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Department of Physiology and Pharmacology (G.M.A., S.L.H., M.V., J.M.C., R.L.G.), West Virginia University, Morgantown, West Virginia 26506; Institute of Veterinary, Animal, and Biomedical Sciences (G.M.A.), Massey University, Palmerston North, New Zealand 5301; and Reproductive Sciences Program and Department of Physiology (H.J.B.), University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. Robert L. Goodman, Department of Physiology and Pharmacology, Health Sciences Center North, Medical Center Drive, Morgantown, West Virginia 26506-9229. E-mail: bgoodman{at}hsc.wvu.edu.
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Introduction |
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A role for thyroid hormones is well described in neonatal brain development (10), and more recently it has also become evident that their presence is essential for the changes in the hypothalamus responsible for the onset of anestrus (11). In particular, thyroidectomized (THX) ewes show neither the increased response to E2-negative feedback (e.g. Ref.12, 13, 14) nor the steroid-independent decrease in GnRH pulse frequency (15) that normally occurs at the onset of anestrus. Similar observations in other mammals (16, 17, 18) and birds (19, 20) suggest thyroid hormones are a common hormonal requirement for these reproductive transitions.
The site and mechanism by which thyroid hormones act in this regard remains to be elucidated, although results from experiments in which T4 was infused into the cerebral ventricles of THX ewes strongly suggest that they act centrally (21). In the current experiments, we sought to determine the specific site of thyroid hormone action by placing T4 microimplants in various brain sites in different groups of THX ewes. The brain sites targeted in the initial experiment were the ventromedial preoptic area (vmPOA), medial preoptic area (mPOA), retrochiasmatic area (RCh), and medial basal hypothalamus (MBH). These sites were chosen based on previous work from our laboratory and others, which led to the following model of E2-negative feedback in anestrus. E2 acts on neurons containing classical estrogen receptor 
in the vmPOA and/or RCh, which project to and activate the A15 dopaminergic neurons (22, 23, 24). These neurons in turn suppress LH pulse frequency by presynaptic inhibition of GnRH neurons with soma in the mPOA and/or MBH (25, 26). Melatonin, the nocturnally secreted indoleamine that acts as a transducer of photoperiod, appears to act in the premammillary region (PMR) (which includes the posterior arcuate and ventral premammillary nuclei) to cue seasonal reproductive transitions (27). Because we had preliminary evidence that T4 affects the neuronal activity within the PMR (28), we also tested whether this area was a site at which thyroid hormones act to mediate the onset of anestrus.
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Materials and Methods |
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To facilitate monitoring of the marked increase in E2-negative feedback that normally occurs at the time of the transition from breeding season to anestrus, all ewes were ovariectomized (OVX) and given a sc E2-containing implant consisting of silicone rubber tubing (Sil-Med, Tri-anim, Sylmar, CA; inner diameter 3.35 mm, outer diameter 4.65 mm) packed to a length of 30 mm with crystalline E2 and plugged at the ends with room temperature vulcanizing silicone sealant; these implants have been shown in previous studies to elevate serum E2 concentrations to luteal phase levels in ewes (2). In this well-characterized model (e.g.2, 3, 15, 23), mean LH concentration and LH pulse frequency are elevated during the period corresponding to the breeding season of ovary-intact ewes and low or undetectable during the season of anestrus. Single blood samples were collected twice weekly by jugular venipuncture to monitor LH and T4 concentrations (2, 15). Serum was removed following centrifugation and stored at -20 C until assayed. All procedures involving animals were approved by the West Virginia University Animal Care and Use Committee (experiments 1 and 2) or the Massey University Animal Ethics Committee and Radiation Safety Officer (experiment 3).
