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Reproductive Sciences Program, Departments of Biology and Physiology, University of Michigan, Ann Arbor, Michigan 48109-0404
Address all correspondence and requests for reprints to: F. J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404.
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Abstract |
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Introduction |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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In the ewe, thyroid hormones are necessary for the seasonal inhibition of pulsatile GnRH secretion that causes the transition from breeding season to anestrus (12). Although the ewe exhibits a seasonal cycle of circulating thyroid hormones (13), with concentrations rising from a nadir in summer to a maximum in winter when anestrus develops, this increase does not actively drive the transition to anestrus (14). Rather, thyroid hormones need only be present for anestrus to develop at the usual time (14).
We have shown previously that, in the ewe, the interaction between the thyroid and reproductive neuroendocrine axes changes dynamically throughout the year. Thyroid hormones, for example, affect only those neuroendocrine processes that lead to seasonal reproductive suppression in midwinter; they are not required for maintenance of anestrus nor for ewes to enter the breeding season at the usual time early in autumn (15). Further, by replacing T4 in ewes that were thyroidectomized (THX) soon after the onset of reproductive activity, we obtained evidence that thyroid hormones are required only during the final 2 months of the breeding season for anestrus to develop at the appropriate time (16). This suggested that the crucial time for thyroid hormone action is limited to the latter stages of the breeding season. American tree sparrows, like ewes, only require thyroid hormone during a limited period for the breeding season to end, although the time of the interaction in this avian species is restricted to the early rather than late breeding season (8).
Collectively, these studies led to formulation of the hypothesis that thyroid hormones are required for seasonal reproductive processes only during a limited interval, which in the ewe occurs very late in the breeding season (16). Further, because an endogenous rhythm drives seasonal changes in reproductive neuroendocrine activity in the ewe (17), this period of time might constitute the only stage of the rhythmic process that is responsive to thyroid hormones. This possibility arises because T4 is present at all times of the year in quantities sufficient for development of anestrus (14). Moreover, rhythmic processes, such as seasonal reproduction, can be differentially responsive to regulatory factors depending on stage of the endogenous rhythm (18, 19, 20).
The present study addresses four questions related to timing of the interaction between thyroid hormones and the neuroendocrine processes that govern seasonal reproduction in the ewe: 1) Is there a limited interval very late in the breeding season when thyroid hormones act on the reproductive neuroendocrine axis to promote development of anestrus? 2) How long is this interval? 3) Is this period the only time of year that thyroid hormones are required to maintain seasonal changes in reproductive neuroendocrine activity? 4) Is there a seasonal change in responsiveness of the reproductive neuroendocrine axis to thyroid hormones?
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Methods and Materials |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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In all but one experiment, T4 replacement consisted of a
daily sc injection of 2.5 µg/kg L-thyroxine in 0.6
M sodium bicarbonate-buffered saline at a concentration of
300 µg/ml. This treatment restored serum T4 to a
euthyroid concentration (
70 ng/ml) observed in winter (13, 14, 16).
In the remaining experiment, T4 was delivered by sc osmotic
minipumps (Alza Corp., Palo Alto, CA; 2ML4 pump delivering 2.5 µl/h).
Information provided by the manufacturer indicated the pumps deliver at
a constant rate for 28 days. In a preliminary study, we established the
concentration of T4 loaded into the pumps that restored the
euthyroid serum concentration of T4 (70 ng/ml) in THX
ewes (3 mg/ml dissolved in a mixture of 1 M NaOH and 95%
ethanol in a ratio of 2:3). This pilot study also indicated that the
pumps maintained serum T4 at or above 30 ng/ml, an amount
sufficient for anestrus to develop (14) for the full 28 days.
(Sequential concentrations after 7, 14, 21, and 28 days averaged
70 ± 8, 69 ± 2, 57 ± 2 and 30 ± 3 ng/ml,
respectively; n = 3 ewes.) In all experiments, the effectiveness
of treatments in restoring the euthyroid serum T4
concentration was tested by measuring total serum T4 in
blood sampled either once (injection replacement) or twice (pump
replacement) a week.
