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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1388-1393
Copyright © 2000 by The Endocrine Society

Original Studies

Effects of Variations in Physiological Cortisol Levels on Thyrotropin Secretion in Subjects with Adrenal Insufficiency: A Clinical Research Center Study1

M. H. Samuels

Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health Sciences University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Dr. M. H. Samuels, Division of Endocrinology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, seven subjects with primary adrenal insufficiency each underwent four studies. In the first study subjects received infusions of saline for 48 h (baseline study). In the second study subjects received infusions of hydrocortisone for 48 h in a pulsatile and diurnal pattern that replicated serum cortisol levels in healthy subjects (physiological study). In most cases, the dose of hydrocortisone was 19 mg/24 h, but this was adjusted as necessary until the resulting serum cortisol levels reproduced those seen in healthy, nonstressed control subjects. In the third study subjects received the same total dose of hydrocortisone as in the physiological study, but with pulses of equal magnitude spaced evenly throughout the time period (constant study). In the fourth study subjects received the same total dose of hydrocortisone, but with the diurnal pattern shifted 12 h from the physiological infusion (reversed study). TSH levels were measured every 15 min during the final 24 h of each study. During the baseline study, the 24-h mean TSH level was 2.87 ± 0.56 mU/L and did not exhibit any diurnal variation. During the physiological study, daytime TSH levels decreased 39% compared to those during the baseline study due to decreased TSH pulse amplitude, and the normal TSH diurnal rhythm was reestablished. The constant and reversed studies did not lead to significant changes in serum TSH levels compared to baseline. These results suggest that the normal circadian variation in endogenous cortisol levels may control TSH secretion, with maximal TSH suppression seen during the time when cortisol levels are highest. However, changing the diurnal pattern of hydrocortisone infusion did not lead to reciprocal changes in TSH levels, and the specific nature of the interactions between cortisol and TSH within the physiological range remains to be fully elucidated.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SUPRAPHYSIOLOGICAL doses of glucocorticoids or elevated endogenous cortisol levels suppress serum TSH levels in humans (1, 2, 3, 4), but the effects of physiological cortisol levels on TSH secretion are less clear. Data from several sources suggest that cortisol levels within the physiological range control TSH secretion. 1) Cortisol and TSH levels follow diurnal rhythms, which are out of phase, such that peak TSH levels occur when cortisol levels are lowest (5). 2) Patients with Addison’s disease may have higher TSH levels when glucocorticoids are withheld than when receiving glucocorticoids (6, 7, 8, 9, 10, 11, 12). 3) Healthy subjects given metyrapone to block cortisol synthesis have TSH levels that are higher than baseline levels (13). 4) Hangaard et al. recently varied hydrocortisone infusion rates in patients with Addison’s disease and showed that TSH levels were higher during low cortisol states (14, 15). Taken together, these data suggest that cortisol exerts an inhibitory influence on serum TSH levels.

We designed a hydrocortisone replacement protocol in Addison’s disease subjects that allowed us to precisely manipulate serum cortisol levels within the physiological range without the confounding effects of endogenous cortisol secretion. We performed frequent measurements of serum cortisol and TSH levels over 24 h under four experimental conditions in these subjects: while receiving no hydrocortisone, while receiving hydrocortisone infusions that replicated normal cortisol pulses and diurnal variation, while receiving the same hydrocortisone dose as pulses of equal magnitude spaced equally apart, and while receiving the same hydrocortisone dose with the diurnal rhythm reversed. This paradigm allowed us to vary cortisol levels during the 24-h period within the range seen in healthy subjects while maintaining a constant amount of total cortisol exposure. Measurements of serum cortisol and TSH during these infusions allowed us to validate the hydrocortisone infusion protocol and to examine the effects of minimal changes in cortisol levels on pulsatile and circadian TSH secretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Seven subjects with primary adrenal insufficiency were recruited (Table 1Go), three women and four men (age range, 29–67 yr). All subjects had had Addison’s disease for at least 1 yr before the study, and all were receiving glucocorticoids at the equivalent of 30–40 mg hydrocortisone daily in divided doses. All subjects were also receiving fludrocortisone. Addison’s disease was originally suspected in these subjects based on typical symptoms and signs of adrenal insufficiency (some of the subjects also had autoimmune hypothyroidism and/or primary gonadal failure). Standard Cosyntropin (ACTH) stimulation testing revealed low basal cortisol levels, elevated basal ACTH levels, and failure of cortisol to respond to cosyntropin. The diagnosis was confirmed by measurement of serum cortisol levels over 24 h during the baseline study, during which no hydrocortisone was given for 48 h. In each case, cortisol levels were near or below the assay detection limits, confirming a lack of endogenous cortisol production.