Surgery and T4 microimplantation
Surgeries were performed under aseptic conditions. Thyroidectomy was performed as previously described (12) under general (halothane + oxygen) anesthesia in early December. Ovariectomy was performed by midventral laparotomy, either at the time of thyroidectomy (about 50% of ewes in experiment 1 and all ewes in experiment 2), or 1–3 months before this procedure under sodium pentobarbital general anesthesia. For ewes receiving local microimplants, bilateral 18-G guide tubes (60 mm long) were inserted into the brain under general (halothane + oxygen) anesthesia as previously described (23) at least 1 month before thyroidectomy (experiments 1 and 2) or several months after thyroidectomy (experiment 3). Guide tubes were lowered to a point 1 mm dorsal to the target sites for the microimplants (Table 1
), cemented in place, and protected with a plastic cap. For icv guide tube placement, 45-mm-long bilateral guide tubes were inserted 5–10 mm rostral of the bregma and 4 mm lateral of the midline. These tubes were then lowered to the lateral ventricles as judged by the depth in which sterile water flowed down the tubes by gravity. Surgeries were followed by an indoor postoperative treatment period during which ewes were monitored daily for 1–2 wk.
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Experiment 1
Because of the technical difficulty of this experiment, it was done in replicate over a 2-yr period. Ewes were randomly allocated to the following treatment groups: vmPOA, mPOA, A15 area, and MBH microimplants. Positive controls included thyroid-intact ewes (n = 10), THX ewes receiving 6 µg/kg sc L-T4 injections three times per week, prepared as previously described (13, 29) (n = 4) and THX ewes with icv microimplants. Each treatment group contained at least two ewes from each year, except for the group receiving T4 replacement by sc injection, which was not repeated in the second year, and the mPOA group, which was not run the first year. Negative controls were THX without T4 replacement (n = 9). Biweekly blood samples were collected from late December to May for hormone assay. T4 replacement by microimplantation or sc injections was conducted from January 5 until the end of the experiment. At the end of April, the E2 implants were removed to check that LH suppression in the presence of the implants was specifically caused by steroid suppression rather than by long-term side effects of the surgeries. Ewes that failed to show increased LH secretion after implant removal or became debilitated before the end of the experiment were removed from the experiment. THX ewes were also excluded from the study if their mean serum total T4 concentrations exceeded 3 ng/ml because the thyroidectomy was presumed to be incomplete. After exclusion of these animals, there were five to six ewes in each of the microimplanted groups, except for the group receiving icv implants, which contained seven ewes.
At the end of the experiment, ewes were deeply anesthetized with 3000 mg iv sodium pentobarbital and, when possible, samples of cerebrospinal fluid (CSF) collected by puncture of the cisterna magna using a 1.5-in.-long hypodermic needle (21). This was stored at -20 C for later assay of total T4 concentration. After CSF collection, the heads were perfused with 6 liters of 4% paraformaldehyde and the hypothalami dissected and sectioned coronally (50 µm) for histological analysis of guide cannulae positions, as previously described (23).
Experiment 2
In this study, we tested the hypothesis that T4 acts in either the PMR or vmPOA. Animals were surgically prepared as previously described, and T4 microimplants were inserted into the vmPOA (n = 5) or PMR (n = 5) beginning January 5. Controls were either thyroid intact (n = 5) or THX (n = 5), as for experiment 1. Serum LH levels were monitored via biweekly serum samples from January through March (under simulated natural photoperiod anestrus begins about 1 month earlier than outdoors; Karsch, F. J., personal communication) and total T4 concentrations measured in selected samples. The E2 implants were removed in late March to monitor LH levels in the absence of E2-negative feedback as in experiment 1.
Approximately 3 wk after E2 implant removal, blood samples were collected by jugular venipuncture every 12 min for 4 h. The E2 implants were then replaced and frequent blood samples collected again 1 wk later to monitor the effects of E2 on LH pulse frequency that occur only during anestrus. As in experiment 1, at the end of the experiment, ewes were sampled for CSF, the heads were perfused, and the hypothalami sectioned for histological analysis of guide cannulae positions.
Experiment 3
To obtain an estimate of the T4 diffusion distance from the implant sites, bilateral guide tubes were lowered to the A15 area in a single THX ewe. Following a recovery period, a unilateral microimplant containing 125I-L-T4 was inserted for 5 d. Cold T4 was added to a 125I-T4 solution of known specific activity (NEN Life Science Products, Boston, MA) to produce the desired specific activity (
10 µCi/mg T4) before drying down and tamping into the microimplant. Immediately following microimplant withdrawal, the ewe was killed with a sodium pentobarbital overdose as in experiments 1 and 2. A sample of CSF was collected from the cisterna magna for radioactivity measurement and the hypothalamus removed from the head without perfusion. The entire hypothalamus was sectioned into thick (300 µm) sections; these were counted for radioactivity on a 
counter and corrected for background.
