may mark the end of the selec-tion process, especially because the follicle with thegreatest growth rate usually emerges first in a waveand becomes dominant (30). In addition, deviation maybe caused by one follicle beginning to exert “dominance”over another. However, whether deviation representsthe earliest functional marker for onset of dominanceremains to be determined.

1992: A transient peak in basal serum concen-trations of FSH preceded each follicular wave andwas required for initiation of a wave and onsetof dominance. The first radioimmunoassay (RIA) todetermine serum concentrations of FSH in cattle wasdeveloped and validated by Akbar et al. in 1974 (4).They demonstrated that serum concentrations of FSHpeaked coincident with the preovulatory LH surge inheifers. A secondary surge of FSH in heifers was firstreported in 1977 by Dobson (15) following RIA of serumsamples collected at 2-h intervals for 3 d during theperiovulatory period. Her results clearly demonstratedthat two transient rises in serum concentrations of FSHoccurred in cattle. One significant transient rise of FSHis coincident with the preovulatory LH surge, and theother commences 12 to 24 h after the peak of the gonado-tropin surge, as serum concentrations of LH remainrelatively low and static. Later studies in cattle usingdifferent RIA formats for FSH were confirmatory (73,79, 94, 96).

Shams et al. (86) reported an association of patternsof secretion of FSH with follicular growth in 1977. Intheir study, FSH RIA of serum samples collected at 2-to 6-h intervals was combined with endoscopic exami-nation of ovaries through a permanent fistula at 2-dintervals. They reported that significant FSH peaksoccurred on d 4, 8, 12 to 13, 17, and 18 of the estrouscycle, and during the preovulatory LH surge. In addi-tion, they argued that enhanced follicular growth wasassociated with each FSH peak, although no statisticalanalysis of their follicular data was reported.

As more investigators became familiar with use ofultrasound, and as FSH assays improved, severalgroups associated the dynamics of turnover of dominantfollicles (Figure 1) with changes in patterns of secretionof the gonadotropins and ovarian steroids. Specifically,it was initially demonstrated that the postovulatoryrise of FSH preceded the first follicular wave in heifers(94). But, the first report of a significant association ofpeaks of FSH with follicle waves throughout an estrouscycle was in 1992 by Adams et al. (3). They showed thatheifers with two follicular waves also had a significant50 to 75% increase in serum concentrations of FSHassociated with the emergence of each wave. Once con-centrations of FSH among heifers are aligned relative


Figure 2. A model depicting the relationship of transient peaksof FSH with each wave of follicular development during the estrouscycle of cattle.

to wave emergence for each heifer, peaks of FSH wereobserved on d 1 (day of ovulation) and 10 of the estrouscycle. Each peak of FSH occurred about 1 d before emer-gence for both the first and ovulatory wave. Althoughnot statistically significant, Adams et al. (3) also re-ported that heifers with three waves had peaks of FSHon d 1, 9, and 15, approximately 1 d before emergencefor each of the three different waves. In subsequentstudies by another laboratory, a combination of dailyultrasound and a blood-sampling regimen of 4- to 6-hintervals were used to evaluate the association of serumFSH (11) with follicular waves during the estrous cycle(10, 92). Results of these studies confirmed the results ofAdams et al. (3) by showing that a significant transienttwofold increase in FSH preceded the first and secondwave of follicular development during the luteal phaseof the estrous cycle.

Despite use of validated RIA for FSH, the majorityof laboratories could not reliably distinguish repeatablepatterns of FSH during the luteal phase or during preg-nancy or postpartum. The best explanation for whysignificant peaks of FSH are not routinely detected ismost likely because emergence, which is associatedwith peaks of FSH, is variable among heifers (30). Ul-trasound, however, makes it possible to align serumconcentrations of FSH relative to wave emergence.Thus, a convincing association of a transient rise inFSH with initiation of each follicle wave has been estab-lished not only during the estrous cycle ([3, 92], Figure2), but also in prepubertal heifers (1, 20) and duringpregnancy (29) and postpartum anestrous (12).

Several laboratories examined the role of FSH in reg-ulation of follicular waves in cattle. In 1979, Miller etal. (60) demonstrated that injections of bovine follicularfluid, a rich source of inhibins (32), during the follicularphase delayed onset of estrus in heifers. Several yearslater other laboratories reported that injections of bo-vine follicular fluid delayed follicle emergence (51), or


suppressed secretion of FSH without altering secretionof LH in both ovariectomized (45) and intact (73) heif-ers. Turzillo et al. (94), however, were the first to reportin 1990 that the administration of follicular fluid toheifers both suppressed the postovulatory rise in FSHand delayed follicular wave emergence. Results of sev-eral subsequent studies were confirmatory (3, 95). Morerecent studies showed that immunization of heifersagainst GnRH or infusion of GnRH agonist suppressedboth rises of FSH and pulses of LH, and blocked emer-gence of follicular waves (31, 70, 71). Taken together,these results convincingly demonstrate that a transientrise in FSH is required to stimulate growth of a waveof follicles during the bovine estrous cycle.