Monitoring seasonal changes in reproductive neuroendocrine
activity
The breeding season in our flock typically begins in September
and ends in February (first to last ovulation) (17, 21). All ewes were
ovariectomized (OVX) in August (late anestrous season) of the year in
which they entered the study. Following ovariectomy, each ewe was
treated sc with a 3-cm SILASTIC brand silicon tubing (Dow Corning,
Midland, MI) capsule packed with crystalline estradiol as described
elsewhere (22). These implants maintain a fixed serum estradiol
concentration of approximately 2 pg/ml, similar to that during the
luteal phase of the estrous cycle (23). In this animal model, serum LH
concentrations provide a robust index of seasonal changes in
reproductive neuroendocrine activity. LH is high during the breeding
season and then decreases more than 20-fold to undetectable levels as
animals undergo the transition to anestrus (15, 17, 24). Blood was
collected twice a week by jugular venipuncture to determine serum
concentrations of LH, total T4, and in some cases, TSH.
Serum was decanted after centrifugation and stored at -20 C.
Hormone assays
LH was measured in duplicate 10- to 200-µl aliquots of serum
by a modification (25) of a previously reported RIA (26, 27).
Concentrations are expressed in terms of NIH-LH-S12. Mean sensitivity
for 200 µl, 95% confidence interval of the buffer control, averaged
0.78 ng/ml (16 assays). Mean intraassay coefficient of variations (CV)
for serum pools displacing radiolabeled LH to approximately 20% and
50% of total bound were 9.9 and 12.6%, respectively. Interassay CVs
for the same serum pools were 16.0 and 12.0%, respectively.
To determine whether thyroidectomy was complete and to monitor T4 replacement, serum concentrations of total T4 were determined in single 25-µl aliquots of serum by use of the Coat-A-Count Total T4 assay kit (Diagnostic Products Corp., Los Angeles, CA), previously validated in our laboratory for use in the sheep by Webster et al. (13). Sensitivity for 25 µl, determined as for the LH assay, averaged 1.95 ng/ml (7 assays). Mean intraassay CVs for serum pools displacing radiolabeled T4 to 20% and 50% of the total bound were 5.2 and 9.7%, respectively. Interassay CVs for the same serum pools were 9.1 and 16.5%, respectively.
TSH was measured in duplicate 100-µl aliquots of serum with a double antibody heterologous RIA previously validated in our laboratory by Dahl et al. (28), using an antiserum to ovine TSH generously provided by Dr. A.F. Parlow at the NIDDK. Mean assay sensitivity was 0.90 ng/ml (2 assays). Mean intraassay CV for a serum pool displacing radiolabeled TSH to approximately 50% of total bound was 6.8%. Interassay CV for the same serum pool averaged 1.2%.
Data analysis
Transition into the neuroendocrine anestrous season was taken as
the date of the first sample that LH fell below 1 ng/ml for three
consecutive samples (10 days). These dates were subjected to ANOVA
followed by mean comparisons among groups using the Bonferroni
t test (29). Significance was set at P 
0.05.
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Results |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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The first approach included three groups of ewes: 1) thyroid-intact controls (n = 7); 2) ewes THX well before the putative period of thyroid hormone action (18–20 October 1994, n = 6); 3) ewes THX just before the expected start of this period (December 15; n = 7). LH was monitored from August 1994 to May 1995.
LH increased in all groups in September (Fig. 1
). In
thyroid-intact controls, values returned to baseline on January 30
± 4 days, marking the onset of neuroendocrine anestrus. As seen
previously (13, 16), thyroidectomy in October blocked this fall in LH
in all ewes. Thyroidectomy in mid-December also blocked the fall in LH,
and values remained elevated in six of seven ewes through May (LH fell
below 1 ng/ml in the remaining ewe on March 16). These findings
indicate the action of thyroid hormones after mid-December is essential
for the development of anestrus.
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illustrates the design used for the second
approach in which we replaced T4 only during the postulated
period of thyroid hormone action. We selected a 90-day T4
replacement beginning in late December for two reasons: T4
replacement begun at this time caused the transition to anestrus in THX
ewes (16); thyroidectomy 90 days later (in early anestrus) did not
prevent maintenance of anestrus for its full duration (15). Three
groups of ewes were THX on October 18–20, 1994, blocked by weight, and
treated as follows: 1) T4 replacement by daily sc injection
from thyroidectomy until the end of the study in May (n = 8); 2)
no T4 replacement (n = 6); or 3) T4
replacement for 90 days beginning December 28 (n = 7). Seven
thyroid-intact ewes provided a time reference for the natural
transition to the neuroendocrine anestrous season. These thyroid-intact
ewes, as well as the nonreplaced THX ewes, were common to both
approaches.