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  		Table 1. Clinical characteristics of the seven subjects

 
Coexisting conditions in the subjects are listed in Table 1Go. We hoped we would be able to recruit volunteers without thyroid disease, but this proved difficult. Therefore, one subject had primary hypothyroidism, and one had subclinical hypothyroidism. These two subjects received LT4 at 0700 h on each day of the studies. Both had normal TSH levels on stable doses of LT4, and data have shown that such subjects have normal 24-h serum TSH patterns (16). When these two subjects’ data were analyzed separately, no differences were seen compared to data from the other subjects (data not shown). Two subjects had premature ovarian failure and were receiving stable doses of conjugated estrogens and progestins. They were studied during the same phase of sex steroid replacement for each study. The third woman had normal menstrual cycles, but was not studied at a specific time during her cycles. One subject had depression and was receiving desipramine. The same subject had pernicious anemia and was receiving monthly B12 injections. One subject had mild seasonal asthma, but was not receiving chronic therapy. All of the medical conditions were stable during the study, all of the medications were given in typical doses, and there were no changes in any dose during the study.

Experimental design

Each subject underwent four studies at the Oregon Health Sciences University (OHSU) General Clinical Research Center (GCRC), performed at least 1 month apart. Subjects discontinued oral glucocorticoid medications 12 h before each admission and continued other medications. During each study, subjects remained at the GCRC for 48 h. One of the infusions described below was given for the first 24 h and was repeated for the second 24 h to wash out the effects of the subject’s oral glucocorticoid medication. During the second 24-h period (0800–0800 h), while the infusion was repeated, blood samples were withdrawn from a separate iv catheter every 15 min. The hydrocortisone infusion patterns described below are shown in Fig. 1Go. These studies were approved by the OHSU institutional review board, and informed consent was obtained from each subject before the study. In the baseline study, subjects received iv normal saline, but no glucocorticoids. In the physiological study, subjects received a hydrocortisone infusion designed to normalize 24-h serum cortisol levels, pulses, and diurnal variation. The infusion pattern was supplied by Dr. Joanna Zawadski (NIH), who empirically developed the protocol based on the normal pattern of cortisol pulses in healthy subjects, and who performed initial testing in subjects with Addison’s disease to confirm that the infusion led to normal 24-h serum cortisol profiles (17). The total amount of hydrocortisone infused over 24 h was 19 mg.



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  		Figure 1. Top, Hydrocortisone infusion rate (cubic centimeters per h; concentration of hydrocortisone, 25 mg/L) that reproduced normal serum cortisol levels in subjects with adrenal insufficiency (physiological study). Middle, Hydrocortisone infusion rate in the constant study. Bottom, Hydrocortisone infusion rate in the reversed study. The total hydrocortisone dose over 24 h during each study was 19 mg. Each infusion pattern was repeated during the second 24 h of the study.

 
After a subject received this infusion, the resulting 24-h serum cortisol levels were compared visually to those obtained in healthy subjects. In five subjects, serum cortisol levels were in the normal range, and this dose was used for subsequent studies, as described below. Two subjects had low cortisol levels with the initial infusion, and they underwent a second study with a doubled dose of hydrocortisone. Serum cortisol levels from the second infusion were in the normal range, and this higher dose was used for subsequent studies in the two subjects. These two subjects were the heaviest of the group, whereas the clearance of administered hydrocortisone was no different in the two subjects compared to that in the other subjects (data not shown). Thus, five subjects received 19 mg hydrocortisone/24 h, and two subjects received 38 mg/24 h.