Although the ascending arm of a transient rise inFSH initiated follicular waves, recent studies show thatthe subsequent decline in FSH ends selection and stim-ulates development of the dominant follicle during awave. Specifically, in 1993 Adams et al. (2) demon-strated that treatment of heifers with FSH at the timeof the spontaneous decline of FSH from its peak delaysonset of dominance during the first follicular wave. Thisfinding was confirmed several years later by anotherlaboratory (59). Together, these results imply that thedescending arm of the postovulatory surges of FSH hasan important role in termination of the selection processand stimulation of the onset of dominance (Figure 1).

1993: A decreased episodic pattern of secretionof LH is associated with termination of a follicu-lar wave. Radioimmunoassays to determine serumconcentrations of LH were first developed and validatedin 1969 by two laboratories (64, 85). Identification ofthe preovulatory surge of LH coincident with estrus incattle was initially reported by Shams and Karg (85)in 1969 and Henricks et al. in 1970 (40). However,more than a decade elapsed before Rahe et al. clearlydemonstrated (75) that secretion of LH during the es-trous cycle of cattle is in episodic patterns. Specifically,heifers were bled via jugular cannulas for 24 h at 10-min intervals on d 3, 10 or 11, and 18 or 19 of an estrouscycle. Results of that study revealed that patterns ofLH secretion change from a high frequency of low ampli-tude pulses during the early luteal phase to a low fre-quency of high amplitude pulses by midcycle. By estrus,the pattern of episodic LH secretion switches to a highfrequency (similar to the early luteal phase) of veryhigh amplitude pulses. Several years later, studies fromother laboratories (84, 97) confirmed the luteal phaseresults of Rahe et al. (75). Results of these earlier stud-ies (75, 84, 97) were then extended by Cupp et al. (13)because they demonstrated that frequency and ampli-tude of LH pulses are significantly altered on severaldifferent days during the luteal phase of the estrouscycle, when progesterone concentrations are high. How-

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ever, none of the aforementioned studies examined therelationship of the changing pulse pattern of LH secre-tion to the dynamics of turnover of dominant folliclesduring the estrous cycle.

Evans et al. (21) were the first to correlate alterationsin the dynamics of LH pulses with ultrasound analysisof follicular waves during the estrous cycle of heifers.They demonstrated that frequency of LH pulses de-creases, but amplitude increases during growth of thefirst-wave dominant follicle. In contrast, during lossof dominance of the first-wave dominant follicle andemergence of follicle growth in the second wave, fre-quency of LH pulses remains unchanged, but amplitudedecreases to levels similar to d 3 to 4 of the estrouscycle. Although Cupp et al. (13) did not correlate thealterations in LH pulse frequency and amplitude tofollicular waves, their results were similar to those re-ported by Evans et al. (21). Taken together, these re-sults imply that the pulse pattern of LH secretion variedduring a follicular wave during the estrous cycle.

Whether alterations in the episodic secretion patternof LH secretion during the estrous cycle have a role inthe regulation of dominant follicle turnover was investi-gated by several laboratories. In 1990, Sirois and For-tune (89) reported that insertion of a progesterone re-leasing device intravaginally at midcycle into heifersmarkedly enhances lifespan, dominance, and estradiolproduction by dominant follicles after spontaneous lu-teolysis. In contrast, insertion of two progesterone-re-leasing devices to mimic luteal phase progesterone lev-els results in a normal lifespan and turnover of a domi-nant follicle. Two key studies published in 1993 byStock et al. (91) and Savio et al. (82), however, demon-strated the important role changes in the dynamics ofLH pulses may have on the lifespan of a dominantfollicle, as shown in Figure 3. Specifically, endogenousprogesterone production decreases in cattle followingtreatment with prostaglandin F2α or spontaneous lutealregression. Progesterone releasing intravaginal devices(Figure 3) or norgestomet implants are then insertedto artificially manipulate concentrations of serum pro-gesterone. Ultrasonography is performed daily or everysecond day of the cycle to monitor development of domi-nant follicles. Frequent blood-sampling regimens areused throughout the treatment period to characterizethe pulse patterns of LH secretion and daily changes inserum concentrations of progesterone. Results of thesestudies showed that low serum concentrations of pro-gesterone are associated with a higher pulse frequencyof LH (Figure 3, dotted line, left panel), and with ex-tended or persistent growth and function of a dominantfollicle, as previously shown (89). In contrast, relativelyhigh concentrations of progesterone result in a reducedfrequency of LH pulses and loss of dominance of the