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; to
simplify graphic presentation, values are omitted for thyroid-intact
ewes; data appear in Fig. 1
). As observed previously (13, 16),
thyroidectomy in October blocked the fall in LH, and T4
replacement from the time of surgery reversed this effect. LH fell to
baseline on February 15 ± 5 days. This fall occurred
approximately 2 weeks later (P < 0.05) than in
thyroid-intact ewes (January 30 ± 4 days). LH also fell in all
THX ewes that received T4 for 90 days beginning December
28. The mean date that LH reached baseline (March 13 ± 5 days)
was 1 month later than in ewes treated with T4 from the
time of thyroidectomy (P < 0.05). Of interest, LH was
fully suppressed after 75 days of treatment in five of seven ewes.
Further, after T4 treatment ended in March, LH remained low
through the end of the study in May. These results, in conjunction with
those of the first approach, support the existence of a limited
interval during which thyroid hormones must be present to promote the
transition to anestrus.
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Ewes were THX October 18–20, 1993, blocked by weight, and allocated to four groups (n = 5/group): 1) controls receiving no further treatment; 2) 1 month of T4 beginning December 28; 3) 1 month of T4 beginning January 28; or 4) 2 months of T4 beginning December 28. A group of five thyroid-intact ewes was included as a time reference for the seasonal LH decline in euthyroid controls. The mode of T4 replacement was changed in this experiment from daily sc injections to 28-day osmotic minipumps, with pumps replaced after 28 days to produce the 2-month replacement. Serum T4 values in twice weekly samples revealed that the expected constant replacement was not achieved for the expected 28-day period. Rather, values declined steadily beginning as early as 17 days after pump insertion and fell below 12 ng/ml after 25.5 ± 1.0 days (n = 10). (Twelve ng/ml is the approximate minimum we estimate is needed for anestrus, based on our unpublished observations in incompletely THX sheep.) Effective replacement, therefore, may have been slightly less than 28 days for each pump installation.
Figure 4 compares mean LH values in THX ewes receiving a
1-pump T4 replacement beginning December 28 or January 28
with LH in both THX and thyroid-intact controls. LH remained high in
both groups of replaced ewes. Values were indistinguishable from those
in nontreated THX controls from the time of thyroidectomy to the end of
the study in May. Therefore, this T4 replacement was not
sufficient for the development of neuroendocrine anestrus.
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, ewe 3002). In the other three ewes, LH remained
high, indicating anestrus was blocked (e.g., Fig. 5B, ewe
3077). Of interest, the different responses were associated with depth
of the decline in circulating T4 before the pump change on
day 28. In the three ewes that maintained high LH, T4
became undetectable or approached this level on day 28 (2.8 ± 0.6
ng/ml; e.g., ewe 3077). The T4 decline was not
as severe in the two ewes in which LH fell (average 12.1 ng/ml on day
28; e.g., ewe 3002).
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Exp 3: Are thyroid hormones necessary only during the limited
interval to maintain the seasonal change in reproductive neuroendocrine
activity?
Our results thus far suggest the transition to anestrus requires
thyroid hormones only for a relatively brief (2-month) period around
the end of the breeding season. It is not clear, however, whether
thyroid hormones at other times of the year are needed for the
expression or appropriate timing of seasonal changes in reproductive
neuroendocrine activity. To address this issue, we THX ewes in March,
within 1 month after they entered anestrus, and replaced T4
beginning the following winter, late in the breeding season
(i.e., beginning 9 months after thyroidectomy). Eleven ewes
were THX on March 13–14, 1994 and assigned to two groups: no
T4 replacement (n = 6) or T4 replacement
via daily sc injection for 90 days beginning December 28 (n = 5).
LH was monitored until May 1995, 14 months after thyroidectomy.
Unfortunately all nontreated controls and one T4-replaced
ewe developed health problems related to the chronic absence of thyroid
hormones and either died or were euthanized. Therefore, useful data
were obtained for only the four T4-replaced ewes that
remained healthy.
