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Biology of Reproduction 66, 701-706 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Thyroid Hormones Mediate Steroid-Independent Seasonal Changes in Luteinizing Hormone Pulsatility in the Ewe1

Greg M. Anderson3,a, John M. Connorsa, Steven L. Hardya, Miroslav Valenta, and Robert L. Goodman2,a

a Department of Physiology, West Virginia University, Morgantown, West Virginia 26506


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Thyroid hormones permit the increase in response to estradiol negative feedback in ewes at the transition to anestrus. In this study, we tested whether the thyroid hormones are also required for steroid-independent seasonal changes in pulsatile LH secretion. In experiment 1, Suffolk ewes were ovariectomized and thyroidectomized (THX) or ovariectomized only (controls) in late November. LH pulse frequency and amplitude were measured for 4 h in December, April, May, June, and August. Pulse frequency was also measured in the presence of estradiol-containing implants during the breeding (December) and early anestrus (March) seasons. As expected, in the presence of estradiol, pulse frequency declined between December and March in control but not THX ewes. In the absence of estradiol, a seasonal decline in frequency and an increase in amplitude occurred in control ewes, concurrent with lengthening photoperiod. A similar trend was seen in THX ewes, but the seasonal changes were lower in magnitude and not significant. In experiment 2, the same protocol was used (pulse measurements in December, May, and June) with a larger THX group size (n = 7). Results were similar to those of experiment 1 for controls. In THX ewes, pulse frequency did not change over time and was significantly elevated relative to that of controls during the summer. Pulse amplitude in THX ewes tended to increase during summer and did not differ from pulse amplitudes in control ewes. These results demonstrate that thyroid hormones are required for steroid-independent cycles in LH pulse frequency; however, some seasonal changes in amplitude still occur in the absence of thyroid hormones. This finding contrasts with the changes in estradiol negative feedback at the transition to anestrus, which are entirely thyroid hormone dependent.

environment, hypothalamus, luteinizing hormone, neuroendocrinology, seasonal reproduction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The ewe has an endogenously generated circannual breeding cycle that is entrained by photoperiod [1, 2]. In the Suffolk breed, estrous cyclicity begins each year about 1 mo prior to the autumnal equinox and, in the absence of pregnancy, persists until about 1 mo prior to the spring equinox [3]. The primary neuroendocrine mechanism underlying the occurrence of seasonal anestrus involves a marked increase in the responsiveness of the hypothalamic GnRH pulse generating system to estradiol negative feedback [3–6]. However, in the absence of estradiol, a seasonal decline in LH pulse frequency and an increase in pulse amplitude occurs gradually beginning in late winter, approximately concurrent with the lengthening of photoperiod [6]. Larger seasonal fluctuations of circulating gonadotropin concentrations are apparent in other species and other types of sheep in the absence of gonadal steroids (e.g., red deer hinds [7], showshoe hare bucks and does [8], Soay [9] and Ile de France [10] rams). These steroid-independent rhythms are often considered to be the result of variations in an underlying direct photoperiodic drive to gonadotropic output [6, 8], which is further modified by steroid negative feedback [11, 12].

More recent observations have led to the hypothesis that thyroid hormones are required for the transition from the breeding to the nonbreeding state in many species of birds [13, 14] and mammals [15–18]. In the ovariectomized, estradiol-treated ewe, pulse frequencies of LH [19] and GnRH [20] are maintained at high levels throughout the nonbreeding season if the animals have been thyroidectomized during the preceding breeding season. In contrast, thyroid hormones are not required for seasonal changes in prolactin secretion in sheep [19, 21], and it is not clear whether these hormones are necessary for steroid-independent changes in LH secretion because this question has not been addressed in this species. The purpose of this study, therefore, was to determine whether thyroidectomy at the peak of the steroid-independent cycle of LH pulse frequency prevented the seasonal decline in this cycle during early summer in the ewe.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

Mature black-faced ewes of predominantly Suffolk breeding were used for these experiments. Ewes were maintained in an open-sided barn that allowed exposure to ambient photoperiod and temperature, with access to water and a daily silage allowance. Thyroidectomy was performed using sterile procedures as previously described [19] under general anesthesia (halothane + oxygen), followed by an indoor recovery period of several days. Ovariectomy was performed by midventral laparotomy using sterile procedures either at the time of thyroidectomy (experiment 1) or 1–2 mo prior to this procedure under sodium pentobarbital anesthesia (experiment 2). All procedures involving animals were conducted in accordance with the International Guiding Principles for Biomedical Research Involving Animals as promulgated by the Society for the Study of Reproduction and were approved by the West Virginia University Animal Care and Use Committee.