RIA analyses
Serum LH concentration was measured in 100- to 200-µl aliquots of all blood samples by RIA, using a modification of a previously described method (30). 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. Gordon Niswender, Colorado State University, Fort Collins, CO; dilution 1:75,000). The sensitivity (95% confidence interval at 0 ng/ml) averaged 0.16 ng/tube over the 21 assays that contributed to the results. Intraassay coefficients of variation (CVs) averaged 13.4% and 16.5%, respectively, for serum pools displacing radiolabeled LH to approximately 16% and 82% of the total bound, and interassay CVs were 13.0% and 18.0% for the same serum pools.
Serum total T4 concentration was monitored in selected serum samples (about once every 3 wk); duplicate 50-µl aliquots were assayed using a commercially available kit (Coat-A-Count Total T4, Diagnostic Products, Los Angeles, CA). CSF total T4 concentration was assayed in 200-µl aliquots using the same kit. The kit has been validated for use with sheep serum (12) and CSF (21). Assay sensitivity averaged 0.04 ng/tube over the four assays that contributed to the results. Intraassay CVs for serum pools that displaced radiolabeled T4 to 48% and 85% of the total bound averaged 14.2% and 6.5%, respectively, and interassay CVs were 14.0% and 16.1% using the same serum pools.
Data analysis
For calculation of mean LH and T4 values, concentrations below the average sensitivity were assigned a value equal to the sensitivity. Individual ewes were defined as having entered neuroendocrine anestrus from the first date that the animal’s serum LH concentration fell below 1 ng/ml for two consecutive samples. For analysis of LH pulse frequencies, a pulse of LH was defined as any increase in concentration in which: 1) concentrations were elevated relative to pre- and postnadirs for at least two consecutive samples, 2) the pulse peaked within two 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 (31). Pulse frequency (peaks/4 h) and mean LH concentration over the 4-h sampling period were calculated for each ewe. Significant differences between numbers of ewes entering neuroendocrine anestrus were identified by a 
2 test for differences between proportions, and LH pulse frequency data were analyzed using Friedman’s two-way ANOVA. All other significant effects of the treatments were identified using ANOVA, with repeated measures when appropriate. Where post hoc comparisons were required, a t test was used. Mean results ± SEM are presented.
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Results |
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); there were no differences in CSF T4 concentrations among untreated THX ewes and THX ewes given site-specific microimplants.
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. In all 10 thyroid-intact, all four sc-injected, five of seven icv-treated, and two of six vmPOA-treated ewes, LH concentrations declined to less than 1 ng/ml (i.e. neuroendocrine anestrus) in early March (Fig. 1, A, B, and F). In all other ewes, LH concentrations remained elevated at breeding season levels through the end of the experiment (Fig. 1, B–F). Based on post mortem histology, all implants were placed within 1–3 mm of the base of the brain (Fig. 2), and all but one pair (Fig. 2K) were bilateral. For vmPOA-treated ewes, the microimplant placements varied 2–3 mm in the anteroposterior (AP) plane, from the diagonal band of Broca to the caudal extent of the organum vasculosum lamina terminalis (OVLT). The two vmPOA-treated ewes that entered neuroendocrine anestrus (Fig. 2D) had more caudally placed implants than all other ewes in this group (Fig. 2, A–C). Microimplants in the mPOA spanned a 1- to 2-mm range in the AP plane, centered on the decussation of the anterior commissure (Fig. 2, E and F). A15 microimplants ranged 1–2 mm in the AP plane; these microimplants were placed just medial to the optic tracts in the anterior hypothalamic area (Fig. 2, G and H). MBH microimplants spanned a 2-mm range in the AP plane. MBH microimplants were placed just lateral to or within the arcuate nucleus (Fig. 2, J and K) or slightly rostral to this nucleus (Fig. 2I). Results were identical for all mPOA-, A15-, and MBH-treated ewes; there was no effect of microimplant placement. Postmortem histological verification of implant placement was not performed for icv-treated ewes.