Figure 3. A model showing the effects of alterations in numberof LH pulses on the development of dominant follicles during theestrous cycle of heifers. The corpus luteum (CL) spontaneously re-gresses or is induced to regress with prostaglandin F2α. Progesteronereleasing intravaginal devices (PRID) are then inserted into a heiferto release either low (first arrow) or higher (2nd arrow in second panel)amounts of progesterone into the blood stream. In turn, number ofLH pulses (dotted lines) and lifespan of the dominant follicle areeither enhanced (first panel) or decreased (second panel), respectively.

dominant follicle (Figure 3, right panel). Both investiga-tors interpreted their results to mean that a high fre-quency of LH pulses is necessary to maintain domi-nance, whereas a reduced frequency of LH pulses trig-gers loss of dominance (Figure 4).

Figure 4. A model showing the interrelationships between thepatterns of secretion of FSH and LH; recruitment, selection, domi-nance, and loss of dominance; and the switch from FSH to LH respon-siveness of the dominant follicle during the first wave of folliculardevelopment for an estrous cycle. Understanding the mechanismsthat regulate each phase of development of dominant follicles andelucidating the relationship of those phases to oocyte growth andmaturation may be necessary before new more improved methods toregulate ovulation are developed in cattle.


Whether the alterations in patterns of episodic secre-tion of LH during an estrous cycle (13, 21, 75, 84, 97)regulate turnover of dominant follicles remains to bedetermined. Nevertheless, in support of an importantrole for alterations in episodic patterns of LH secretionin turnover of dominant follicles, it has been well estab-lished that dominant follicles switch from FSH to LHdependency as they develop (47, 48, 49, 100) (Figure4). Thus, a decrease in LH pulse frequency, such asthat observed during the later stages of a follicle waveduring an estrous cycle, is not only associated with,but also may cause loss of dominance of the dominantfollicle in each follicle wave (Figure 4).

The important role of the fluctuating patterns of se-cretion of both FSH and LH during a follicle wave wasrecently demonstrated by Gong et al. (31). They usedmini-pumps to infuse a relatively low followed by ahigher dose of a GnRH agonist in heifers. This treat-ment regimen results initially in preovulatory LH andFSH surges. These gonadotropin surges are followedby a persistent reduction in serum LH, but normal tran-sient surges of FSH associated with follicular waves.During this period, the dominant follicle of the firstwave grows to ovulatory size, then regresses. However,the size of the subsequent dominant follicle in the nextwave is reduced to 7 to 9 mm in diameter and persistsfor several weeks. Infusion of a higher dose of agonistdecreased serum FSH, which results in regression ofthe dominant follicle and abatement of subsequent folli-cle growth at the 4 mm size. Taken together, theseresults show the important roles that postovulatorysurges of FSH and LH have in initiation of follicularwaves, growth of the dominant follicle in each wave toovulatory size, and perhaps termination of a wave dur-ing an estrous cycle.

1990-present: Intrafollicular factors have poten-tial autocrine or paracrine roles important fordominant follicle turnover. Evidence has accumu-lated, primarily from in vitro studies over the past de-cade, that intrafollicular factors, especially growth fac-tors such as inhibin, activin, IGF-I and -II, and theirbinding proteins, have an important role in regulationof follicular growth, differentiation, and function (5, 6,19, 22, 23, 25, 30, 41, 43, 50, 52, 53, 61, 62, 78, 80,90, 98, 99). For example, inhibin and follistatin havenegative feedback effects, whereas activin has a posi-tive feedback effect on FSH secretion in many speciesincluding cattle (52, 80). In addition to these endocrineroles, inhibin, activin, IGF, follistatin, and IGF bindingproteins have autocrine or paracrine actions that stimu-late or inhibit function of granulosal and thecal cells(52, 80, 99). Moreover, the action of one factor antago-nizes the other, especially inhibin versus activin, ac-tivin versus follistatin, and IGF versus IGF binding