Experiment 1

At about the time of the peak of the steroid-independent seasonal cycle of LH pulse frequency (November), ewes were ovariectomized and thyroidectomized (THX, n = 5) or ovariectomized only (controls, n = 6). Thyroidectomy at this time is known to block the decline in LH secretion at the time of the onset of seasonal anestrus in ovariectomized, estradiol-treated ewes [22]. To monitor steroid-independent changes in LH pulsatility, 3-ml blood samples were collected every 10 min for 4 h by jugular venipuncture in December, April, May, June, and August. To monitor the steroid-dependent changes in LH pulsatility that occur at the time of the transition from breeding season to anestrus, all ewes received a subcutaneous estradiol-containing implant beginning immediately after collection of the December pulse blood sample until late March (removed 3 wk before blood collection in April). The implants consisted of silicone rubber tubing (inside diameter 3.35 mm, outside diameter 4.65 mm, Sil-Med; Tri-anim, Sylmar, CA) packed to a length of 30 mm with crystalline estradiol-17ß and plugged at the ends with room temperature vulcanizing silicone sealant. In previous studies, these implants elevated serum estradiol concentrations to luteal phase levels in ewes [3, 23]. Serial blood samples for pulse frequency analysis were collected in the presence of the implants during the breeding season (December, 10 days after implant insertion) and the nonbreeding season (March, immediately before withdrawal). A single blood sample was also collected twice weekly from all ewes to determine when serum LH concentrations declined [3]. Serum was removed following centrifugation and stored at -20°C until assayed.

Experiment 2

Because of the low number of completely THX ewes in experiment 1, the experiment was repeated in a following year. Chronically ovariectomized ewes were thyroidectomized (THX, n = 8) or left untreated (controls, n = 6) early in December, and serially blood samples were collected as before in December, May, and June (these times were chosen based on the results of experiment 1). To measure steroid-dependent changes, ewes received subcutaneous estradiol implants as before from immediately after the blood collection in December until the end of April (4 wk before sample collection in May). LH pulse frequency was not measured in the presence of these implants, but blood samples were collected twice weekly from all ewes for measurement of mean serum LH concentration and serum total thyroxine concentration.

Radioimmunoassay

Serum LH concentration was measured in 100- to 200-µl aliquots by RIA, using a modification of a previously described method [24]. Values are expressed in terms of the ovine standard, NIH S24. Iodinated ovine LH (LER1374A; Dr. L.E. Reichert, Jr., Albany Medical College, Albany, NY) was used as tracer, and primary antiserum was CSU-204 (Dr. G. Niswender, Colorado State University, Fort Collins, CO; dilution 1:75 000). The sensitivity (95% confidence interval at 0 ng/ml) averaged 0.2 ng/tube over the 53 assays that contributed to the results. Intraassay coefficients of variation (CVs) averaged 8.6% and 16.7%, respectively, for serum pools displacing radiolabeled LH to approximately 54% and 84% of the total bound, and interassay CVs were 19.3% and 23.6% for the same serum pools.

Serum total thyroxine concentration was monitored in selected serum samples (about once every 3 wk); duplicate 25- to 50-µl aliquots were assayed using a commercially available kit (Coat-A-Count Total T4; Diagnostic Products Corp., Los Angeles, CA) validated for use with sheep serum [19]. Assay sensitivity averaged 0.04 ng/tube over the 4 assays that contributed to the results. Intraassay CVs for serum pools that displaced radiolabeled thyroxine to 51% and 85% of the total bound averaged 6.0% and 10.6%, respectively, and interassay CVs were 5.8% and 14.5% using the same serum pools.

Data Analysis

In experiment 2, 3 THX ewes became debilitated and were killed in June; therefore, the final pulsatile LH measurement (late June) does not include results from these ewes. Thus, data from this group were analyzed in 2 ways: by excluding the June results and by limiting the analysis to those ewes for which a complete data set was available. The method of analysis affected the level of probability but did not alter conclusions as to significance; the probability values reported are those from the latter approach. Hormone concentrations below the average sensitivity were assigned a value equal to the sensitivity. A pulse of LH was defined as any increase in concentration in which 1) concentrations were elevated relative to pre- and postnadir values for at least 2 consecutive samples, 2) the pulse peaked within 2 sampling intervals, 3) the increment between peak and nadir concentrations exceeded the pre- and postnadir values by at least 2 SDs of the peak value, and 4) the amplitude exceeded the sensitivity of the assay [25]. Pulse frequency (peaks/4 h), pulse amplitude (peak minus preceding nadir), and mean LH concentration over the 4-h sampling period were calculated for each ewe. The date of onset of the anestrous season for an individual ewe was defined as the first date that the individual's serum LH concentrations first fell below 1 ng/ml for 2 consecutive samples while estradiol implants were in place. Significant effects of treatment and time were identified using two-way ANOVAs for repeated measurements, followed where appropriate by a Fisher least significant difference multiple comparison test to determine at which point significant effects occurred, after first checking for normality. Mean results are presented plus/minus the SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiments 1 and 2: Serum Thyroxine Concentration