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Experiment 2: reproductive neuroendocrine activity and microimplant placement
Postmortem histology showed that all implants were bilateral and, with the exception of two pairs of misplaced vmPOA microimplants, within 1–2 mm of the base of the brain (Fig. 3). The microimplant placements in vmPOA-treated ewes tended to be more caudal than in experiment 1, spanning a 1- to 2-mm AP range within the POA (Fig. 3, A and B). Two misplaced vmPOA-treated ewes had microimplants located within the optic chiasm (Fig. 3, A and B); neither of these ewes entered neuroendocrine anestrus (see below). PMR microimplants spanned a 1- to 2-mm AP range. These microimplants were placed close to or within the posterior portion of the arcuate nucleus (Fig. 3C) or slightly caudal to it (Fig. 3D) in the PMR of the hypothalamus.
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). The mean dates of neuroendocrine anestrus onset were February 4 ± 10 d and January 30 ± 11 d, respectively. LH concentrations in the two ewes with misplaced microimplants remained elevated similar to those in untreated THX animals (Fig. 4A). In the other eight animals, there was no effect of microimplant placement.
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). All groups exhibited LH pulse frequencies of three to four pulses/4 h in the absence of E2 (Fig. 5B) with no significant differences among groups. In contrast, there were marked differences among groups in response to 1 wk of E2 treatment. In the thyroid-intact, PMR-, and vmPOA-treated ewes with accurate placements, pulse frequencies decreased dramatically to less than one pulse/4 h, whereas in the THX controls and vmPOA ewes with microimplants in the optic chiasm, frequencies remained elevated and were not significantly inhibited by E2 (Fig 5B).
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. Peak radioactivity declined rapidly to less than 0.3% within 1.2 mm either side of the microimplantation site, so that 98% of the total radioactivity in the hypothalamus (equating to about 0.1 mg T4) was within this region (Fig. 6). Nevertheless, radioactivity was detectable throughout the hypothalamus (Fig. 6) and in the CSF (560 cpm/ml), but these levels were very low, compared with those within 1 mm of the microimplant.
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Discussion |
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The assumption that the T4 microimplants acted locally is supported by three observations. First, the results of experiment 3 showed that the spread of thyroid hormone from the site of microimplantation was mostly within a radius of 1.2 mm. Although a relatively constant background level of radioactivity was clearly detectable beyond this distance throughout the whole hypothalamus, the level was less than 0.3% of that adjacent to the microimplant. It is likely that much of this background radiation was from free iodine released in the process of intracellular deiodination of T4 and other iodothyronine (33). Second, microimplants were ineffective at sites in close proximity to effective sites. This was particularly evident with microimplants in the rostral and medial POA (Fig. 2, A–C and E and F; compare with effective placements in Fig. 2D) as well as in the MBH (Fig. 2, J and K) in which ineffective placements were in close proximity to effective PMR placements (Fig. 3C). Thus, the biologically effective volume of distribution from these microimplants appears to be quite circumscribed. Third, the fact that the CSF T4 concentration in all microimplanted ewes was indistinguishable from those in THX untreated ewes indicates that the amount of T4 released was low and/or limited in the extent of its diffusion. The dose delivered by the microimplants, although sufficient to induce neuroendocrine anestrus when administered to the appropriate sites, was therefore probably considerably lower than the 4 µg/d icv infusion reported by Viguié et al. (21), which elevated cisterna magna CSF T4 concentrations to euthyroid levels. Interestingly in that study, the infused T4 did not appear to reach the pituitary gland in sufficient quantity to affect TSH secretion, providing further evidence that the dose was not overtly pharmacological.
