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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1593
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6490-6497
Copyright © 2005 by The Endocrine Society

Circadian and Stimulated Thyrotropin Secretion in Cranially Irradiated Adult Cancer Survivors

Ken H. Darzy and Stephen M. Shalet

Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: It has been claimed that with the use of the TRH test and knowledge of the nocturnal TSH surge, the diagnosis of so-called hidden central hypothyroidism might be uncovered in a substantial proportion of euthyroid cranially irradiated children.

Study Subjects: We conducted 24-h TSH profiles and TRH tests in 37 euthyroid adult cancer survivors 2–29 yr (median, 11.5) after irradiation (18–64 Gy) and in 33 matched normal controls.

Results: Basal and stimulated TSH levels (during the TRH test) were significantly (P < 0.05) higher in the patients who had received craniospinal irradiation, more so in those with severe GH deficiency. Six patients (16%) had a hypothalamic TSH response to TRH. The maximum TSH surge calculated from the highest peak (average of the highest three sequential samples) and the smallest nadir (average of the smallest three sequential samples) in the whole 24-h profile period was above the cutoff value of 50% in all except one control subject and two patients. However, the nocturnal TSH surge was greatly reduced or absent in eight normal subjects (24%) and six patients (16%), not due to a genuine loss of diurnal rhythm, but simply to a shift in the timing of the peak TSH and/or the nadir TSH to outside the recommended sampling times (for the nocturnal surge) of 2200–0400 and 1400–1800 h, respectively; thereby potentially leading to an erroneous diagnosis of hidden central hypothyroidism. Overall, the maximum TSH surge was significantly (P = 0.01) reduced only in the GH-deficient patients (100.7 ± 11%) compared with normal subjects (154.9 ± 18.2%). Free T4 levels did not correlate with TSH surge results.

Conclusions: The normality of free T4 levels and the wide discrepancy between the high rate of these TSH abnormalities and the very low rate of overt secondary hypothyroidism (3–6%) after prolonged periods of postirradiation follow-up strongly suggest that in the vast majority of patients, these abnormalities in TSH dynamics represent subtle functional disturbances in the hypothalamic-pituitary axis rather than genuine pathology that may progress with time. We suggest that in this context, use of the term hidden central hypothyroidism is inappropriate, because these subtle changes may not have any clinical significance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF radiation-induced central hypothyroidism remains low (3–6%) after conventional radiotherapy (30–45 Gy) for nonpituitary brain tumors (1, 2) and virtually unreported after prophylactic cranial irradiation (18–24 Gy) or total body irradiation (3, 4, 5, 6, 7, 8, 9). In contrast, the prevalence increases dramatically in those irradiated for pituitary tumors (10) and after more intensive irradiation schedules (11, 12).

Most patients with overt central hypothyroidism (subnormal free T4 level with inappropriately low/normal TSH concentration) have a diminished nocturnal TSH surge (13) and/or an abnormal TSH response to TRH stimulation (14). Consequently, it has been claimed that the use of these TSH dynamics tests may uncover the diagnosis of so-called hidden central hypothyroidism in a substantial proportion of the irradiated cancer survivors who would otherwise have been considered euthyroid based on normal TSH and free T4 levels (15). Rose et al. (15) suggested that the absence of the nocturnal TSH surge diagnosed cases missed by the TRH test and that both tests are required to maximize sensitivity. It was also claimed that hypothalamic-pituitary (h-p) axis irradiation can affect TSH secretion even before the development of abnormalities in GH secretion (15), a view contrary to the generally accepted belief that the GH axis is the most radiosensitive, and that radiation-induced GH deficiency often evolves in isolation (1, 16). However, careful scrutiny of the study design and analytical methods used raises concerns about the strength of these conclusions.

Thus, this study was particularly designed to examine the utility of the TSH surge test and the possible existence of hidden central hypothyroidism in adult cancer survivors. Matched healthy normal controls were included in this study to demonstrate normal variations in TSH secretion, which are critically important if erroneous conclusions about the TSH status in the irradiated patients are to be avoided.


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

Patients (n = 37) in this study were part of a larger cohort whose clinical details were described in a previous study (17). All had a history of whole brain irradiation and/or focal irradiation (18–64 Gy), which included the h-p axis, for leukemia or a brain tumor anatomically distinct from the h-p region and had been shown to be free from tumor recurrence or any other medical condition that might influence their h-p function. Twenty-seven patients had also received spinal irradiation (Table 1Go). The biological effective dose of radiation (BED) to the h-p axis was calculated (median, 58.3; range, 23–106.4 Gy) for comparative purposes, as described previously (17).


