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Selection of the dominant follicle in cattle and
horses
O.J. Ginther
)Animal Health and Biomedical Sciences, 1656 Linden DriÕe, UniÕersity of Wisconsin-Madison, Madison,
WI 53706, USA
Abstract
The nature of selection of the dominant follicle is reviewed by comparing research results between cattle and horses. In both species, emergence of a follicular wave is stimulated by an FSH surge. The surge reaches a peak by the time the follicles attain 4 mm in diameter in cattle and 13 mm in mares. In cattle, all of the growing follicles G5 mm contribute to the decline in FSH concentrations. However, the declining FSH concentrations are still needed by the growing follicles. Several days after the peak of the FSH surge and emergence of the wave, the two largest follicles reach means of 8.5 and 7.7 mm in cattle and 22 and 19 mm in horses. At this approximate time, the follicles begin to undergo deviation in follicle diameters, which is characterized by continued growth of the largest follicle to become the dominant follicle and reduced or terminated growth of the remaining follicles to become subordinate follicles. In both species, on average, the future dominant follicle emerges before the future largest subordinate follicle, and the two follicles grow in parallel until deviation. The difference in diameter between the two largest follicles at the beginning of deviation is equivalent in growth to approximately 8 h in cattle and 24 h in mares. Apparently, this is adequate time for the largest follicle to establish the deviation process before the second-largest follicle reaches a similar diameter. During this time, the largest follicle plays the primary role in further suppressing circulating FSH concentrations to below the requirements of the smaller follicles, which causes their regression. The follicle-pro-duced FSH suppressants appear to be estradiol and inhibin. In addition to enhancing its FSH-suppressing ability, the largest follicle also develops the ability to utilize the reduced concentrations of FSH for its continued growth. It is therefore postulated that the essence of selection of a dominant follicle in these two species is a close two-way functional coupling between changing FSH concentrations and follicle growth and development. Elevated concentra-tions of circulating LH encompass deviation in both species and may play a role in continued growth of the largest follicle. It is not known if LH begins to be utilized by the largest follicle
)Tel.:q1-608-262-1037; fax:q1-608-262-7420.
Ž .
E-mail address: ojg@ahabs.wisc.edu O.J. Ginther .
0378-4320r00r$ - see front matterq2000 Elsevier Science B.V. All rights reserved.
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before, at, or after the beginning of diameter deviation. However, results of studies in mares suggested that LH does not influence growth of the dominant follicle until after the beginning of deviation.q2000 Elsevier Science B.V. All rights reserved.
Keywords: Cattle; Dominant follicle; Horses; Follicle selection; Follicular waves; Subordinate follicles
1. Introduction
Follicle selection is the mechanism whereby only one of the many available follicles becomes the ovulatory follicle in monovular species and has been a long-time mystery in reproductive biology. Primarily because of the transrectal ultrasound technique, changes in follicle populations have been well characterized in the large farm species, and progress is being made toward resolution of the follicle-selection mystery. The ultrasound technique is being used for characterizing follicle-population changes, track-ing individual follicles from examination to examination, monitortrack-ing the effects of treatment, and eliminating, treating, or sampling specific follicles at specific times during a follicular wave. Among farm species, cattle and horses have the most effective selection mechanism as indicated by a greater frequency of single ovulations than for swine, sheep, and goats. The purpose of this report is to examine the current scientific status of the follicle-selection phenomenon by comparing research results between cattle and horses. Most of the review considers the morphologic extrafollicular aspects of
Ž
selection changes in follicle diameters and circulating gonadotropin and estradiol
.
concentrations ; less is known about the intrafollicular biochemical aspects.
2. Follicular waves
Cattle and horses have similar follicle-selection characteristics. The two species make good comparative research models because of suitability for different experimental approaches, utilizing, for example, a consistent early diestrous follicular wave in cattle and two- to threefold larger follicles in mares.
2.1. Cattle
Based on histologic study, two waves of antral follicular development were proposed initially for the bovine estrous cycle, and each wave resulted in a follicle of preovulatory
Ž .
diameter Rajakoski, 1960 . Subsequently, results of various experimental approaches
Ž
were interpreted to agree or disagree with the two-wave proposal for reviews see
.
Matton et al., 1981; Fortune et al., 1991; Ginther et al., 1996b . Transrectal ultrasonic imaging for the study of bovine ovarian follicles was introduced in Pierson and Ginther
Ž1984 . Using this technology, it was reported that, on average, two waves of follicular. Ž
growth for various diameter categories occurred during the estrous cycle Pierson and
.
several days before the largest follicle reached maximum diameter. Functional selection against nonovulatory follicles approximately 5 days before ovulation was confirmed by
Ž
a reduced response to a superovulatory gonadotropin regimen Pierson and Ginther,
. Ž
1988a . Ultrasonic tracking of individual follicles from day-to-day Fortune et al., 1988; Pierson and Ginther, 1988b; Savio et al., 1988; Sirois and Fortune, 1988; Knopf et al.,
.
