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 follicles 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 .
retained Fig. 4 . No such increase occurred when only the smaller follicle was retained. In conclusion, in mares, estradiol production increases in the largest follicle and
estrogen-like echotextural changes occur in the follicular wall on the day before the beginning of diameter deviation. In cattle, follicle deviation and increased estradiol
production seem to occur simultaneously.
Ž .
Ž . Fig. 6. Mean SEM diameters of the two largest follicles a and estradiol concentrations in follicular fluid
Ž . Ž .
b before and after the beginning of deviation. Black bars b are for the largest follicle, and white bars are for 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 Ž
. Ž
. black bars and smaller white bars follicles in mares with two retained follicles. The follicles were
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 .
Ž .
expected beginning of deviation . Adapted from Gastal et al. 1999d .
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 G 10 mm follicles during a follicular wave and the number of ovulations in cattle
Ž .
Kaneko 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