As seen previously (15), LH increased in late summer despite the lack
of thyroid hormones for all but the first month of the anestrous season
(Fig. 6). LH remained elevated for the duration of the
breeding season; concentrations dropped somewhat in late
November-December but remained well above values characteristic of
anestrus. Thereafter, during the 90-day T4 replacement, LH
plummeted to the basal value on March 23 ± 7 days. This date was
later than that for thyroid-intact ewes during the same year (January
30 ± 4 days) but similar to that for ewes THX in October and
treated with T4 for 90 days from December 28 the same year
(March 13 ± 5 days; see Fig. 3).
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). LH increased in late
summer/early autumn and decreased in late winter/early spring of both
years. (Two animals were not sufficient to compare timing of these LH
swings and those of thyroid-intact controls.) These results, in
conjunction with those presented in Fig. 6, indicate the presence of
thyroid hormones at times other than winter are not required to
generate seasonal reproductive cyclicity. In addition, these findings
provide further evidence that a 60-day exposure to T4 can
be sufficient for the transition to anestrus.
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To test the hypothesis that responsiveness to thyroid hormones varies seasonally, we replaced T4 in THX ewes beginning in summer, rather than winter. If LH did not fall to baseline, we would conclude that responsiveness to T4 changes seasonally. Alternatively, if LH fell, we would conclude ewes remain responsive to T4 at this markedly different time of year. We selected mid-August as the start time for T4 treatment. If T4 were effective at this time, LH should fall in September-October, approximately 6 months out of phase with the usual time and around the onset of the breeding season in thyroid-intact ewes. Such result would provide powerful evidence that thyroid hormones could be effective at all times of year.
The study was conducted on seven ewes THX 8–10 months before onset of T4 replacement in August 1995 (i.e. THX during the breeding season of 1994, October or December). As a consequence of thyroidectomy before development of anestrus, these ewes maintained elevated LH until August, when they were allocated to two groups: nontreated (n = 3) or T4-replaced by daily sc injection for 90 days beginning August 11 (n = 4). A group of thyroid-intact ewes was included to provide a time reference for seasonal swings in LH in euthyroid animals (n = 7).
Nontreated THX controls maintained high LH from the time of
thyroidectomy (autumn 1994) until the end of the study in November 1995
(Fig. 8). Of special interest, LH also remained elevated
in ewes replaced with T4 for 90 days beginning in August.
Values in these ewes were indistinguishable from those in untreated THX
controls, despite their receiving T4 for 90 days.
Thyroid-intact ewes expressed the expected high amplitude LH swings,
including a rise in LH during September 1995, confirming that
T4 replacement spanned onset of the neuroendocrine breeding
season. The finding that T4 replacement in summer was not
effective in provoking the transition to anestrus supports the
hypothesis that the responsiveness to thyroid hormones varies
seasonally.
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), indicate that a general insensitivity to thyroid hormones did
not develop in the long-term absence of thyroid hormones. |
Discussion |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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In a sense, this seasonal loss of responsiveness to thyroid hormones is similar to the changes in response to thyroid hormone action during brain maturation. If thyroid hormones are absent for a 10-day critical period postnatally in rats, the brain does not mature normally (31); restoration of thyroid hormone to euthyroid levels after this critical period cannot reverse this deficit. The seasonal change in thyroid hormone responsiveness identified in our experiments resembles such a critical period in that, if thyroid hormones are lacking when the reproductive neuroendocrine axis is responsive, then anestrus is blocked. Subsequent restoration of T4 is ineffective in restoring the transition to anestrus. Thus, this seasonal change in responsiveness to thyroid hormone provides evidence for a critical period of thyroid hormone action on initiation of seasonal reproductive suppression in the ewe. Unlike the critical period for thyroid hormone action in development, which occurs only once during the life of the animal, the critical period for seasonality recurs at the end of each breeding season the animal experiences.