In the constant study, subjects received hydrocortisone in the same total dose and number of pulses as in the physiological study, but with pulses of equal amplitude spaced evenly apart over 24 h. In the reversed study subjects received hydrocortisone in the same dose and number of pulses as in the physiological study, but with the diurnal rhythm reversed (shifted 12 h).

The infusions were given in random order, except that the physiological infusion always preceded the constant and reversed infusions to be able to calculate the correct hydrocortisone dose. At the end of each 2-day study (0800 h), a standard TRH stimulation test was performed, with the administration of 250 µg TRH as an iv bolus, and blood sampling 20, 30, and 60 min after TRH administration.

Laboratory methods

All samples were analyzed for cortisol and TSH levels by two-site chemiluminescent assays (Nichols Institute Diagnostics, San Juan Capistrano, CA). Coefficients of variation were 3–5% (intraassay) and 6–10% (interassay) at the serum hormone levels measured in the subjects. The assay sensitivity was 0.8 µg/dL for cortisol and 0.02 mU/L for TSH. Free T4 levels were measured every 4 h by equilibrium dialysis (Nichols Institute Diagnostics), and total T3 levels were measured every 4 h by in-house RIA. All samples from an individual were run in duplicate, and all samples from a single study were run in the same assay.

TSH pulses were located by Cluster analysis, using dose-dependent coefficients of variation calculated from sample replicates in each subject’s hormone series. Cluster parameters were two points for test nadirs and one point for test peaks. The t statistics were 2.0 for up-strokes and down-strokes. These parameters yield false positive and negative peak detection rates of less than 5%, determined by analysis of pooled serum samples and simulated hormone series (18).

Repeated measures ANOVA with Bonferroni’s t test were used to compare the following results: 1) daytime (0800–1945 h), nocturnal (2000–0745 h), and 24-h mean TSH levels and TSH pulse parameters; 2) mean serum cortisol levels over 24 h and divided into 6-h time blocks (0800–1345, 1400–1945, 2000–0145, and 0200–0745 h); and 3) mean serum free T4 and total T3 levels measured every 4 h over 24 h.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Validation of hydrocortisone infusion protocol

Figure 2Go shows mean serum cortisol levels measured every 15 min over 24 h during the second day of physiological hydrocortisone infusions in the seven subjects. For comparison purposes, mean serum cortisol levels measured every 15 min in 12 normal volunteers are also shown. As can be seen, this infusion protocol appropriately mimics normal serum cortisol levels, pulses, and circadian variation.



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  		Figure 2. Mean serum cortisol levels measured every 15 min over 24 h in the Addison’s subjects during the final 24 h of the physiological hydrocortisone infusion (solid line), compared to the range of serum cortisol levels measured over 24 h in 12 healthy subjects (dashed lines).

 
Serum cortisol levels during the four infusions

Figure 3Go and Table 2Go show mean cortisol levels measured every 15 min over 24 h during the second day of each of the infusions. Cortisol levels were almost undetectable during the baseline study, as expected. In each case, serum cortisol levels matched those expected from the experimental design, with daytime levels higher during the physiological infusion, and nocturnal levels higher during the reversed infusion. Mean 24-h serum cortisol levels did not differ among the three hydrocortisone infusions, but were higher than those during the baseline study and varied appropriately during the 24-h period. Table 2Go summarizes 24- and 6-h (0800–1345, 1400–1945, 2000–0145, and 0200–0745 h) mean cortisol levels during the four studies.



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  		Figure 3. Mean serum cortisol levels measured every 15 min over 24 h in the subjects during each of the four hydrocortisone infusion protocols. Solid line, Physiological infusion; dashed line, constant infusion; dotted line, reversed infusion; dashed and dotted line, baseline study (no hydrocortisone administered).

 

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  		Table 2. Mean serum cortisol levels during hydrocortisone infusions in patients with adrenal insufficiency

 
Serum TSH levels during the four infusions

Figure 4Go shows mean TSH levels measured every 15 min over 24 h during the second day of each of the infusions. For the sake of clarity, the baseline and physiological studies are shown in the top panel, and the constant and reversed studies are shown in the bottom panel.