The existence of normal seasonal prolactin and melatonin patterns in THX ewes (12, 17, 18, 34) indicates that neuroendocrine perception of photoperiodic changes can occur without thyroid hormones; it is specifically the reproductive neuroendocrine response that is altered by thyroidectomy. Thyroid hormones therefore appear to be required for transduction of the melatonin signal before the level of the GnRH neurosecretory system. The observation that thyroid hormones act in the PMR is particularly interesting because this region has been implicated in processing information encoded by melatonin secretory profiles needed for the control of seasonal reproduction. First, Malpaux et al. (27) have identified the PMR as a site of 125I-melatonin binding and demonstrated that melatonin acts in this area to induce the transition to the breeding season (27) and inhibit nighttime Fos expression (35). Second, Lincoln and Maeda (36) and Lincoln (37) have demonstrated similar effects of melatonin microimplants placed in the posterior hypothalamus of Soay rams and, more recently, reported that PMR lesions advanced testicular growth and delayed testicular regression in rams exposed to constant photoperiods (38).
In light of this role of the PMR, one possible interpretation of the requirement for thyroid hormones in this area to permit the transition to anestrus is that PMR cells require thyroid hormones to respond to a long-day melatonin pattern. For example, during the nonbreeding season, projections from PMR cells may activate (or allow steroidogenic activation of) inhibitory neuronal systems (such as dopaminergic A15 neurons) that act on the GnRH pulse generator, suppressing reproductive neuroendocrine activity. A short-day melatonin pattern (or PMR ablation in experimental situations) inhibits the activity of these PMR neurons allowing reproductive activity to begin, although a long-day melatonin pattern does the reverse. According to this model, thyroidectomy would prevent the latter action of melatonin and thus onset of anestrus. The reproductive axis of the THX ewe is clearly unable to respond to long-day patterns of melatonin (34), and there is preliminary evidence that thyroidectomy blocks the inhibitory action of melatonin on Fos expression in the PMR (28). In this regard, it is of interest to note that thyroid hormones have been shown to be able to modify the gene expression of the putative melatonin receptor, retinoic acid-related orphan receptor (10, 39, 40).
One important limitation to this argument is that it is clear from experiments involving pinealectomy (e.g.41, 42) or constant short photoperiods (e.g.5, 6) that the transition to anestrus can occur in ewes without the appropriate melatonin signal; the endogenous circannual rhythm still cues the transition at approximately the correct time of year. Although under normal conditions the information provided by the endogenous rhythm is used to determine the appropriate reproductive state, this information can clearly be overridden by a contradictory melatonin pattern (e.g. alternating 16-wk periods of long and short days create a 32-wk reproductive cycle in rams) (43). It may be that the PMR acts as a hub through which the endogenous rhythm and information encoded by melatonin secretory profiles are integrated and thyroid hormones are required for the processing of both sources of information in terms of the onset of GnRH inhibition. Recent evidence that thyroidectomy may alter the endogenous circannual rhythm in reproduction (29) supports this possibility. It is also interesting to consider that, because seasonal prolactin oscillations are not disrupted by thyroidectomy in ewes (12, 34), the PMR may require thyroid hormones to respond to melatonin, whereas the pars tuberalis (the site of melatonin signaling for the prolactin rhythm) (44) does not.
Our evidence supporting the vmPOA as another site of T4 action is limited by the apparent inconsistency of the effects of T4 in vmPOA-microimplanted ewes. However, those ewes in which no decrease in LH levels was observed either had the most rostrally placed microimplants (experiment 1, see Fig. 2, A–C) or were misplaced in the optic chiasm (experiment 2, see Fig. 3, A and B). The effective microimplants from both experiments were all similarly placed in the more caudal aspect of the vmPOA, indicating that this may be an important site of thyroid hormone action. E2 receptors clustered in this area participate in steroid negative feedback during anestrus but not during the breeding season (22, 23), and their expression also increases slightly in number during anestrus (22, 45). Furthermore, the negative feedback pathway they employ appears to involve dopamine neurons (23). These data and retrograde tract tracing experiments (46) led to the following model for E2 negative feedback in anestrus: E2 stimulates these E2-receptor-containing cells in the vmPOA that project to and stimulate the A15 dopaminergic neurons inhibiting GnRH secretion (23). E2 receptors located in the POA caudal of the OVLT do not appear to participate in this system (22), a finding consistent with the inability of T4 microimplants in the mPOA to bring about neuroendocrine anestrus in the current study.