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  		TABLE 1. Clinical characteristics

 
All patients (except two with TSH values of 4.7 and 4.8 mU/liter) had free T4 and TSH levels in the normal range for our laboratory (9–26 pmol/liter and 0.35–3.5 mU/liter, respectively), and none was receiving T4.

Of the 37 patients, 28 (seven women and 21 men) had received their cranial irradiation during childhood, at an age of 1.3–14 yr (median, 7.5 yr). The remaining nine (four women and five men) were irradiated at the age of 17–49 yr (median, 26.8 yr). Patients were studied 2–29 yr (median, 11.5 yr) after irradiation.

Among the 37 patients, eight men had sustained variable degrees of testicular damage, evidenced by elevated gonadotropin levels, attributed to chemotherapy and/or testicular irradiation, of whom five had normal circulating testosterone levels. The other three were receiving testosterone replacement. Twenty-one patients had severe or partial GH deficiency, and none had ACTH or gonadotropin deficiency (Table 1Go).

An age-, gender-, and body mass index-matched healthy control group was studied for comparative purposes (Table 2Go). They all had normal endocrine parameters, as described previously (17, 18).


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  		TABLE 2. Comparisons between TSH and T4 data of normal controls and all patients

 
Study procedures

The study was approved by the south Manchester local research ethics committee, and informed consent was obtained from all subjects before testing.

The TRH test involved the iv administration of TRH (Protirelin, 200 µg, Cambridge Laboratories, Newcastle upon Tyne, UK) at 0 min. Blood samples for TSH estimation were taken at 0, 20, and 60 min.

Twenty-four-hour profiling was performed as described previously (18). Blood sampling at 20-min intervals was carried out between 0900 and 0840 h next morning. Three standard hospital meals were provided at 0830, 1230, and 1800 h, and physical activity was restricted to within the ward. Sera were separated and immediately frozen at –80 C. TSH estimation was performed on the 24 hourly samples.

The GH status of all subjects had previously been determined using well-defined diagnostic thresholds (17). GH deficiency is defined by markedly subnormal responses to both the insulin tolerance test and the combined GHRH plus arginine stimulation test (peak GH response, <3 and <9 µg/liter, respectively), whereas normal GH status is defined by peak GH responses above 5 and 16.5 µg/liter, respectively. GH insufficiency is defined by peak GH responses in between these thresholds (17). The final definition of GH status in a few patients with discordant peak GH responses was determined by the results of the 24-h physiological GH profile (18).

Free T4 measurements

Free T4 was estimated at 1200, 1800, 2400, and 0600 h. Little variability (<10%) was found among the four values, and the mean value was used in the analysis.

Analysis of TRH test

Absolute TSH responses to the TRH test (TSH20 min – TSH0 min) were noted as well as relative responses (fold responses), expressed as the ratio of the stimulated to basal TSH (TSH20 min/TSH0 min). The rate of TSH decline between 20 and 60 min [(TSH20 min – TSH60 min) x 100/TSH20 min] was noted.

Diurnal variation: TSH surge test and cosinor analysis

The maximum TSH surge is defined as the percent increase in the highest TSH peak (the average of the highest three sequential samples) in the 24-h period above the lowest nadir level (the average of the lowest three sequential samples) in the same period. It is calculated as follows: TSH surge = (peak TSH – nadir TSH) x 100/nadir TSH.

Based on the assumption that TSH secretion reaches its peak level in the night (2200–0400 h) and its nadir levels in the afternoon (1400–1800 h) in most individuals and in concert with previous literature (15), we also calculated the nocturnal TSH surge (using the peak and nadir TSH levels in these restricted night and day periods). A nocturnal TSH surge value lower than the maximum surge was encountered when the timing of the TSH peak and/or the TSH nadir was shifted outside the 2200–0400 and 1400–1800 h periods, respectively.

We also used cosinor analysis (19) to appraise the diurnal variation in TSH concentration profiles. This analysis was conducted as previously described (18) (Fig. 1Go).



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  		FIG. 1. Cosinor analysis involves fitting a cosine function to the TSH concentration time series (continuous line). The horizontal dotted line represents the mean, and the vertical dotted line represents the amplitude at the time when the curve reaches its maximum value or acrophase. A, Typical acrophase around 0230 h, resulting in a nocturnal TSH surge (108%) that is identical with the maximum TSH surge in the profile (108%); B, the acrophase is shifted to 0830 h (shift in diurnal rhythm), resulting in a normal maximum TSH surge (70%) in the profile, but a greatly attenuated (almost absent) nocturnal TSH surge (0.12%).