1989 confirmed these interpretations and provided additional and more detailed charac-terization. In various herds, a predominance of either two-wave or three-wave estrous cycles was found, accounting for earlier reports of two versus three waves. Each wave is characterized by emergence of a group of follicles at 4 mm, growth of all follicles for a few days, and then dissociation into a large follicle that continues to grow and smaller follicles that regress. The anovulatory wave which begins as 4-mm follicles during the periovulatory period will be featured in this report because it has the most consistent characteristics and has been most extensively studied. In the earlier studies, the follicles
Ž . Ž .
were defined as largest F1 and second largest F2 , followed by the terminology
Ž . Ž
dominant Goodman and Hodgen, 1983 , dominant and nondominant Ireland and
. Ž
Roche, 1987; Sirois and Fortune, 1988 , or dominant and secondary Ireland and Roche,
.
1987; Savio et al., 1988 . Thereafter, the terms dominant and subordinate follicles have been used most frequently.
2.2. Mares
Ž
The types of follicular waves that develop in mares are major waves characterized
. Ž
by dominant and subordinate follicles and minor waves largest follicle does not attain
.
the diameter of a dominant follicle . Based on transrectal palpation, a single major
Ž .
follicular wave was proposed initially for the equine estrous cycle Ginther, 1979 . The wave of follicles dissociated about 6 days before ovulation into a single growing preovulatory follicle and several regressing follicles. The palpation work was subse-quently substantiated by ultrasound, based on grouping of follicles into diameter
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categories Palmer, 1987; Pierson and Ginther, 1987a and tracking of individual
Ž .
follicles Sirois et al., 1989; Ginther, 1990 . There are profound breed differences in
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wave patterns during the estrous cycle for review see Ginther, 1992 . In some breeds
Žquarter horses, ponies , usually only one major wave develops in late diestrus and.
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culminates in the estrous ovulation. In other breeds thoroughbreds , a secondary major wave frequently develops in early diestrus, and the dominant follicle may be anovula-tory, as in cattle, or ovulatory. The secondary-wave phenomenon accounts for the earlier
Ž .
intriguing discovery Hughes et al., 1972 of diestrous ovulations. Minor follicular
Ž
waves have been demonstrated statistically in mares Ginther, 1993; Ginther and
.
Bergfelt, 1992 . The selection phenomenon of the major ovulatory wave that begins at midcycle for all breeds will be used for this report and will be compared to the selection aspects of the anovulatory wave that begins near ovulation in cattle.
3. Stimulation of waves by FSH surges
Ž . Ž
major waves occurs in calves Evans et al., 1994 , during much of pregnancy Ginther et
. Ž .
al., 1996a , and during prolonged progesterone administration Bergfelt et al., 1991a . Also, in mares, the major and minor waves develop during various status levels
ŽBergfelt and Ginther, 1992; Ginther, 1993; Ginther and Bergfelt, 1992 . The occurrence.
of follicular waves during many diversified hormonal environments attests to the robustness of the follicle-selection phenomenon and is a consideration in the develop-ment of hypotheses on controlling mechanisms.
Emergence of follicular waves refers to the earliest ultrasonic detection of follicles compatible with retrospective tracking. Emergence of each wave is temporally
associ-Ž
ated with an FSH surge for the major waves in cattle Adams et al., 1992; Sunderland et
. Ž
al., 1994; Gong et al., 1995; Evans et al., 1997 and horses Palmer, 1987; Ginther and
.
Bergfelt, 1992; Bergfelt and Ginther, 1993; Fig. 1 and for the minor waves in horses
ŽGinther, 1993; Ginther and Bergfelt, 1992 . The FSH surge reaches a peak or plateau. Ž
when the largest follicle reaches about 4–5 mm in cattle Bodensteiner et al., 1996a;
. Ž .
Kulick et al., 1999 and about 13 mm in mares Gastal et al., 1997 . The concentrations then decline. In cattle, 3-mm follicles did not suppress FSH, but acquired this capability
Ž .
during their growth to 5 mm Gibbons et al., 1999 . More than one of the growing follicles contributes to the FSH decline as indicated by the rate of decline when all
Ž
follicles, all but one follicle, all but two follicles, or no follicles were ablated Gibbons
.
et al., 1997 ; FSH declined more slowly when fewer follicles were retained.