Mean serum total thyroxine concentrations in control ewes declined between midwinter and midsummer, ranging from 65 to 40 ng/ml. Two THX ewes from experiment 1 and 1 THX ewe from experiment 2 had serum total thyroxine concentrations in excess of 3 ng/ml; results from these ewes (in which thyroidectomy was presumed to be incomplete) were analyzed and presented separately. In all other THX ewes, serum total thyroxine concentrations fell below assay detection levels within 2 wk of thyroidectomy and remained low throughout the experiment (Fig. 1).



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  		FIG. 1. Mean (±SEM) serum concentrations of total thyroxine in ewes from experiment 1 (left) and experiment 2 (right). Individual data for 3 ewes with presumed incomplete thyroidectomy are plotted separately (dashed lines). Arrows show the time of thyroidectomy

Experiment 1

In control ewes, LH pulse frequency declined (P < 0.05) between December and March in the presence of the estradiol implants (Fig. 2). LH concentrations also declined in all control ewes and the 2 incompletely THX ewes to <1 ng/ml while estradiol was present during late February or March (Fig. 3). The mean date of onset of anestrus was 14 February ± 7 days for control ewes, and 23 February and 9 March for incompletely THX ewes. In contrast, LH pulse frequency and concentration both remained high in the 3 completely THX ewes while estradiol was present (Figs. 2 and 3). In control ewes in the absence of estradiol implants, LH pulse frequency declined (P < 0.05) and pulse amplitude increased (P < 0.05) between midwinter and midsummer, approximately concurrent with lengthening photoperiod. A similar pattern was observed for the 2 incompletely THX ewes. Although LH pulse frequency and amplitude in the 3 completely THX ewes both appeared to undergo some seasonal fluctuations and did not differ significantly from those of the controls, the magnitude of the changes was less for THX ewes and the effects of season were not significant. Mean LH concentration increased between midwinter and midsummer in both groups (P < 0.001); there was no effect of thyroidectomy on this parameter (Fig. 4).



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  		FIG. 2. Mean (±SEM) LH pulse frequency in the presence of estradiol implants during December (breeding season) and March (early anestrous season) in ewes from experiment 1. The asterisk denotes an effect of season (P < 0.05)



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  		FIG. 3. Mean serum concentrations of LH during estradiol implantation around the end of the breeding season in ewes from experiment 1 (left) and experiment 2 (right). Individual data for 3 ewes with presumed incomplete thyroidectomy are plotted separately (dashed lines). Average SEM is shown for clarity



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  		FIG. 4. Mean (±SEM) LH pulse frequency (upper), LH pulse amplitude (middle), and LH concentration (lower) in the absence of estradiol in ewes from experiment 1 (left) and experiment 2 (right). Individual data for 3 ewes with presumed incomplete thyroidectomy are plotted separately (dashed lines). The asterisk denotes a sampling point where treatment means differ (P < 0.01). Note that the range of the x-axis differs between experiment 1 and experiment 2 and that for experiment 2 only 4 ewes are represented in the June data points for the THX group

Experiment 2

As in experiment 1, LH concentrations declined to <1 ng/ml during late February or March in the presence of the estradiol implants in all control ewes (mean date: 1 March ± 9 days) and the 1 incompletely THX ewe (24 February). In contrast, LH concentration did not decline in any of the other THX ewes; there was rather a gradual increase in mean LH concentrations (P < 0.001) (Fig. 3). In the absence of estradiol implants in control ewes, LH pulse frequency declined to nadir values in May (P < 0.001) and pulse amplitude increased progressively in May and June (P < 0.05). A similar pattern was observed for the incompletely THX ewe. In contrast, there was no effect of season on LH pulse frequency in completely THX ewes; frequency remained elevated throughout the experiment (P < 0.01 for season x treatment interaction). However, thyroidectomy did not significantly affect pulse amplitude; amplitude tended to increase over time in THX ewes (P = 0.08) albeit to a slightly lesser degree than in controls (see Fig. 5 for representative examples). Mean LH concentration increased between midwinter and midsummer in both groups (P < 0.01); there was no significant effect of thyroidectomy on this LH concentration, although the change appeared greater in magnitude for THX ewes (Fig. 4).



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  		FIG. 5. Individual serum LH pulse profiles from experiment 1, representative of control (upper) and THX (lower) ewes in the absence of estradiol during late December (left) and late May (right). Closed circles denote the peaks of pulses


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These results describe seasonal profiles of LH pulsatility from midwinter to spring for thyroid-intact and THX ovariectomized ewes (experiment 1). The steroid-independent decline in LH pulse frequency that occurs as day lengths increase is dependent on the presence of thyroid hormones, and thyroidectomy around the time of maximal frequency prevented this decline (experiment 2). This dependence on thyroid hormones is similar to the thyroid hormone-induced suppression of LH pulse frequency due to increased responsiveness to estradiol negative feedback at the beginning of anestrus [19, 26]. The role of thyroid hormones in the steroid-independent annual LH rhythm has not been directly studied in the ewe until now, although the results of Moenter et al. [19] suggested a possible role for the thyroid hormones in this system. The current results and those from comparable experiments in starlings [27] and red deer [28] extend the thyroidectomy effect from the steroid-dependent component of seasonal reproduction to include the steroid-independent component.

In experiment 1, there appeared to be a very low amplitude steroid-independent seasonal pattern of LH pulse frequency in THX ewes, but these changes were not significant. There was no evidence of such a trend in experiment 2 (Fig. 4). The difference is likely due to variability in experiment 1 arising from the very small sample size. However, one difference between the 2 experiments that we cannot discount is that in experiment 1 thyroidectomy was conducted around the time of maximal pulse frequency in mid-November [6], whereas in experiment 2 thyroidectomy was conducted in early December. Even if thyroidectomies had been conducted close to a threshold time for affecting the steroid-independent system, it is unlikely that this difference in timing was the cause of any variation between experiments because, contrary to our results, the earlier thyroidectomies would be expected to yield the largest treatment effects. Variability between the experiments is also evident in the difference in mean LH concentrations in control groups during summer (Fig. 4). This difference appears to be a result of higher nadir concentrations in experiment 1. The same effect accounts for the increase in mean LH concentration in experiment 1 while pulse frequency and amplitude were both decreasing (Fig. 4). This variability among non-THX ewes is consistent with previous reports [4, 6, 9, 10, 29–31] and has been attributed to differences in breeds [31] and time after ovariectomy [29]. Such variability emphasizes the importance of monitoring LH pulse patterns in the same animals at different times of the year.

In the absence of estradiol, the effect of thyroidectomy was restricted to the decline in LH pulse frequency; there was little or no effect on the concurrent seasonal increase in LH pulse amplitude or the (presumably resultant) tendency for LH concentration to increase with time, even when larger groups were used in experiment 2. Despite the similarity of these results to those of Moenter et al. [19], where LH pulsatility was measured in ovariectomized THX ewes on a single occasion during the spring, such a finding is surprising given that LH pulse amplitude is a function of releasable LH, which is in turn inversely related to GnRH pulse frequency [32, 33]. Thus, a high GnRH/LH pulse frequency should be temporally coupled to a low pulse LH amplitude; in contrast, our results suggest that the seasonal modulation of amplitude in ovariectomized ewes can be controlled separately from frequency and that only the neuroendocrine mechanisms for the latter are dependent on thyroid hormones. The ewe may be similar to the red deer hind in this regard. Seasonal patterns of LH pulse amplitude in hinds are greatly confounded by a marked decline in pituitary responsiveness during summer [7, 28]; however, this decline appears to be at least partly offset by thyroidectomy, so that the resultant LH pulses presumably reflect more closely GnRH pulses in amplitude [28]. In agreement with our results using ewes, thyroidectomy has been shown to overcome the steroid-independent decline in pulse frequency in hinds, but a marked increase in pulse amplitude persists [28]. This is not the case with the steroid-dependent system, for which thyroidectomy during the breeding season prevents the seasonal changes in both frequency and amplitude from occurring [19]. The divergent effects of thyroidectomy on pulse amplitude for the 2 systems do not support the hypothesis that steroid-independent seasonal changes in ovariectomized animals are artifacts caused by adrenally derived estrogen, which can reach significant levels in some circumstances [34].

Support for the presence of separate control mechanisms for LH pulse frequency and amplitude may also be derived from the results of Meyer and Goodman [35]. Although both the frequency and amplitude of LH pulses in ovariectomized ewes during midsummer could be restored to levels characteristic of midwinter by the same receptor antagonist (cyproheptadine, which blocks serotonergic 5HT2 and histaminergic H1 receptors), a decrease in amplitude following administration of this drug was also seen in winter. Thus, the seasonal change in amplitude could not be attributed to serotonergic or histominergic neural pathways. Although serotonin inhibition appears to mediate the steroid-independent decline in LH pulse frequency in summer [35, 36], the central control system underlying the increase in pulse amplitude remains unclear. Nevertheless, this change probably reflects a hypothalamic rather than pituitary effect, because in most domestic sheep breeds the responsiveness of the anterior pituitary gland to GnRH exhibits little or no seasonal variation [37, 38]. Furthermore, GnRH pulse size increases in summer in concert with LH pulse size [39].

There is ample evidence for a close temporal (and presumably causal) coupling between GnRH and LH pulses [5, 39–42]; by inference, it can be assumed that the effects of season and thyroidectomy described here reflect changes at the level of the hypothalamic GnRH neurons. The fact that thyroid hormones can act centrally to permit seasonal change in the estradiol negative feedback system [22] supports this view. In the 2 reports to date describing annual steroid-independent patterns of episodic GnRH secretion in ewes [5, 42], no significant seasonal differences in GnRH pulsatility were detected. However, in these experiments the ewes were not used as their own controls, as they were in our study, because the GnRH sampling technique precluding repeated pulse measurements [42].

The mechanisms by which thyroidectomy prevents the seasonal changes in GnRH pulse frequency are completely unknown. However, these mechanisms are unlikely to reflect metabolic effects of hypothyroidism because the reduced metabolic rate and nerve conduction velocity seen in hypothyroid patients [43] might be expected to decrease, not increase, GnRH pulse frequency. Alternatively, the absence of thyroid hormones during spring might impair the establishment of inhibitory neuronal circuitry or the synaptic connections between such systems and GnRH neurons, similar to the impairment of neural development seen in neonatal hypothyroidism [44].

The physiological importance of steroid-independent seasonal reproduction should be considered in an evolutionary context. Steroid-independent seasonal changes in gonadotropin secretion have been found in all species studied, although the magnitude varies widely. Goodman and Karsch [45] suggested that this seasonality may reflect the degree of domestication that a particular species has been subjected to, with the less domesticated animals (e.g., red deer hinds [7] and many birds [46, 47]) exhibiting profound steroid-independent seasonal rhythms and the more domesticated animals (e.g., most sheep breeds [3, 4, 6]) relying proportionately more on steroid-negative feedback to time their breeding. Even in the red deer hind, however, steroid-dependent suppression of LH (as seen in ovariectomized hinds treated with subcutaneous estradiol implants) profoundly suppresses circulating LH concentrations so that the steroid-independent effect is masked [7]. This finding prompts questions about the physiological importance of the steroid-independent system in mammalian seasonal reproduction. In less domesticated animals such as deer, during the time of maximal steroid-independent suppression this system and steroid-negative feedback may be additive in preventing ovulation, as indicated by the inability to artificially induce a preovulatory-like LH surge or ovulation during a portion of the anestrous season [48–50]. Such variations in the "depth" of anestrus are not as apparent in the domestic ewe [51–54], although they have been noted in studies of sheep breeds characterized by a long anestrous season [55].

In summary, we have demonstrated that the seasonal decline in LH pulse frequency that occurs in the ewe in the absence of gonadal steroids during spring and summer is dependent on the presence of thyroid hormones. In contrast, the concurrent seasonal increase in LH pulse amplitude does not require thyroid hormones to be present. The ewe appears to be similar to another seasonal breeder, the red deer hind, in regard to both of these findings, but the lack of an effect of thyroidectomy on pulse amplitude differs from the steroid-dependent changes in pulse amplitude that require thyroid hormones.


   ACKNOWLEDGMENTS
 
We thank Dr. Gordon Niswender, Dr. Leo Reichert, Jr., and the National Pituitary Agency for LH RIA reagents.


   FOOTNOTES
 
First decision: 18 July 2001.

1 This work was supported by NIH grant HD17864. Back

2 Correspondence: Robert L. Goodman, Department of Physiology, Health Sciences Center North, Medical Center Dr., Morgantown, WV 26506-9229. FAX: 304 293 3850; bgoodman{at}hsc.wvu.edu Back

3 Current address: Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand Back

Accepted: October 24, 2001.

Received: June 29, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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