We do not yet know the phenotype of the E2 receptor-containing neurons in this system or the neurons acted on by the T4 or even if they are the same cells. The latter possibility is supported by a recent report that 90% of progesterone receptor-immunoreactive cells in the POA also contain -thyroid hormone receptors (47). In addressing this issue, it would be most informative to determine whether the downstream components of the vmPOA E2-receptive system (e.g. the activity of the A15 neurons) are modified by thyroidectomy, as would be predicted from a vmPOA site of T4 action and whether this is reversed by vmPOA T4 microimplants. Interestingly, there is evidence that the response to some E2 receptor-mediated mechanisms can be modified by interplay with thyroid hormone signaling (e.g. Refs. 48 and 49). Indeed, estrogen and T3 receptors are part of a subfamily that share similar DNA-binding domains and target hormone response elements, enabling them to compete for binding and, in some cases, block each other’s transcriptional effects (50, 51, 52). For example, thyroid hormones have been shown to modify the control of E2 receptor mRNA levels by E2 in the brain of the female rat (53); this is of potential interest, given the seasonal changes in vmPOA E2 receptor numbers observed in ewes (22, 45).
It is thus conceivable that the role played by thyroid hormones in the PMR and vmPOA might be to facilitate seasonal changes in melatonin and estrogen receptor function. Thyroid hormones may also be necessary for a process of synaptic reorganization that facilitates seasonal suppression of GnRH secretion by inhibitory neurons, such as the A15 dopaminergic system. Such a role would not be surprising, given that euthyroidism is vital to normal neonatal brain development (10) and peripheral nerve regeneration (54); processes that may be analogous to the anatomical changes underpinning the development of the seasonally anestrous state.
It was somewhat surprising that T4 microimplants in the RCh were ineffective because this area contains both A15 perikarya and E2-receptive cells that participate in E2-negative feedback during anestrus (24, 55). The lack of effect of thyroid hormones in this area suggests that the functional and structural changes in A15 cells (9) and functional changes in the local E2-responsive neurons (24) may be driven by afferents from the vmPOA or PMR.
An even more perplexing question arising from these results is why do thyroid hormones appear to be needed in either the PMR or vmPOA but not both regions? This question cannot be answered by possible diffusion of hormone between sites because of the distance involved and the fact that the centrally placed mPOA, A15, and MBH microimplants did not bring about neuroendocrine anestrus. This may be another example of the redundancy that seems to be common in the hypothalamo-hypophyseal-ovarian axis (e.g.56). Again we cannot answer this question at the current time, but the issue could potentially be further studied by microimplantation of either or both sites in thyroid-intact ewes with a compound that blocks T4 deiodination and hence its cellular action (33).
In conclusion, T4 microimplants placed in the mPOA, A15 region, or MBH were not able to reverse the effects of thyroidectomy on seasonal reproductive changes at the end of the breeding season. In contrast, microimplants in the PMR and vmPOA permitted the onset of anestrus so that these are likely to be important sites at which thyroid hormones act. The functional changes that occur in the PMR and vmPOA leading to anestrus and the role of thyroid hormones in these changes warrant closer examination.
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Acknowledgments |
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Footnotes |
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Present address for H.J.B.: Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati, Cincinnati, Ohio 45267.
This work was supported by NIH Grant HD-17864. Preliminary reports have appeared in Society for Neuroscience Abstracts 27 (Abstract 631.14) and Neuroendo 2000 (satellite meeting of the 11th International Congress of Endocrinology, Poster 10).
Abbreviations: AP, Anteroposterior; CSF, cerebrospinal fluid; CV, coefficient of variation; E2, estradiol; MBH, medial basal hypothalamus; mPOA, medial preoptic area; OVLT, organum vasculosum lamina terminalis; OVX, ovariectomized; PMR, premammillary region; RCh, retrochiasmatic area; THX, thyroidectomized; vmPOA, ventromedial preoptic area.