Circulating FSH continues to be needed by the growing follicles in heifers, even when the FSH concentrations are decreasing during the declining portion of the FSH
Ž .
surge Ginther et al., 2000 . A minimal dose of estradiol was used to decrease FSH concentrations without an associated change in LH concentrations. Estradiol treatment
Ž .
Fig. 1. Mean "SEM day-to-day diameter of follicles and circulating concentrations of FSH in 14 mares.
Ž .
Normalizing the data to the day of deviation b produced a sharper dissociation between follicles than when
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data were normalized to the day of emergence of the future dominant follicle a . A star indicates the first
Ž . Ž .
when the largest follicle reached G6.0 mm resulted in depression of both FSH concentrations and diameter of the largest follicle within 8 h. The smaller follicles were also inhibited. Thus, there is a close two-way functional coupling between FSH and the follicles during the declining portion of the FSH surge. The growing follicles cause the FSH decline and, even though decreasing in concentrations, the FSH remains essential for the growing follicles.
4. Follicle selection and deviation
Selection is a general term used for monovular species to indicate that usually only one follicle of a follicular wave reaches dominant status, especially as indicated by ovulation. More broadly, the term could be used for multiovular species when the number of follicles of a wave exceeds the number of ovulations. This does not imply that the mechanism of selection is similar in both monovular and multiovular species. However, the occasional occurrence of multiovulations in monovular species and the frequent occurrence in other species could be useful for studying the nature of selection
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of one follicle Wiltbank et al., 2000 . There is no consensus on use of the term selection for a specific point during follicle growth, and the term is confusing when used to
Ž
discuss time of occurrence. In the earlier ultrasound studies in cattle Ginther et al.,
. Ž .
1989 and mares Bergfelt and Ginther, 1993 , means for the future dominant and largest subordinate follicles gradually diverged in diameter beginning on the day of follicle emergence. This gave the impression that the dissociation into dominant and subordinate follicles was a gradual event beginning at emergence. Later inspection of individual follicle-diameter profiles indicated that dissociation was often an abrupt event and was
Ž . Ž .
termed deviation in cattle Ginther et al., 1996a, 1997a and mares Gastal et al., 1997 . The gradual mean divergence was attributable to the occurrence of deviation at different
Ž .
times among waves Fig. 1 .
Deviation is characterized by continued growth of the largest follicle to become the dominant follicle and a reduction or cessation of growth by the remaining follicles to become subordinate follicles. Diameter deviation is retrospectively judged to have begun at the ultrasound examination preceding the first examination with an apparent change in diameter difference between the two largest follicles. For some waves, the time of deviation may not be obvious, especially because the subordinate follicles may continue to grow for )1 day, but at a reduced rate. Averaged over several reports, the mean diameters of the two largest follicles in cattle at the beginning of deviation were 8.5 and 7.7 mm with deviation beginning a mean of 2.5 days after emergence of the largest
Ž .
follicle at 4 mm Ginther et al., 1997a, 1998, 1999; Kulick et al., 1999 . The corresponding values in mares were 22 and 19 mm and 6.2 days after emergence of a
Ž .
6-mm follicle Gastal et al., 1997, 1999a,c,d .
The future dominant follicle emerges earlier, on average, than the other follicles of
Ž
the wave. In cattle, the future dominant follicle emerged at 3 mm a mean of 6 h Ginther
. Ž .
et al., 1997a or at 4 mm a mean of 7 h Kulick et al., 1999 earlier than the future
Ž
largest subordinate follicle. The follicles grow in parallel, on average Ginther et al.,
.
0.5-mm-diame-Ž .
ter advantage until deviation Kulick et al., 1999 . Similarly in mares, on average, the future dominant follicle reached 6 mm before the future largest subordinate follicle and
Ž
maintained a mean diameter advantage of 3 mm until the beginning of deviation Gastal
.
et al., 1997 .
Although none of several experiments have statistically detected a mean difference in diameter growth rates between the two largest follicles from emergence to deviation, considerable variation occurs among individual waves, presumably reflecting biologic variation as well as measuring error. Error can be considerable, especially when distortion of the ultrasound image of the follicle occurs because the face of the transducer is not optimally oriented relative to the surface of the follicle or the walls of
Ž .
the follicle are obscured by artifacts Ginther, 1995 . In heifers, the future dominant
Ž
follicle was the largest follicle 2 days after wave emergence at 4 mm Bodensteiner et
. Ž .
al., 1996a or 4–5 mm Evans and Fortune, 1997 in 82% and 79% of follicular waves, respectively. Examples of the occasional occurrence of the largest follicle reaching a diameter equivalent to the expected diameter at deviation and then ceasing to grow have
Ž . Ž .