proteins. Because the aforementioned growth factorsand binding proteins are in follicular fluid of bovinefollicles (52, 80, 99), alterations in intrafollicular ratiosof the various growth factors and their binding proteinsmay, therefore, have an important role in establishingwhich follicle in a wave becomes dominant. For exam-ple, dominant follicles have lower intrafollicular levelsof small molecular weight IGF binding proteins com-pared with subordinate follicles (80). The reduced levelof IGF binding proteins may result in a greater avail-ability of IGF-I, which would enhance gonadotropin ac-tion on granulosal and thecal cells within the dominantcompared with subordinate follicles. Consequently, dif-ferences in intrafollicular ratios of IGF-I:IGF bindingproteins could explain why a dominant follicle outgrowsand produces more estradiol than subordinate follicles.In support of this idea, we have recently demonstratedin heifers that intrafollicular levels of IGF-binding pro-tein-4 are lower and estradiol concentrations are higherin the first-wave follicle destined to become dominantcompared with follicles destined to become subordinate(58). In general, intrafollicular factors are hypothesizedto act not only in an endocrine fashion to regulate secre-tion of gonadotropins, but also in an autocrine or para-crine fashion to modify gonadotropin action, and in turnfollicular growth, differentiation, and function. Al-though this hypothesis has merit, it has been difficultto test in vivo. Thus, the precise mechanisms explaininghow gonadotropins interact with intrafollicular growthfactors to regulate turnover of a single dominant follicleduring a follicle wave remain unclear.

SUMMARY, CONCLUSIONS,AND FUTURE QUESTIONS

In summary: 1) Antral follicles develop in distinctpatterns or waves of 7 to 10 d in length. 2) Two or threewaves of follicular growth usually occur during a 21-destrous cycle. 3) During each wave, a dominant follicledevelops to ovulatory size and usually undergoes atre-sia unless it ovulates. 4) During growth of a cohort ofantral follicles in a wave, they undergo recruitment,selection, dominance, and loss of dominance or ovula-tion. During recruitment, a cohort of primordial folliclesbegins to grow and all “recruited” follicles thereafterbecome dependent on FSH for their continued growthto ovulatory size. Selection reduces the number of “re-cruited” follicles in a cohort to the ovulatory quota.Dominance enables a single follicle to prevent growthof other follicles or grow in a hormonal milieu unfit forgrowth of other follicles. Loss of dominance results inatresia of the dominant follicle, thus initiating growthof a new follicular wave. 5) Based on ultrasound analy-sis, emergence is the first day a 4- or 5-mm follicle is

IRELAND ET AL.1656

the largest in a new wave. Thus, emergence marks thebeginning of a wave. Deviation occurs when growthrates between the dominant and largest subordinatefollicle begin to differ. The end of selection occurs coinci-dent with onset of dominance. Dominance occurs whenthe largest follicle is 1 to 2 mm larger in diameter thanthe next largest follicle and growth of all subordinatefollicles ceased. Loss of dominance marks the end of awave and occurs at emergence of the next wave. 6)The ascending arm of the transient rise in serum FSHinitiates a follicle wave, whereas the descending armends selection and initiates onset of dominance. 7) Dur-ing an estrous cycle, a decreased amplitude of LH pulsesis associated with loss of dominance of the dominantfollicle in a wave. Based on these results, we concludethat: two or three FSH-stimulated waves of folliculargrowth usually occur during the bovine estrous cycle,and each follicular wave culminates in development ofa single nonovulatory or ovulatory dominant follicle.

Past studies have firmly established that two or threewaves of follicular development occur during the bovineestrous cycles. However, as outlined in Figure 4, thefollowing fundamental questions remain unanswered:How do gonadotropins and intrafollicular factors inter-act to regulate recruitment, selection, deviation, domi-nance and loss of dominance during a follicular wave?What causes the great variability among heifers inemergence of each wave, maximum size of the dominantfollicle in each wave, and persistence of each wave dur-ing an estrous cycle? Do the dynamics (number of folli-cles, sizes, growth rate) for individual waves influencequality of oocytes? Do factors such as nutrition, aging,parity, or milk yield alter number of follicular wavesper estrous cycle? Does number of follicular waves perestrous cycle influence fertility? We speculate that thedevelopment of new, more efficient methods to regulategrowth of follicles with high quality oocytes to improvefertility in cattle may depend on resolution of the afore-mentioned questions.

ACKNOWLEDGMENTS

Research supported by grants to JJI from USDA (90-27240-5508) and Research Excellence Funds, and JFRfrom the Department of Agriculture and Food Stimu-lus Funds.

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historical perspective of turnover of dominant follicles ... · lot.msu.edu. 2000 j dairy sci...

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