The findings described in our studies prompt several questions related to the interaction between thyroid hormones and the reproductive neuroendocrine axis. One involves the time course of thyroid hormone action. Previous findings in the ewe and other seasonal breeders had suggested the action of thyroid hormones on seasonal reproduction is confined to a limited time of the year. In the American tree sparrow, for example, thyroid hormones are necessary only during the early portion of the breeding season to promote the subsequent seasonal inactivation of gonadal activity (8). Removal of thyroid hormones after 4 weeks of photostimulation does not affect the timing or degree of reproductive suppression. Prior studies in the ewe suggest thyroid hormones are required only to initiate seasonal reproductive suppression, not to maintain anestrus once it is established (15). Thus, although thyroidectomy during the breeding season blocks anestrus, thyroidectomy at the start of anestrus does not prevent continuation of anestrus nor does it alter the development or timing of the next breeding season. Additional work in the ewe suggests thyroid hormones during the latter stages of the breeding season are especially important in promoting development of anestrus (16). The present study extends these earlier observations by determining that, in the ewe, thyroid hormones are necessary only during a limited interval that falls within a critical period for thyroid hormone action.
A second question raised by our study relates to when the time frame of thyroid hormone action actually begins and ends. Because thyroid hormones are present year round in quantities sufficient for anestrus to develop (14), the period of action most likely begins when the responsiveness to thyroid hormones develops (i.e. when the critical period begins). Although our study does not pinpoint this date, it does allow an approximation. Specifically, thyroidectomy in mid-December blocked the fall in LH, suggesting exposure to thyroid hormones up to that time was not sufficient for anestrus. Further, replacement of thyroid hormones beginning in late December did cause LH to fall in THX ewes, but the fall was delayed by approximately 1 month (Exps 1 and 3). Together, these observations suggest that thyroid hormones begin to act around the start of December. The time frame of thyroid hormone action most likely ends once the reproductive neuroendocrine axis has been exposed to thyroid hormones for a sufficient duration for anestrus to develop, approximately 60–90 days as estimated in this study. Thus, if we accept that the limited interval of exposure to thyroid hormones begins early in December, it follows that the interval ends in February, a time coincident with the end of the breeding season in our flock (17, 21). We emphasize that these are only approximations. Further, we emphasize that the end of the interval of thyroid hormone action does not necessarily coincide with the end of the critical period (i.e. the period of responsiveness), which may be later.
The 60- to 90-day duration of the interaction of thyroid hormones with the reproductive neuroendocrine axis of the ewe stands in sharp contrast to findings in the European starling, another species in which the end of the breeding season is dependent upon thyroid hormones. A single injection of T4 is sufficient to promote gonadal regression in THX starlings, indicating thyroid hormones may interact only briefly with the processes responsible for development of the nonbreeding season in that species (30). The longer time requirement in sheep is in keeping with thyroid hormone action in other physiological processes, such as maintenance of metabolic homeostasis and energy balance (32). The long-term nature of the interaction also offers insight into the possible mode of action of thyroid hormones. In this regard, the seasonal reproductive cycle of the ewe appears to be generated by an endogenous rhythm consisting of an interaction of various physiological processes and requiring approximately 1 yr to progress through its full cycle (17, 33). Perhaps thyroid hormones interact with one or more of the processes that contribute to the rhythm. In this case, the critical period might represent the point that the rhythm reaches a thyroid-dependent stage.
Consistent with an action of thyroid hormone on the endogenous rhythm are certain similarities related to the influence of thyroid hormones and photoperiod on seasonal reproduction in the ewe. Both thyroid hormones (this study) and photoperiod (20, 34, 35) require a period of weeks to months for their actions to become evident. Each of these factors elicits the greatest effect at a particular time of the calendar year or at a specific stage of the seasonal reproductive cycle, although the times specific to each differ. In the case of thyroid hormones, the strongest interaction occurs during the winter, late in the breeding season as determined here. Photoperiod, however, expresses its most powerful influence in the spring/summer, during the anestrous season (36). Further, the fundamental action of these two factors on the rhythm differs. Photoperiod synchronizes the rhythm to the seasons (36, 37), whereas thyroid hormones appear to be necessary for either generation or expression of the rhythm itself.
With regard to this last point, another question arising from our study concerns the nature of the interaction between thyroid hormones and the physiological processes that produce the endogenous rhythm. We can envisage two general modes of thyroid hormone action. First, thyroid hormones may be required for generation of the rhythm, such that the rhythm stops in their absence. Second, thyroid hormones may be needed for expression of one of the rhythm outputs, i.e. linking the rhythmic process to the GnRH neurosecretory system to cause development of anestrus. Our observation that T4 replacement beginning in December caused anestrus to develop, but the same treatment given in August did not, suggests that some element of annual rhythmicity continued in THX ewes, namely responsiveness to thyroid hormones. Thus, rather than stop, the rhythm may simply have progressed beyond the stage that is responsive to thyroid hormones. According to this view, the fundamental mechanisms underlying endogenous rhythmicity may remain intact following thyroidectomy, whereas one of the rhythm outputs, seasonal reproduction, ceases to progress through a full cycle. Thus, we suggest thyroid hormones are needed for expression of the rhythm at the level of the reproductive neuroendocrine axis.
Given the importance of photoperiod as a time cue for seasonal reproduction in sheep (3, 20, 34, 35, 36, 37), it is important to consider whether the action of thyroid hormones on seasonality involves the photoperiodic response mechanism. This might be especially relevant because the ewes in our study were maintained outdoors and exposed to natural changes in photoperiod. Nevertheless, an interaction with the photoperiodic response mechanism was not likely to be a major factor in the outcome of our studies for several reasons. First, changes in day length do not appear to drive the end of the breeding season under natural conditions (21). Rather, the transition to anestrus is driven by the endogenous rhythm (21, 36, 37, 38), and this transition appears to be timed by photoperiodic cues perceived before the autumnal equinox (36, 39), well before thyroidectomy in our studies. Second, anestrus is blocked in THX ewes, whether they remain in natural conditions, as in this study, or on fixed short days (11, 13, 14). Even if challenged with photoperiodic manipulations, THX ewes still remain reproductively active (40), suggesting that photoperiod does not influence the response to thyroidectomy. Third, we are not aware of any photoperiodic manipulation that can consistently prevent development of anestrus in the ewe, perhaps because the circannual drive is so powerful that it precipitates this transition regardless of the prevailing photoperiod. Taken together, these considerations are most parsimonious with the view that thyroid hormones influence seasonal reproduction via the circannual mechanism rather than by an interaction with the photoperiodic response system.
Finally, because male and female sheep respond differently to thyroidectomy in the spring (15, 41), gender may influence the temporal relationship between thyroid hormones and the seasonal reproductive mechanism. Like the ewe, the ram requires thyroid hormones for transition into the nonbreeding season (10, 41, 42). The ram, however, also requires thyroid hormones for maintenance of the nonbreeding state (41); this is not the case for the ewe (15). Thyroidectomy in spring, after the testes have regressed, promotes a rapid and profound increase in gonadotropin secretion and premature testicular recrudescence (41). It is likely, therefore, that the timing of the interaction between thyroid hormones and the mechanisms driving seasonal reproduction in sheep differ according to gender.
We conclude that thyroid hormones exert their influence on the neuroendocrine mechanisms that lead to seasonal reproductive suppression in the ewe only during a limited interval, consisting of a 60- to 90-day period of time just before anestrus. Moreover, the reproductive neuroendocrine axis undergoes seasonal changes in responsiveness to thyroid hormones. These findings are consistent with the conclusion that thyroid hormones can influence seasonal reproduction in the ewe only during a critical period, when mechanisms involved in the expression of the endogenous reproductive rhythm become responsive to thyroid hormones.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Internal Medicine, Division of
Endocrinology and Metabolism, 5570 Medical Science Research Building
II, University of Michigan, Ann Arbor, Michigan 48109-0678.
3 Current address: Department of Animal Sciences, 1415A Animal
Science Building, University of Maryland, College Park, Maryland
20742-2311.
4 Current address: Department of Neurobiology, Babraham Institute,
Babraham Hall, Cambridge CB2 4AT, United Kingdom.
Received January 27, 1997.
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References |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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) and ewes THX (arrows) either well before
hypothesized limited interval of thyroid hormone action (October, 
)
or just before this interval (December, •). Values are mean ±
SEM for ewes THX in December and means in other groups
(SEM omitted for clarity). Horizontal black
bars indicate presence of endogenous thyroid hormone before
THX. Bar at top depicts time of breeding season observed
previously in this laboratory (21). Number of animals in each group is
designated by n.
). Points depict mean values
for five ewes in each group; SEM omitted for clarity. See
Fig. 1