been published for cattle Ginther et al., 1996b and mares Gastal et al., 1997 . Because of the diameter advantage of the largest follicle, it could be concluded that selection occurs or begins before ultrasonic detection of emerging follicles. With this reasoning, however, the beginning of selection would not be definable, since other factors may determine which of the underlying follicles becomes sensitive to an FSH surge; the largest follicle in a range of responsive diameters may be designated by chance. A further consideration against use of the term selection before deviation is that the future nondominant follicles retain their capacity to become dominant until after deviation; that is, they have not been selected against. In cattle, many of the growing follicles are capable of becoming dominant; a randomly selected 5-mm follicle can be
Ž
directed toward dominance by destroying other 5-mm follicles as they appear Gibbons
. Ž . Ž .
et al., 1997 . In both heifers Ginther et al., 1999 and mares Gastal et al., 1999c , the second-largest follicle becomes dominant when the largest follicle is ablated at the expected beginning of deviation. Furthermore, initiation of FSH treatment early in a
Ž
wave resulted in a delay in the apparent equivalent of deviation in cattle Adams et al.,
.
1993; Mihm et al., 1997 and development of dominance by several follicles in horses
ŽSquires et al., 1986; Rosas et al., 1998 , demonstrating the pre-deviation capabilities of.
follicles. It appears that the terms deviation and selection can be used synonymously, but to minimize confusion, deviation will be used in the remainder of this report to assure focusing on the relatively narrow time span where the future dominant follicle and future largest subordinate follicle begin to differ in growth rates in individual follicular waves.
5. Control of deviation
When two spherical follicles of different diameters increase in diameter at the same rate, the rate of change in surface area over the same time span is greater for the larger
Ž .
increasing advantage over the next-largest follicle, even though the difference in diameter between the two follicles is constant. It is not known if the increasing advantage in surface area for the largest follicle plays a role in deviation. Surface area changes seem more representative of functional changes, because function involves the cells that line the follicle. Nevertheless, this review will use diameters because of tradition.
Concentrations of FSH decline for a few days after the peak of the FSH surge in
Ž . Ž .
cattle Adams et al., 1992 and mares Bergfelt and Ginther, 1992 . The decline, therefore, encompasses deviation. More specifically, low FSH concentrations are
tempo-Ž
rally associated with deviation in cattle Ginther et al., 1997a, 1998, 1999; Kulick et al.,
. Ž .
1999 and mares Gastal et al., 1997 . The concentrations continue to decline for several
Ž .
days after deviation in mares Fig. 1 , whereas the decline ends within hours after
Ž . Ž .
expected deviation in cattle Fig. 2 . In a recent study in cattle Ginther et al., 1999 , attainment of a diameter of G8.5 mm by the largest follicle was used as a reference for
Ž .
the expected beginning of deviation Hour 0 ; FSH concentrations were determined for Hours y16, y8, and 0, every hour between Hours 0 and 16, and then every 8 h. Concentrations decreased between Hoursy16 and 0, continued to decrease until Hour
Ž .
10, and then increased after Hour 16 Fig. 2 . The results indicated a close association between the attainment of a mean diameter of G8.5 mm and a continued decrease in FSH concentrations for a short time thereafter. As noted earlier, a role for the low concentrations of FSH in the deviation mechanism in both species is consistent with the findings of a delay or prevention of deviation following administration of FSH.
Ž . Ž .
We postulated in cattle Ginther et al., 1996b; 1997a and mares Gastal et al., 1997 that the events underlying the beginning of diameter deviation are abrupt. Even when the intervals between scanning in cattle was 8 h, the beginning of deviation was readily
Ž
assigned to a specific examination in six of eight profiles of follicular waves Kulick et
Ž . Ž . Ž .
Fig. 2. Mean "SEM circulating concentrations of FSH at 8-h a and 1-h b intervals normalized to the
Ž .
expected time of deviation largest follicle atG8.5 mm; Hour 0 . In the ablation group, theG8.5-mm follicle
Ž .
was ablated. The stars indicate changes P-0.05 between hours for the indicated groups, and the pound
Ž .
marks indicate a difference P-0.05 between groups within hours. The data indicate that FSH concentra-tions continued to decrease for 8 h after expected deviation and that FSH concentraconcentra-tions increased between 5
Ž .
.
al., 1999 . Apparently, when the largest follicle reaches a decisive developmental stage, rapid activation of the deviation mechanism blocks the second largest follicle before it reaches a similar decisive diameter. Thus, the difference in diameter between the two largest follicles indicates that the smaller follicle must be inhibited in -8 h in cattle
Žequivalent to a diameter difference of 0.5 mm and in. -1 day in mares equivalent to aŽ .
difference of 3 mm . Diameter deviation is likely preceded by biochemical or functional deviation. In this regard, echotextural changes were detected in the wall of the largest
Ž
follicle on the day before the beginning of diameter deviation in mares Gastal et al.,
.
1999b . Thus, diameter deviation was preceded by echotextural or structural deviation. The depression of FSH concentrations could be the pivotal event in deviation if the FSH is depressed below the quantities required by the smaller follicles, but not the largest follicle, and the changes in FSH concentrations and follicle development are closely coupled. This last stipulation is to satisfy the postulate that deviation must occur rapidly before the next largest follicle reaches a diameter similar to the diameter of the largest follicle at the beginning of deviation. The closeness of coupling between the two events was investigated in heifers by ablating the largest follicle when it reached G8.5
Ž .
mm expected beginning of deviation and, in another experiment, administering a
Ž .
known FSH depressant Ginther et al., 1999 . Ablation of the largest follicle when it
Ž .
reached G8.5 mm Hour 0 resulted in increased circulating FSH concentrations
Ž .
between Hours 5 and 8 Fig. 2 . Growth rate of the retained second-largest follicle between Hours 0 and 8 was greater in the ablation group than in the controls. A single
Ž
injection of a minimal dose of an FSH depressant 4.4 ml of a near steroid-free follicular
.
fluid at the expected time of deviation resulted in decreased FSH concentrations by Hour 6. Reduced growth rate of the largest follicle occurred within 6 h after the suppression in FSH concentrations. These studies demonstrated that a close temporal coupling between a change in FSH concentrations and the follicle response could establish the deviation mechanism in -8 h before the second-largest follicle reaches a similar critical diameter. In conclusion, the largest follicle affected FSH concentrations and FSH affected the follicles within the time represented by the difference in diameters between the two largest follicles at deviation.
Following administration of a near steroid-free fraction of follicular fluid, the FSH concentrations and diameters of the largest follicle were lower than the corresponding
Ž .
values in controls at the expected time of deviation Ginther et al., 1999 . These results indicated that the largest follicle in controls required the basal FSH concentrations. The requirement for the basal FSH concentrations for continued growth of the largest follicle has also been demonstrated by administration of a single minimal dose of estradiol
ŽGinther et al., 2000; Fig. 3 . Although regression of the smaller follicles at the time of.
deviation can be attributed to inadequate FSH, these results indicate that the low concentrations of FSH are required for continued growth of the largest follicle. Thus, deviation involves a change in the largest follicle so that it is sensitive to a concentration of FSH that is inadequate for the smaller follicles.
Ž .
Ablation or retention Hour 0 of the largest follicle was done at G7.5 mm vs.G8.5
Ž .
Ž . Ž . Ž .
Fig. 3. Mean "SEM circulating concentrations of FSH a and diameters of the largest follicle b when
Ž
estradiol injections were given when the largest follicle reachedG8.5 mm expected time of deviation; Hour
.
0 . There was a significant interaction between estradiol-treated and control groups for both end points. The data indicate that the low concentrations of FSH after deviation were required for continued growth of the
Ž .
dominant follicle. Adapted from Ginther et al. 2000 .
hypothesis that by the time the largest follicle reaches the expected beginning of deviation it has developed a greater capacity for suppressing FSH. In a similar ablation
Ž .
study in mares, a two-follicle model was used Gastal et al., 1997 . When the larger
Ž .
follicle reached G20 mm actual diameter, 21.2 mm; expected day of deviation; Day 0 follicle ablation was done so that both follicles, only the larger follicle, or only the smaller follicle was retained. The decline in FSH concentrations of the wave-stimulating FSH surge continued for several days after Day 0 in the groups with both follicles or
Ž .
only the larger follicle retained Fig. 4 . In the group with only the smaller follicle retained, the FSH concentrations and diameter of the smaller follicle increased between Days 0 and 1. The continued decrease in FSH at the expected beginning of deviation
Ž . Ž . Ž .
Fig. 4. Mean "SEM circulating concentrations of FSH a and estradiol b in mares in which two follicles
Ž
were studied; the remaining follicles were ablated. When the larger follicle reachedG20 mm expected day of
.
deviation , one of the follicles was ablated, resulting in groups with retention of the smaller, larger, or both follicles. In both groups with the larger follicle present, FSH continued to decrease and estradiol increased.
Ž .
was attributable to the larger follicle; there was no indication that the smaller follicle was involved. Thus, the continued FSH suppression at the expected beginning of deviation was a function of the larger follicle. These findings support the hypothesis, in mares as in heifers, that when the largest follicle reaches a critical diameter the FSH depression continues and thereby the next largest follicle is depressed before it reaches a similar critical diameter. Thus, two abilities develop in the future dominant follicle by
Ž .
the beginning of diameter deviation: 1 ability to suppress circulating FSH to below the
Ž .
concentrations required by other follicles and 2 ability to utilize the low FSH concentrations in its further growth and development.
Fig. 5. Schematic model of the proposed functional coupling between circulating FSH concentrations and diameters of the two largest follicles during development of a follicular wave. The following numbered
Ž .
statements refer to the circled numbers in the figure. 1 Emergence of a follicular wave is stimulated by an FSH surge that reaches its peak approximately when the largest follicle of the wave is 4.0 mm. The declining
Ž . Ž .
FSH concentrations continue to exert a required positive effect on the follicles solid arrows . 2 By the time the follicles reach 5.0 mm, they develop an FSH-suppressing ability. All of the growing folliclesG5.0 mm
Ž . Ž .
contribute to a decline in the FSH surge for approximately the next 2 days broken arrows . 3 By the time the largest follicle reaches a diameter of 8.5 mm, it plays a major role in the continued FSH decline. Follicle deviation begins when the FSH concentrations are suppressed and temporarily maintained below the
Ž .
concentrations required by the smaller follicles. Hence, the smaller follicles become subordinate follicles. 4 The suppressed FSH concentrations are adequate and required for at least the initial continued growth of the
Ž . Ž .
largest follicle dominant follicle after the beginning of deviation. 5 At an unknown point relative to deviation, LH begins to play a role in the continued growth of the dominant follicle. From Ginther et al.
It has been proposed that regression of the smaller follicles involves a direct effect of
Ž
follicle inhibitors secreted by the larger follicle for review see Armstrong and Webb,
. Ž .
1997 , but the evidence for such an effect is not convincing Fortune, 1994 . There have been no reports that suggest that such inhibitors can be produced specifically by the largest follicle at the beginning of deviation and enter the vascular system to affect other follicles. Taken together, the ablation studies in cattle and horses indicate that inhibition of the smaller follicles during follicle deviation is attributable to continued suppression of FSH concentrations below the concentrations required by the smaller follicles, but not the largest follicle. It does not seem necessary to invoke a follicle-to-follicle inhibitory mechanism, unless indicated by further studies. It is postulated, instead, that the essence of the selection of a dominant follicle is a close two-way functional coupling between
Ž .
changing FSH concentrations and follicular growth and development Fig. 5 .
6. Follicular systemic inhibitors of FSH
The identities of the substances produced by follicles and causing the FSH decline after the peak of the surge and at the beginning of follicle deviation are not known. Estradiol, as well as androgens, are secreted by the developing follicles and are
Ž .
candidates for an inhibitory effect on FSH secretion Evans et al., 1997 . However, it is not known if estradiol enters the circulation in concentrations adequate for a negative feedback effect on FSH, especially during the initial portion of the FSH decline. In cattle, estradiol concentrations increase in the follicular fluid of the largest follicle and in
Ž
the systemic circulation at about the time deviation would be expected to occur Kaneko
.
et al., 1991; Mihm et al., 1997; Evans et al., 1997 . The increase in plasma estradiol
Ž
occurred from a single ovary and encompassed 3 to 7 days after the LH surge Ireland et
. Ž .
al., 1984 or occurred from the ovary with the dominant follicle Evans et al., 1997 . In a study in which follicles were sampled in vivo before, during, and after deviation, the mean increase in estradiol in the largest follicle relative to the second-largest follicle
Ž .
began on the same day as follicle deviation Fig. 6; Ginther et al., 1997b .
Ž .
In mares, a similar study was done, using a two-follicle model Gastal et al., 1999d . Fluid from each follicle was sampled on the day the larger follicle reached 15, 20, or 25 mm. An increased difference between the two follicles in estradiol concentrations
Ž .
occurred when the larger follicle was 20 mm expected beginning of deviation; Fig. 7 . In contrast, an increased difference in diameter between follicles did not occur until the largest follicle was 25 mm. Thus, the beginning of a difference in estradiol concentra-tions preceded the beginning of diameter deviation. In another study using the two-fol-licle model, ablation of one or none of the foltwo-fol-licles was done on the day of the expected
Ž .
beginning of deviation Day 0; Gastal et al., 1999c . Systemic estradiol increased between Days 0 and 2 in the groups with both follicles or only the larger follicle
Ž .
Ž . Ž .
Fig. 6. Mean "SEM diameters of the two largest follicles a and estradiol concentrations in follicular fluid
Ž .b before and after the beginning of deviation. Black bars b are for the largest follicle, and white bars are forŽ .
the second-largest follicle. The number of waves with sampled follicles is shown in parentheses for each day.
Ž .
Means for the two largest follicles for each end point were significantly different P-0.05 only on the day
Ž .
after the beginning of deviation as indicated by different letters. Adapted from Ginther et al. 1997b .
A negative feedback effect of inhibin or other proteinaceous products of the follicles
Ž .
also may regulate the declining portion of the FSH surge Mihm et al., 1997 , including the low levels during deviation. Inhibin has been measured in growing and atretic
Ž . Ž . Ž .
Fig. 7. Mean "SEM diameters of follicles a and estradiol concentrations in follicular fluid b for larger
Žblack bars and smaller white bars follicles in mares with two retained follicles. The follicles were. Ž .
monitored by ultrasound and were sampled when the larger follicle first reached the indicated diameters. The
Ž .
number in parentheses is the number of mares in each diameter group. The letters XYZ indicate that the
Ž .
difference in diameters between the two follicles was greater P-0.05 for the 25-mm group than for the other two groups, but the differences between follicles for estradiol concentrations progressively increased over groups. An increased difference in diameter between follicles did not occur until the larger follicle was 25 mm, whereas an increased difference in estradiol concentrations occurred when the larger follicle was 20 mm
Ž
follicles of different diameters in cattle at different reproductive stages Martin et al.,
.
1991; Ireland et al., 1994; Sunderland et al., 1996; Mihm et al., 1997 . The results are complex, resulting from the subunit make-up and the wide array of forms with different molecular weights and the manner in which the subunits converge to form structurally similar, but functionally different, compounds. Administration of an inhibin antiserum
Ž .
increases plasma FSH Glencross et al., 1994 and increases the number of )8 mm or
G10 mm follicles during a follicular wave and the number of ovulations in cattle
ŽKaneko et al., 1993; Glencross et al., 1994; Hillard et al., 1995 and the number of.
Ž .
ovulations in mares McKinnon et al., 1992; McCue et al., 1993; Nambo et al., 1998 . These results with anti-inhibin may reflect an interference with follicle deviation, indicating that inhibin is needed for the deviation process; however, this has not been studied directly. Immunoreactive inhibin concentrations increase in the circulation at the
Ž
time FSH concentrations decline in mares Bergfelt et al., 1991b; Nagamine et al.,
.
1998 . This occurs at the reported time of development of the ovulatory follicular wave. These results with inhibin assays and inhibin antisera suggest that inhibin or other proteinaceous follicular factors may be involved in the deviation mechanism through depression of circulating FSH.
It has been proposed that the decline in FSH plays a role in stimulating the follicle to
Ž .
synthesize inhibin, as well as estradiol and growth factors Mihm et al., 1997 . It appears that the declining concentrations of FSH and the developmental stage reached by the largest follicle interact to initiate deviation before other follicles reach the critical diameter. The initiation involves a further release of FSH suppressants, which further depresses FSH below the requirements of the smaller follicles. As noted earlier, a treatment at the time of expected deviation with a minimal dose of either estradiol or a near estrogen-free fraction of follicular fluid reduced the FSH concentrations to a level below the concentrations found in controls. These findings and the temporal relation-ships, discussed above indicate that both estradiol and inhibin are candidates for the role of FSH suppressants during diameter deviation.
7. Role of LH
Several studies have suggested that LH is utilized as a gonadotropin stimulant by the
Ž
selected dominant follicle for reviews see Goodman and Hodgen, 1983; Gong et al.,
.
1996; Ginther et al., 1996b . In cattle, a change in emphasis to LH dependency so that continued development of the dominant follicle is driven at least partly by LH is
Ž .
consistent with the following results: 1 Follicles did not grow beyond 7–9 mm when
Ž . Ž .
LH was suppressed Gong et al., 1995, 1996 . 2 The growth phase of the dominant follicle was associated with higher-frequency LH pulses than for the plateau phase
ŽRhodes et al., 1995 . 3 The life span of the dominant follicle can be extended by. Ž .
Ž . Ž .
increasing the LH-pulse frequency Fortune et al., 1991; Savio et al., 1993 . 4 The largest follicle acquires LH receptors or gene expression for LH receptors between 2 and
Ž
4 days after wave emergence Xu et al., 1995; Bodensteiner et al., 1996b; Evans and
. Ž .
Ž . Ž .
of the largest follicle was less than in controls Grimard et al., 1995 . 6 After the 90th day of pregnancy, there was both a transitional decrease in diameter of the largest
Ž .
follicle of successive waves Ginther et al., 1996a and a decrease in LH-pulse
Ž .
frequency Schallenberger et al., 1985 , indicating the two events are temporally related.
Ž .7 LH concentrations increased to a plateau before deviation, remained elevated noŽ
. Ž
significant changes until after deviation, and then decreased Ginther et al., 1998, 1999;
.
Kulick et al., 1999 , indicating that elevated LH as well as reduced FSH concentrations encompass the time of deviation. However, whether the dominant follicle utilizes LH in cattle in association with diameter deviation is not known.
In mares, LH receptors were higher in the theca when the mean diameter of the
Ž .
largest follicle was 29 mm Fay and Douglas, 1987 ; this would presumably be after deviation. Recently, values for LH receptors,a-inhibin, and aromatase were reported to
Ž
be lower in the granulosa of follicles 5–9 mm than in larger follicles Goudet et al.,
.
1999 , but this would be well before deviation. The status of LH receptors and other factors in follicles before, during, and after deviation needs study in mares. An increase
Ž .
in circulating LH concentrations occurs before deviation Gastal et al., 1997, 1999c . In some mares, the increase continued as part of the prolonged ovulatory LH surge in this species, but in others, a plateau encompassed deviation or a transient decrease occurred between deviation and ovulation. Thus, in mares, as well as cattle, elevated circulating
Ž .
LH is available during deviation. In recent studies in ponies Gastal et al., 1999a,e , LH concentrations were manipulated by daily treatment with various doses of progesterone beginning before the emergence of the follicular wave. A dose that did not alter FSH concentrations did affect LH. After an LH increase in both treated and control mares, a decrease occurred in the treated group 1 or 2 days before deviation in the controls; the reduced levels were similar to pretreatment levels. The decrease in the progesterone group was associated to reduced diameter of the largest follicle within 2 days after deviation in the controls. However, the reduced LH did not affect the second-largest follicle. Thus, the onset of deviation, as assessed by the second-largest follicle, was not delayed by the reduced LH, but the post-deviation growth of the largest follicle was reduced. Although not conclusive, these results indicate that LH was not involved in the
Ž .
initiation of follicle deviation inhibition of the other follicles through FSH depression in mares, but was required for continued growth of the largest follicle after the beginning of deviation.
8. Intrafollicular facilitators of gonadotropins
The intrafollicular facilitating substances that favor a lower requirement for FSH and a hypothesized change in gonadotropin dependency from FSH to LH by the largest
Ž .
There is considerable evidence implicating a number of growth factors in local
Ž
regulation of follicular development in cattle Findlay, 1994; Campbell et al., 1995; Erickson and Danforth, 1995; Stewart et al., 1996; Khamsi and Armstrong, 1997; Mihm
.
et al., 1997; Monniaux et al., 1997 and have also been associated with an increase in
Ž .
intrafollicular estradiol in mares Gerard and Monget, 1998 . Reportedly, the intrafollic-
´
ular growth factors have many paracrinerautocrine roles, including enhancing FSH action, inducing expression of LH receptors, and regulating aromatase activity. The
Ž .
insulin-like growth factor IGF-1 system has received particular attention, especially in
Ž
its influence on facilitating the utilization of low circulating levels of FSH Mihm et al.,
.
1997 . Activity of IGF-1 increases rapidly in the dominant follicle because of the disappearance of binding proteins, whereas the binding proteins remain active in the subordinate follicles. In this regard, administration of growth hormone in cattle resulted
Ž .
in an increased number of gonadotropin-responsive follicles Campbell et al., 1995 , perhaps by increasing liver production and circulatory concentrations of IGF-1. The conclusion that the IGF system acts as a facilitator within the dominant follicle and thereby plays a role in deviation will remain tentative until the temporal and functional relationships between the IGF system and follicle-diameter deviation and growth of the dominant follicle after deviation are verified. The role of other intrafollicular factors in deviation or in subsequent growth of the dominant follicle also have not been clarified.
Ž .
These other factors include aromatase inhibitors Goudet et al., 1999 , follicle regulatory
Ž . Ž .
protein diZerega et al., 1987 and androgens Evans et al., 1997 .
Acknowledgements
Original research supported by grants from the United States Department of Agricul-ture, by the University of Wisconsin-Madison, and by Equiservices Publishing, Cross Plains, Wisconsin. Research from this laboratory is based on reported studies senior-authored by O.J. Ginther or one of the following Research Assistants and Associates: G.P. Adams, D.R. Bergfelt, K.J. Bodensteiner, E.L. Gastal, J.R. Gibbons, L. Knopf, K. Kot, L.J. Kulick, and R.A. Pierson.
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