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  		Figure 4. Mean serum TSH levels measured every 15 min over 24 h in the subjects during each of the four hydrocortisone infusion protocols. Top, Physiological infusion (solid line) and baseline study (dashed line). Bottom, Constant infusion (solid line) and reversed infusion (dashed line).

 
Daytime TSH levels were higher during saline infusions and decreased during physiological hydrocortisone infusions (Fig. 4Go, top). In contrast, at night while cortisol levels were low during both of these studies, TSH levels in the two studies were indistinguishable. Thus, the normal circadian variation in TSH levels was lost during hydrocortisone withdrawal, but was reestablished by the physiological hydrocortisone infusion.

The bottom panel of Fig. 4Go shows that, in contrast to the initial hypothesis, TSH levels during constant hydrocortisone infusions did not appear lower than baseline levels, and TSH levels during reversed hydrocortisone infusions did not appear to be the reverse of the physiological hydrocortisone infusions, but were lower during the day as well as at night.

Table 3Go summarizes the TSH results from the four studies. Twenty-four-hour mean TSH levels did not differ among the studies, but daytime levels were decreased 39% below the baseline study by physiological hydrocortisone infusions. The normal nocturnal surge in TSH was not present during the baseline study, but was reestablished by the physiological hydrocortisone infusion pattern due to the decrease in daytime TSH levels. None of the other hydrocortisone infusion patterns led to any diurnal variation in TSH levels. The physiological hydrocortisone infusion pattern decreased daytime TSH pulse amplitude by 38% without altering TSH pulse frequency. Serum TSH responses to TRH were not different among any of the studies.


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  		Table 3. Mean TSH levels and TSH pulse parameters during hydrocortisone infusions in patients with adrenal insufficiency

 
Thyroid hormone levels during the four infusions

Figure 5Go shows serum T3 and free T4 levels measured every 4 h during the infusions. There were no changes during any of the infusions and no differences among the four infusions.



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  		Figure 5. Mean serum T3 (top) and free T4 (bottom) levels measured every 4 h during each of the four infusions. There were no changes in levels during any of the infusions and no differences among the four infusions.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Many studies of TSH secretion in humans have shown that exogenous glucocorticoids suppress TSH secretion (3, 4, 19, 20), but most of these studies involved supraphysiological levels of glucocorticoids. In contrast, in the current study we precisely varied cortisol levels within the physiological range. This is conceptually similar to the paradigm employed by Hangaard et al. in their recent studies of pulsatile TSH secretion in patients with Addison’s disease (14, 15). Their studies used graduated doses of hydrocortisone given to mimic the normal diurnal rhythm of cortisol. Our study more closely approximated the normal physiology of cortisol dynamics by replicating the usual pulsatile nature as well as diurnal pattern of cortisol secretion. This allowed us to maintain the same total 24-h hydrocortisone dose while varying the circadian rhythm of cortisol. Finally, we measured TSH levels frequently over a full 24 h, which allowed us to examine the effects of the various hydrocortisone infusion protocols on pulsatile secretion of and circadian variation in TSH. Thus, our findings extend those of Hangaard et al. and others who have described reciprocal changes in serum cortisol and TSH levels.

Our main finding is that hydrocortisone withdrawal increases TSH levels during the day. Under these conditions, daytime and nocturnal TSH levels are indistinguishable, and there is no diurnal rhythm of TSH. Reestablishment of a physiological cortisol pattern leads to significant decreases in TSH levels during the day, when cortisol levels are highest. During this cortisol pattern, there is no change in TSH levels at night, when cortisol levels are low. This suggests that the early morning increase in endogenous cortisol levels in healthy subjects causes the normal circadian variation in TSH levels. It is intriguing to speculate that this fine-tuning of serum TSH levels within the normal range by physiological variation in cortisol levels is one way that cortisol affects intermediary metabolism and stress responses throughout the circadian time period. However, the biological relevance of this regulation has yet to be determined.

Our results also have clinical implications for the measurement of TSH levels in subjects with Addison’s disease, as mildly elevated TSH levels are possible if the patient has not taken his/her daily hydrocortisone dose. Based on these data, it is also likely that TSH levels may be affected by low doses of glucocorticoids taken by patients for rheumatic or other conditions.