 
Assays

A third-generation TSH assay (Heterogeneous Sandwich Magnetic Separation Assay) on the Immuno 1 System (Bayer, Pittsburgh, PA) was used in this study. The sensitivity of this method is 0.005 mU/liter, with a reported normal range of 0.35–3.5 mU/liter. The inter- and the intraassay coefficients of variations are 9.8–15.2% and 2.3–4.5%, and 8.8–12.2% and 1.9–2.4% for TSH concentrations less than 0.028 mU/liter and greater than 0.5 mU/liter, respectively. Samples from each profile were assayed in the same run to avoid interassay variability.

Free T4 was measured using the Heterogeneous Sandwich Magnetic Separation Assay on the Bayer Immuno 1 System. The sensitivity of this assay is 1.287 pmol/liter, with a reported normal range of 9–26 pmol/liter. The intra- and interassay coefficients of variation are 2.7–8.9% and 3.1–15.4% across the entire analytic range.

Statistics

The data were expressed as the mean ± SEM if normally distributed or as the median and range if the data were skewed. Simple correlations to examine the relationship between variables were carried out using the Spearman rank order correlation test. Differences between groups were examined by t test if the data were normally distributed or by Mann-Whitney rank-sum test if the data were skewed. Statistical significance was accepted at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
TSH surge test

Almost all subjects exhibited distinct diurnal variation in the TSH concentration profile; a TSH surge was evident in these subjects, although the timing of the peak and nadir TSH levels greatly influenced its magnitude.

The maximum (but not the nocturnal) TSH surge was significantly reduced in the patients, with a reduction in the median value of about 25% (Table 2Go). No correlation was noted between the TSH surge and the BED, age at radiotherapy, postirradiation interval, free T4 levels, or mean TSH levels. One normal control had a maximum TSH surge of 35%, and two patients had values of 25% and 42%, whereas all other subjects had values above 50% (previously reported cutoff level for normality) (20).

The nocturnal TSH surge was lower than the maximum TSH surge in 27 of the 35 (77%) patients and in 28 of 33 (85%) normal controls (who had maximum TSH surge >50%). Of the 27 patients and 28 controls who had a lower nocturnal TSH surge, the values of six patients and eight controls actually dropped below 50%, of whom four normal subjects and one patient had negative values signifying the absence of the nocturnal TSH surge (Fig. 1Go and Table 3Go).


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  		TABLE 3. Data on study subjects with normal maximum (>50%), but subnormal nocturnal (<50%), TSH surge

 
The peak TSH level was located outside the traditional nocturnal sampling period (2200–0400 h) in eight normal subjects (24%) and eight patients (21%). In addition, the nadir TSH was located before or after the traditional afternoon sampling time for this value (1400–1800 h) in 20 normal subjects (60%) and 17 patients (46%). In the majority of those with a subnormal nocturnal TSH surge, cosinor analysis confirmed that the acrophase was located between 0400 and 0900 h. In others, a subnormal TSH surge was the result of a mild to moderate shift in the timing of the peak and/or nadir TSH levels (Table 3Go).

TSH responses to TRH test and free T4 levels

Mean profile TSH, basal TSH (TSH0 min) and absolute TSH responses to TRH test (but not fold responses) were significantly higher in the patients (Table 2Go).

A subnormal TSH peak at 20 min (blunted response) was not seen in any patient; the TSH fold responses were above the minimum normal of 2.9 in all patients. Eleven patients (30%) had brisk responses, manifested as a peak TSH at 20 min and/or an absolute or fold TSH response higher than the maximum achieved in normal subjects. The TSH decline between 20 and 60 min was slightly, but significantly, delayed in the patients. However, none of the patients had a TSH60 min value higher than the TSH20 min value (Fig. 2Go and Table 2Go).



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  		FIG. 2. Individual TSH responses (at 0, 20, and 60 min) to TRH stimulation test in normal subjects and patients. CIR, Cranial irradiation; CSI, craniospinal irradiation. Note the impact of spinal irradiation and that of GH deficiency (GHD) or GH insufficiency (GHI) on basal and stimulated TSH levels.

 
Six patients (16%) had a hypothalamic TRH test, as indicated by a slow TSH decline (less than the lower normal limit of 14%). The maximum TSH surge and free T4 levels were insignificantly reduced in these six patients [102 ± 14% vs. 145 ± 12% (P = 0.1) and 13.7 ± 0.9 vs. 15.5 ± 0.3 pmol/liter (P = 0.07), respectively], and none had a subnormal TSH surge.

Patients and normal subjects had similar free T4 distributions. No correlation was seen between free T4 levels and any of the basal or stimulated TSH measurements, TSH decline, TSH surge, BED, age at irradiation, or postirradiation interval in either normal subjects or the patients.

Patients (n = 16) with free T4 levels in the lowest third of the normal range (<15 pmol/liter) had similar mean profile TSH, TSH responses to TRH test, maximum and nocturnal TSH surges, and acrophase as those in the patients (n = 21) with higher free T4 levels (Table 4Go). Alternatively, patients with a lower TSH surge (<50% or <100%) had a similar free T4 distribution as normal subjects or patients with a TSH surge higher than 100% as well as similar mean profile TSH, TSH responses to TRH, and acrophase.


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  		TABLE 4. TSH dynamics in patients according to free T4 levels

 
Spinal irradiation and GH status: effects on TRH test and TSH surge

The increase in basal and stimulated TSH levels only involved patients who had received craniospinal irradiation (n = 27) and was greater in those who had severe GH deficiency (Tables 5Go and 6Go and Fig. 2Go).


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  		TABLE 5. TSH data in CSI and CIR patients

 

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  		TABLE 6. TSH levels in craniospinally irradiated patients according to GH status

 
Patients with normal GH status (n = 16) had a maximum TSH surge similar to that in normal subjects (154.9 ± 18.2% vs. 145.2 ± 11.8%; P = 0.5), whereas patients with GH deficiency or GH insufficiency) (n = 21) had a significantly (P = 0.01) lower maximum TSH surge (100.7 ± 11%; Fig. 3Go). No differences were seen in free T4 levels or acrophase among these subgroups of patients or in comparison with normal subjects.



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  		FIG. 3. Maximum TSH surge in normal subjects and patients according to GH status. The upper boundary of the box and the upper error bar represent the mean and the mean ± 1 SD, respectively. GHD, Severe GH deficiency; GHI, GH insufficiency (partial GHD).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Traditionally, the TRH test has been used to appraise abnormalities in TSH secretion that may denote the presence of central hypothyroidism. However, this test is frequently normal even in the presence of overt secondary hypothyroidism (21, 22, 23, 24, 25, 26, 27). Thus, its sensitivity has been questioned, and greater reliance has been placed on more physiological ways of appraising TSH secretion, namely, the nocturnal TSH surge (24, 25). Although loss of the nocturnal TSH surge has been considered to be a characteristic of overt central hypothyroidism (13, 25), its persistence has been demonstrated in some patients with overt secondary hypothyroidism (28, 29, 30) and its absence in patients with nonthyroidal illnesses (31, 32, 33) and during fasting (34).

Neuroendocrine mechanisms that control the circadian rhythm in TSH secretion are poorly understood (35, 36, 37), but the evidence suggests a link with the sleep cycle and the biological clock (38, 39, 40). The nocturnal timing for the TSH surge test relies on the observation that TSH release usually increases in the late afternoon and reaches a peak around midnight or early morning, then plateaus for several hours before declining to nadir values in the afternoon. However, although this pattern has been consistently reported in many studies (20, 35, 41), others have reported an absence or attenuation of the nocturnal surge in normal individuals (42), questioning the specificity of this test. The latter study (42), however, failed to show whether the loss of nocturnal surge in some normal individuals was attributable to a genuine loss of the TSH diurnal rhythm. In our study, the TSH diurnal rhythm was maintained in all study subjects except one normal individual and one patient, albeit with a significant shift in the timing of the peak and/or nadir TSH, resulting in an apparent loss of the nocturnal TSH surge in about 24% of normal individuals and 16% of patients. In most of these subjects, cosinor analysis showed that the acrophase had occurred between 0400 and 0900 h.

A genuine loss of diurnal rhythm may denote a pathological process, whereas a shift in the timing of the surge (or acrophase) is a healthy physiological adaptation to environmental influences and social factors (such as changes in sleep cycle and shift work) that can affect the biological clock and biological circadian rhythms (38, 39, 40).

Therefore, had we followed the recommended sampling time and adopted the definition of a normal nocturnal surge of 50–300% (20, 43), six more patients (16%) would have been erroneously diagnosed with hidden central hypothyroidism! This echoes the results reported by Rose et al. (15); in this study, 53 of 208 (26%) cranially irradiated cancer survivors exhibited a subnormal nocturnal TSH surge. The cutoff limits of a normal nocturnal TSH surge (50–300%) used in the latter study were derived from a previous study by the same researchers (20), in which calculation of the TSH surge was based on 24-h profiling; in addition, the study clearly stated that about 9% of the study population had a TSH nadir before or after 1400–1800 h, and 8% had peak TSH before or after 2200–0400 h. This discrepancy in the methodology between the two studies may explain the high incidence of a subnormal nocturnal TSH surge in cranially irradiated cancer survivors (15). Furthermore, the study included patients with suprasellar tumors (12.5%), who are likely to have abnormal TSH dynamics even without irradiation (29), and 10 of the 53 patients (19%) who had a subnormal nocturnal TSH surge had not received irradiation, suggesting mechanisms other than radiation damage to the h-p axis. The study also failed to reveal the extent of the reduction in TSH surge and how many patients in fact had borderline responses.

In our study, an overall reduction in the maximum TSH surge was only seen in patients with severe GH deficiency. This reduction in the TSH surge reflects mild dampening of the diurnal rhythm, as evidenced by a strong correlation with the relative amplitude in cosinor analysis (r = 0.9; P = 0.0001). The association of diminished TSH surge with the presence of GH deficiency may indicate a common etiological factor, i.e. radiation damage, causing both endocrine dysfunctions, rather than a causal relationship. In support of this, the study by Municchi et al. (44) revealed no change in the nocturnal TSH surge after GH replacement in GH-deficient children. Alternatively, the mild reduction in the TSH surge may reflect the mild increase in the mean TSH concentration in these patients, in a similar fashion as the loss of the TSH surge and the diurnal variation in patients with primary hypothyroidism, who exhibit a more sustained pattern of TSH release throughout the day and night (45).

The absence of differences in TSH dynamics between patients with low normal free T4 levels and those with high normal free T4 levels, and the normality of free T4 distribution even in those patients with the lowest TSH surge and established h-p damage (evidenced by the presence of severe GH deficiency) or those with apparent loss of nocturnal TSH surge argue against attributing any functional significance or diagnostic importance to the reduction in the TSH surge in cranially irradiated cancer survivors. In addition, the one patient who had a genuinely reduced TSH surge (maximum, <35%) had a normal TRH test and free T4 of 16 pmol/liter. Thus, although the diagnosis of secondary hypothyroidism is difficult to exclude in patients with low-normal free T4 levels, because of the broad range of normal free T4 levels that does not account for individual set points, the use of TSH dynamics to confirm such a diagnosis can be misleading. In this context, it is more appropriate to rely on a clinical picture suggestive of hypothyroidism when considering a therapeutic trial of T4 replacement.

Many factors account for the observed increase in basal and stimulated TSH levels in the irradiated patients. Thyroid exposure to radiation during spinal irradiation is a well-established cause of primary thyroid dysfunction (46). In its mild form, when TSH is not yet increased beyond normal limits, it may at least render the axis more responsive to TRH stimulation. This mimics the so-called subbiochemical hypothyroidism, a term used to denote patients who exhibit normal free T4 and basal TSH, but exaggerated TSH, responses to TRH test (47). Our findings of increased TSH levels in craniospinally irradiated patients echo those reported by Schmiegelow et al. (46), but in sharp contrast to their findings, our patients who did not receive spinal irradiation had normal TSH levels.

Basal and stimulated TSH levels have been shown to be higher in the presence of GH deficiency (30, 48, 49, 50), changes that can be reversed with GH replacement therapy (48). This has been attributed to the loss of GH positive feedback on hypothalamic somatostatin release (50) leading to reduced somatostatin tone, which normally inhibits TSH release (37, 50, 51, 52). In our study, however, it was not possible to directly examine the isolated effect of GH deficiency on TSH secretion, because all those patients (except two) had received spinal irradiation. Nevertheless, spinally irradiated patients with severe GH deficiency had higher basal and stimulated TSH levels than those who were not GH deficient, observations consistent with an additional effect of GH deficiency.

In addition to somatostatin, TSH release is under inhibitory control by dopamine (37). Thus, radiation-induced hypothalamic damage with a reduction in hypothalamic somatostatin and dopamine tone (12, 53, 54) can lead to additional enhancement of basal TSH secretion and pituitary responsiveness to TRH.

The possible contribution of an increase in immunoreactive and bioinactive TSH, previously reported in patients with central hypothyroidism (22, 55) and in isolated cases of cranially irradiated hypothyroid patients (56), remains to be studied in this cohort of euthyroid patients.

The presence of a hypothalamic pattern of TSH response to TRH has been reported as early as 12 months after radiotherapy in as many as 90% of patients intensively irradiated for nasopharyngeal carcinoma (57); however, progression to frank secondary hypothyroidism after 5 yr of follow-up occurred in only a few patients (13%). In concert, our findings and those of a previous study (15), reporting a high rate of abnormal TSH surge tests and/or TRH tests in the presence of normal free T4 levels despite long periods of postradiation follow-up, suggest that these abnormalities in TSH secretion reflect subtle changes in the function of the h-p-thyroid axis. Thus, the label hidden central hypothyroidism is inappropriate, because it can imply an evolving pathology that does not exist in the majority of patients. Furthermore, in terms of clinical practice, an analogy can be drawn with the exaggerated TSH response to TRH in patients with compensated primary hypothyroidism with mild elevation in TSH levels; these patients have normal free T4 levels, and the clinical benefit of thyroid hormone replacement remains unproven (58).

In conclusion, euthyroid cranially irradiated patients have increased basal and stimulated TSH levels compared with normal subjects. This is associated with mild dampening of the amplitude of the maximum TSH surge and mild abnormalities in TSH responses to TRH stimulation due to a variety of factors. Apparent loss or reduction of the nocturnal TSH surge can result from a physiological shift in the timing of the peak and/or nadir TSH without actual loss of the diurnal variation; this is normal adaptation of the h-p axis to environmental factors and does not reflect the presence of h-p axis dysfunction. The high frequency of these abnormalities compared with the very low rate of overt secondary hypothyroidism after prolonged periods of postirradiation follow-up suggest that these abnormalities are subtle in nature and do not necessarily reflect the presence of genuine/progressive damage or significant dysfunction of the h-p-thyroid axis. In this context, the use of the term hidden central hypothyroidism is inappropriate and misleading.


   Acknowledgments
 
We are grateful to Dr. G. Wieringa and the staff of the biochemistry department at Christie Hospital National Health Service Trust for performing the TSH and T4 assays, and to Bayer Pharmaceuticals for providing the TSH assay kits.


   Footnotes
 
This work was supported by a grant from the Endowment Fund at Christie Hospital National Health Service Trust.

First Published Online October 4, 2005

Abbreviations: BED, Biological effective dose of radiation; h-p, hypothalamic-pituitary.

Received July 18, 2005.

Accepted September 26, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Livesey EA, Hindmarsh PC, Brook CG, Whitton AC, Bloom HJ, Tobias JS, Godlee JN, Britton J 1990 Endocrine disorders following treatment of childhood brain tumours. Br J Cancer 61:622–625[Medline]
  2. Oberfield SE, Allen JC, Pollack J, New MI, Levine LS 1986 Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function. J Pediatr 108:219–223[CrossRef][Medline]
  3. Ogilvy-Stuart AL, Clark DJ, Wallace WH, Gibson BE, Stevens RF, Shalet SM, Donaldson MD 1992 Endocrine deficit after fractionated total body irradiation. Arch Dis Child 67:1107–1110[Abstract]
  4. Littley MD, Shalet SM, Morgenstern GR, Deakin DP 1991 Endocrine and reproductive dysfunction following fractionated total body irradiation in adults. Q J Med 78:265–274
  5. Mohn A, Chiarelli F, Di Marzio A, Impicciatore P, Marsico S, Angrilli F 1997 Thyroid function in children treated for acute lymphoblastic leukemia. J Endocrinol Invest 20:215–219[Medline]
  6. Voorhess ML, Brecher ML, Glicksman AS, Jones B, Harris M, Krischer J, Boyett J, Forman E, Freeman AI 1986 Hypothalamic-pituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis. A retrospective study. Cancer 57:1287–1291[CrossRef][Medline]
  7. Lando A, Holm K, Nysom K, Rasmussen AK, Feldt-Rasmussen U, Petersen JH, Muller J 2001 Thyroid function in survivors of childhood acute lymphoblastic leukaemia: the significance of prophylactic cranial irradiation. Clin Endocrinol (Oxf) 55:21–25[CrossRef][Medline]
  8. Carter EP, Leiper AD, Chessells JM, Hurst A 1989 Thyroid function in children after treatment for acute lymphoblastic leukaemia. Arch Dis Child 64:631
  9. Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega JA, Hammond GD 1985 Thyroid abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Res 19:266A
  10. Littley MD, Shalet SM, Beardwell CG, Robinson EL, Sutton ML 1989 Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf) 31:363–373[Medline]
  11. Lam KS, Wang C, Yeung RT, Ma JT, Ho JH, Tse VK, Ling N 1986 Hypothalamic hypopituitarism following cranial irradiation for nasopharyngeal carcinoma. Clin Endocrinol (Oxf) 24:643–651[Medline]
  12. Constine LS, Woolf PD, Cann D, Mick G, McCormick K, Raubertas RF, Rubin P 1993 Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87–94[Abstract/Free Full Text]
  13. Caron PJ, Nieman LK, Rose SR, Nisula BC 1986 Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab 62:960–964[Abstract]
  14. Trejbal D, Sulla I, Trejbalova L, Lazurova I, Schwartz P, Machanova Y 1994 Central hypothyroidism–various types of TSH responses to TRH stimulation. Endocr Regul 28:35–40[Medline]
  15. Rose SR, Lustig RH, Pitukcheewanont P, Broome DC, Burghen GA, Li H, Hudson MM, Kun LE, Heideman RL 1999 Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab 84:4472–4479[Abstract/Free Full Text]
  16. Darzy KH, Shalet SM 2003 Radiation-induced growth hormone deficiency. Horm Res 59(Suppl 1):1–11
  17. Darzy KH, Aimaretti G, Wieringa G, Gattamaneni HR, Ghigo E, Shalet SM 2003 The usefulness of the combined growth hormone (GH)-releasing hormone and arginine stimulation test in the diagnosis of radiation-induced GH deficiency is dependent on the post-irradiation time interval. J Clin Endocrinol Metab 88:95–102[Abstract/Free Full Text]
  18. Darzy KH, Pezzoli S, Thorner MO, Shalet SM 2005 The dynamics of GH secretion in adult cancer survivors with severe GH deficiency acquired following brain irradiation in childhood for non-pituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretory disorderliness. J Clin Endocrinol Metab 90:2794–2803[Abstract/Free Full Text]
  19. Nelson W, Tong YL, Lee JK, Halberg F 1979 Methods for cosinor-rhythmometry. Chronobiologia 6:305–323[Medline]
  20. Rose SR, Nisula BC 1989 Circadian variation of thyrotropin in childhood. J Clin Endocrinol Metab 68:1086–1090[Abstract]
  21. Patel YC, Burger HG 1973 Serum thyrotropin (TSH) in pituitary and-or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J Clin Endocrinol Metab 37:190–196[Medline]
  22. Faglia G, Bitensky L, Pinchera A, Ferrari C, Paracchi A, Beck Peccoz P, Ambrosi B, Spada A 1979 Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 48:989–998[Abstract]
  23. Horimoto M, Nishikawa M, Ishihara T, Yoshikawa N, Yoshimura M, Inada M 1995 Bioactivity of thyrotropin (TSH) in patients with central hypothyroidism: comparison between in vivo 3,5,3'-triiodothyronine response to TSH and in vitro bioactivity of TSH. J Clin Endocrinol Metab 80:1124–1128[Abstract]
  24. Rose SR 1995 Isolated central hypothyroidism in short stature. Pediatr Res 38:967–973[Medline]
  25. Rose SR, Manasco PK, Pearce S, Nisula BC 1990 Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders. J Clin Endocrinol Metab 70:1750–1755[Abstract]
  26. Spencer CA, Schwarzbein D, Guttler RB, LoPresti JS, Nicoloff JT 1993 Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 76:494–498
  27. Hartoft-Nielsen ML, Lange M, Rasmussen AK, Scherer S, Zimmermann-Belsing T, Feldt-Rasmussen U 2004 Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Horm Res 61:53–57[CrossRef][Medline]
  28. Adriaanse R, Romijn JA, Endert E, Wiersinga WM 1992 The nocturnal thyroid-stimulating hormone surge is absent in overt, present in mild primary and equivocal in central hypothyroidism. Acta Endocrinol (Copenh) 126:206–212[Medline]
  29. Adriaanse R, Brabant G, Endert E, Wiersinga WM 1993 Pulsatile thyrotropin release in patients with untreated pituitary disease. J Clin Endocrinol Metab 77:205–229[Abstract]
  30. Villares SM, Knoepfelmacher M, Salgado LR, Liberman B, Faria A, Evans WS, Wajchenberg BL, Nicolau W 1996 Pulsatile release and circadian rhythms of thyrotropin and prolactin in children with growth hormone deficiency. Pediatr Res 39:1006–1011[Medline]
  31. Romijn JA, Wiersinga WM 1990 Decreased nocturnal surge of thyrotropin in nonthyroidal illness. J Clin Endocrinol Metab 70:35–42[Abstract]
  32. Custro N, Scafidi V, Notarbartolo A 1992 Alterations in circadian rhythm of serum thyrotropin in critically ill patients. Acta Endocrinol (Copenh) 127:18–22[Medline]
  33. Custro N, Scafidi V, Gallo S, Notarbartolo A 1994 Deficient pulsatile thyrotropin secretion in the low-thyroid-hormone state of severe non-thyroidal illness. Eur J Endocrinol 130:132–136[Abstract]
  34. Romijn JA, Adriaanse R, Brabant G, Prank K, Endert E, Wiersinga WM 1990 Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J Clin Endocrinol Metab 70:1631–1636[Abstract]
  35. Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, Kummer B, Feistner H, Hesch RD, von zur Muhlen A 1990 Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab 70:403–409[Abstract]
  36. Brabant G, Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, von zur Muhlen A 1990 Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res 23(Suppl):12–17
  37. Behrends J, Prank K, Dogu E, Brabant G 1998 Central nervous system control of thyrotropin secretion during sleep and wakefulness. Horm Res 49:173–177[CrossRef][Medline]
  38. Weibel L, Brandenberger G, Goichot B, Spiegel K, Ehrhart J, Follenius M 1995 The circadian thyrotropin rhythm is delayed in regular night workers. Neurosci Lett 187:83–86[CrossRef][Medline]
  39. Weibel L, Follenius M, Brandenberger G 1999 Biologic rhythms: their changes in night-shift workers. Presse Med 28:252–258
  40. Allan JS, Czeisler CA 1994 Persistence of the circadian thyrotropin rhythm under constant conditions and after light-induced shifts of circadian phase. J Clin Endocrinol Metab 79:508–512[Abstract]
  41. Weeke J, Gundersen HJ 1978 Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol (Copenh) 89:659–672[Medline]
  42. Dericks-Tan JS, Merz PG, Schrodter A, Taubert HD 1996 Differences in the nyctohemeral secretion of TSH and PRL in healthy euthyroid men. Exp Clin Endocrinol Diabetes 104:145–150[Medline]
  43. Custro N, Scaglione R 1980 Circadian rhythm of TSH in adult men and women. Acta Endocrinol (Copenh) 95:465–471[Medline]
  44. Municchi G, Malozowski S, Nisula BC, Cristiano A, Rose SR 1992 Nocturnal thyrotropin surge in growth hormone-deficient children. J Pediatr 121:214–220[CrossRef][Medline]
  45. Persani L, Terzolo M, Asteria C, Orlandi F, Angeli A, Beck-Peccoz P 1995 Circadian variations of thyrotropin bioactivity in normal subjects and patients with primary hypothyroidism. J Clin Endocrinol Metab 80:2722–2728[Abstract]
  46. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Poulsen HS, Muller J 2003 A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor. J Clin Endocrinol Metab 88:136–140[Abstract/Free Full Text]
  47. Sheth JJ, Thakore PB, Trivedi BB, Shah NN, Vaidya RA 1999 Sub-biochemical hypothyroidism: an exaggerated thyroid stimulating hormone response to thyrotrophin releasing hormone. J Assoc Physicians India 47:275–279[Medline]
  48. Porter BA, Refetoff S, Rosenfeld RL, De Groot LJ, Lang US, Stark O 1973 Abnormal thyroxine metabolism in hyposomatotrophic dwarfism and inhibition of responsiveness to TRH during GH therapy. Pediatrics 51:668–674[Abstract/Free Full Text]
  49. Illig R, Krawczynska H, Torresani T, Prader A 1975 Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. J Clin Endocrinol Metab 41:722–728[Abstract]
  50. Cobb WE, Reichlin S, Jackson IM 1981 Growth hormone secretory status is a determinant of the thyrotropin response to thyrotropin-releasing hormone in euthyroid patients with hypothalamic-pituitary disease. J Clin Endocrinol Metab 52:324–329[Abstract]
  51. Tannenbaum GS 1988 Somatostatin as a physiological regulator of pulsatile growth hormone secretion. Horm Res 29:70–74[Medline]
  52. Prescott RW, Weightman DR, Kendall-Taylor P, Johnston DG 1984 Differential TSH and PRL responses to dopamine receptor blockade in acromegaly. Clin Endocrinol (Oxf) 21:369–375[Medline]
  53. Ogilvy-Stuart AL, Wallace WH, Shalet SM 1994 Radiation and neuroregulatory control of growth hormone secretion. Clin Endocrinol (Oxf) 41:163–168[Medline]
  54. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML 1989 Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 70:145–160
  55. Persani L, Ferretti E, Borgato S, Faglia G, Beck-Peccoz P 2000 Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 85:3631–3635[Abstract/Free Full Text]
  56. Lee KO, Persani L, Tan M, Sundram FX, Beck-Peccoz P 1995 Thyrotropin with decreased biological activity, a delayed consequence of cranial irradiation for nasopharyngeal carcinoma. J Endocrinol Invest 18:800–805[Medline]
  57. Lam KS, Tse VK, Wang C, Yeung RT, Ho JH 1991 Effects of cranial irradiation on hypothalamic-pituitary function–a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med 78:165–176
  58. Col NF, Surks MI, Daniels GH 2004 Subclinical thyroid disease: clinical applications JAMA 291:239–243



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W. Russell, R. F. Harrison, N. Smith, K. Darzy, S. Shalet, A. P. Weetman, and R. J. Ross
Free Triiodothyronine Has a Distinct Circadian Rhythm That Is Delayed but Parallels Thyrotropin Levels
J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2300 - 2306.
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