Received March 13, 2003.
Accepted for publication March 28, 2003.
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-containing neurons in the preoptic area of the ewe depends on reproductive status. Endocrinology 141:190–196, but not ß, mediates seasonal changes in the response of the ovine retrochiasmatic area to estradiol. Biol Reprod 68:846–852) distribution in hamster and sheep brain: colocalization in gonadotropin-releasing hormone and other identified neurons. Endocrinology 138:5039–5047 gene expression in the perinatal rat cerebellum: ontogeny and thyroid hormone regulation. Endocrinology 139:2335–2341)-containing afferents to the hypothalamic A15 region of the ewe. Program of the 29th Annual Meeting of the Society for Neuroscience, Miami Beach, FL, p 1452 (Abstract)
in the ovine diencephalon: no effect of estradiol. Neuroendocrinology 77:51–58[CrossRef][Medline]
, cholecystokinin, and preproenkephalin messenger ribonucleic acid in the limbic-hypothalamic circuit. Endocrinology 139:1221–1228This article has been cited by other articles:
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  P. Barrett, F. J. P. Ebling, S. Schuhler, D. Wilson, A. W. Ross, A. Warner, P. Jethwa, A. Boelen, T. J. Visser, D. M. Ozanne, et al. Hypothalamic Thyroid Hormone Catabolism Acts as a Gatekeeper for the Seasonal Control of Body Weight and Reproduction Endocrinology, August 1, 2007; 148(8): 3608 - 3617. [Abstract] [Full Text] [PDF]
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 C. J McManus, M. Valent, S. L Hardy, and R. L Goodman Does nitric oxide act in the ventromedial preoptic area to mediate oestrogen negative feedback in the seasonally anoestrous ewe? Reproduction, July 1, 2007; 134(1): 137 - 145. [Abstract] [Full Text] [PDF]
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V. L. Adams, R. L. Goodman, A. K. Salm, L. M. Coolen, F. J. Karsch, and M. N. Lehman Morphological Plasticity in the Neural Circuitry Responsible for Seasonal Breeding in the Ewe Endocrinology, October 1, 2006; 147(10): 4843 - 4851. [Abstract] [Full Text] [PDF]
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S. Yasuo, N. Nakao, S. Ohkura, M. Iigo, S. Hagiwara, A. Goto, H. Ando, T. Yamamura, M. Watanabe, T. Watanabe, et al. Long-Day Suppressed Expression of Type 2 Deiodinase Gene in the Mediobasal Hypothalamus of the Saanen Goat, a Short-Day Breeder: Implication for Seasonal Window of Thyroid Hormone Action on Reproductive Neuroendocrine Axis Endocrinology, January 1, 2006; 147(1): 432 - 440. [Abstract] [Full Text] [PDF]
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R. L. Goodman, L. M. Coolen, G. M. Anderson, S. L. Hardy, M. Valent, J. M. Connors, M. E. Fitzgerald, and M. N. Lehman Evidence That Dynorphin Plays a Major Role in Mediating Progesterone Negative Feedback on Gonadotropin-Releasing Hormone Neurons in Sheep Endocrinology, June 1, 2004; 145(6): 2959 - 2967. [Abstract] [Full Text] [PDF]
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 J. H. Sliwowska, H. J. Billings, R. L. Goodman, L. M. Coolen, and M. N. Lehman The Premammillary Hypothalamic Area of the Ewe: Anatomical Characterization of a Melatonin Target Area Mediating Seasonal Reproduction Biol Reprod, June 1, 2004; 70(6): 1768 - 1775. [Abstract] [Full Text] [PDF]
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M. Watanabe, S. Yasuo, T. Watanabe, T. Yamamura, N. Nakao, S. Ebihara, and T. Yoshimura Photoperiodic Regulation of Type 2 Deiodinase Gene in Djungarian Hamster: Possible Homologies between Avian and Mammalian Photoperiodic Regulation of Reproduction Endocrinology, April 1, 2004; 145(4): 1546 - 1549. [Abstract] [Full Text] [PDF]
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, effect of E2 implantation (P < 0.05).