We hypothesized that constant hydrocortisone infusions would lower TSH levels evenly over 24 h. However, TSH levels were not significantly lower during this infusion compared to baseline values. It is possible that a certain minimum cortisol level is necessary for TSH suppression. For example, the mean 0800–1345 h cortisol level during the physiological infusion was 11.8 µg/dL (during maximal TSH suppression), but was never higher than 8.9 µg/dL during constant infusions. This implies that there might be a precise threshold for TSH suppression at physiological levels of cortisol.

We also hypothesized that reversed hydrocortisone infusions would lead to higher TSH levels during the day and lower levels at night, reversing the physiological pattern. Instead, the reversed infusion lowered TSH levels throughout the 24-h period by 20% compared to baseline, although this was not statistically significant. This may be due to persistent effects of higher nocturnal cortisol levels from the previous night’s infusion at a time when cortisol levels are normally low, to changing sensitivity of the thyrotroph to cortisol during the 24-h period, or to effects of other factors that affect TSH secretion, such as somatostatin. It is also possible that cortisol can only exert a minor inhibitory effect on TSH during the night, when TRH levels are presumed to be highest. In that case, administering more cortisol at night, as in the reversed study, would not be able to overcome the increased TRH effect on TSH secretion.

TSH responses to TRH did not differ among the studies. This suggests that physiological cortisol levels act via the hypothalamus, rather than the pituitary, to suppress TSH secretion. This contrasts with studies in humans that report blunted TSH responses to TRH after supraphysiological doses of glucocorticoids (21, 22, 23). Animal and in vitro studies have shown that dexamethasone administration changes serum TRH levels, hypothalamic TRH content, and/or pro-TRH messenger ribonucleic acid levels (24, 25, 26, 27, 28). However, the described changes depend on the dose and time course of dexamethasone administration and cannot be applied to our experimental paradigm. Studies in primary rat pituitary cell cultures report conflicting results about whether glucocorticoids directly suppress TSH secretion (29, 30), using doses that are probably pharmacological. Finally, the TRH tests were administered at 0800 h, 1 h after two subjects had received exogenous L-T4 for primary hypothyroidism. It is possible that this affected the TRH tests, although the results for these subjects did not differ from those of the other five subjects.

A number of hypothalamic factors besides TRH control TSH secretion, including somatostatin, dopamine, and opioids. From our data, it is impossible to ascertain whether cortisol affects TSH secretion by acting directly on TRH at the hypothalamus or whether any of these other factors is involved. For example, it is possible that cortisol increases somatostatin or opioid levels in the hypothalamus, which, in turn, would decrease TSH secretion (30, 31, 32).

T3 and free T4 levels were no different among the studies. This is not surprising, given the short time course and low doses of hydrocortisone administered. In contrast, higher doses of glucocorticoids and longer periods of administration lower serum thyroid hormone levels (3, 33, 34). Some of this effect may be via suppression of TSH secretion, although changes in peripheral metabolism of thyroid hormone levels may also occur with glucocorticoid administration (33). In addition, two of the subjects received replacement doses of L-T4 during the studies, which may have precluded changes in serum thyroid hormone levels.

In summary, we administered a hydrocortisone infusion protocol designed to precisely mimic the normal secretion of cortisol to subjects with adrenal insufficiency and measured resulting changes in serum TSH levels. We found that this protocol significantly reduced daytime serum TSH levels and reestablished the normal circadian rhythm of TSH. This suggests that the normal endogenous diurnal rhythm of cortisol controls the 24-h TSH rhythm. However, changing the diurnal pattern of hydrocortisone infusion did not lead to the expected reciprocal changes in TSH levels, and the specific nature of the interactions between cortisol and TSH within the physiological range remains to be fully elucidated.


   Acknowledgments
 
I thank the OHSU General Clinical Research Center staff for excellent patient care, sample collection, and assay performance.


   Footnotes
 
1 This work was supported by NIH Grant R29-DK-48366, and the OHSU General Clinical Research Center (NIH GCRC Grant M01-RR-00334). Back

Received June 7, 1999.

Revised November 24, 1999.

Accepted December 29, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals