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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1054-1060
Copyright © 2001 by The Endocrine Society

Original Studies

Usefulness of Thyrotropin (TSH)-Releasing Hormone Test and Nocturnal Surge of TSH for Diagnosis of Isolated Deficit of TSH Secretion

Noriyoshi Yamakita, Takashi Komaki, Toshihiro Takao, Toshihiro Murai, Kozo Hashimoto and Keigo Yasuda

Department of Internal Medicine (N.Y., T.K., T.M.), Matsunami General Hospital, Kasamatsu, Gifu-Prefecture 5016062; Komaki Medical Clinic (T.K.), Gifu-City 5008865; The Second Department of Internal Medicine (T.T., K.H.), Kochi Medical School, Oko-Cho, Nankoku-City 7838505; and The Third Department of Internal Medicine (K.Y.), Gifu University School of Medicine, Tsukasa-Machi, Gifu-City, 5008076 Japan

Address correspondence and requests for reprints to: Noriyoshi Yamakita, M.D., Ph.D., Department of Internal Medicine, Matsunami General Hospital, Kasamatsu, Gifu-Prefecture 5016062, Japan. E-mail: nyamakita{at}matsunami-hsp.or.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Six patients with idiopathic isolated deficit of TSH secretion were examined and reported on. Their clinical symptoms and routine biochemical data were unclear and were not specific for hypothyroidism. Serum triiodothyronine, free thyroxine and TSH levels were slightly low or low-normal. Basal metabolic rate and thyroidal 123I-uptake were also slightly low or low-normal. The response of serum TSH to TRH stimulation was blunted in all patients. No nocturnal surge of serum TSH level could be seen in any of the patients. Empty sella was revealed in three patients, and pituitary microadenoma in one patient via magnetic resolution imaging. Antihuman pituitary cytosol antibody was seen in five patients. Autoimmunity may have played a role in the pathogenesis of idiopathic isolated TSH deficiency.

Routine examination of thyroid function cannot easily detect this disease. TSH response to TRH stimulation and nocturnal surge of TSH should be examined when this disease is suspected.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CENTRAL HYPOTHYROIDISM REFERS to thyroid hormone deficiency due to a disorder of the pituitary and/or hypothalamus. The causes of central hypothyroidism are the same as those for hypopituitarism. Impaired TSH secretion is frequently associated with deficient secretion of other pituitary hormones. Disorders or diseases such as pituitary macroadenoma compressing normal pituitary tissue, various inflammatory diseases and infiltrative disorders including sarcoidosis, tuberculosis, toxoplasmosis and syphilis in the pituitary or hypothalamus, pituitary apoplexy and/or hemorrhage can be associated with impaired secretion of pituitary hormones (1). In general, however, TSH and ACTH secretion are less vulnerable to impairment when compared with gonadotropin and GH secretion. Isolated impairment of ACTH, GH, or gonadotropin secretion has been well documented. It has been reported, however, that idiopathic isolated TSH deficiency is rare (1, 2). Hashimoto (2) noted in his review that approximately sixty cases of isolated TSH deficiency have been reported since Shuman’s first report in 1953 (3). Recently, it was reported that central hypothyroidism could not be detected only by measurement of peripheral thyroid hormone and TSH (4). We experienced six patients with idiopathic isolated impairment of TSH secretion. In this report, we present the clinical and endocrine features of idiopathic isolated TSH deficiency and discuss its relationship with antihuman pituitary cytosol antibody. Contrary to what has been reported earlier, this disease may, in fact, not be as rare as postulated.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects (Table 1Go)

Five women and one man with a mean age of 46.2 yr were investigated. The complaints of the patients are listed in Table 1Go, but are very unclear. All of them complained of mild lethargy and fatigue. Cold intolerance and leg heaviness were present in two of them (patients 1 and 2), and constipation was found in five (patients 1, 2, 4–6). Sleepiness was noted in two (patients 1 and 4). However, physical examination revealed no typical features associated with hypothyroidism. Only a delayed relaxation phase of the Achilles tendon reflex was seen in all patients. Only one patient (patient 5) exhibited any kind of facial expression that could suggest hypothyroidism. Serum total cholesterol and creatine kinase levels were within normal ranges except for one patient. Basal metabolic rate, of which measuring method was described later, was, however, slightly low to lownormal as shown in Table 1Go. Struma with a finger head size was palpable in three (patients 1–3), whose ultrasonic findings indicated adenomatous goiter in two (patients 1 and 2) and simple goiter in one (patient 3). In the other patients, thyroidal ultrasonic findings were unremarkable. Dynamic magnetic resolution imaging (MRI) of the pituitary gland and hypothalamus revealed complete empty sella in patients 1 and 6, a partially empty sella in patient 4, and a suspected pituitary adenoma, measuring 4 mm in diameter, in patient 2. However, no abnormal findings could be found through MRI in the other patients, although lacunae were detected in the hemisphere of patient 5. The duration from the initial hospital consultation to making the final diagnosis was three to six years in four patients (patient 1–4), but only 0.1 and 0.6 yr in the other two patients (patients 5 and 6) who consulted our hospital following our experiences with the previous four patients. After confirming the disease, levothyroxine sodium (50–150 µg/day) was administered and the symptoms ameliorated in all patients.


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  		Table 1. Clinical and laboratory features of the patients with isolated TSH deficiency

 
Materials and methods

The responses of plasma pituitary hormone levels to the administration of respective hypothalamic stimulating hormones were examined. After drawing basal plasma samples through a plastic canula inserted into the antecubital vein following a one hour bed rest, 500 µg TRH (TRH injection, Tanabe Seiyaku, Osaka, Japan), 100 µg GnRH (LH-RH injection, Tanabe Seiyaku), 100 µg hCRH (hCRH injection, Mitsubishi-Tokyo Seiyaku, Tokyo, Japan) or 100 µg hGRH (GRF injection, Sumitomo Seiyaku, Tokyo, Japan) was iv administered. Plasma samples were obtained after 15, 30, 60, 90 and 120 min. Serum TSH, plasma PRL and {alpha}-subunit levels were measured during TRH stimulation. Serum free T3 (fT3) level was measured before and 120 min after the administration of TRH. Plasma LH, FSH and {alpha}-subunit levels were measured during GnRH stimulation, while plasma GH was measured during GRH stimulation, and plasma ACTH and cortisol levels were measured during hCRH stimulation. For the examination of the nocturnal surge of serum TSH level, blood samples were drawn hourly beginning at 1400 h and ending at 1800 h, and again, beginning at 2100 h and ending at 0400 h, according to the study of Rose et al. (4). 500 µg TRH was administered intramuscularly, daily, for eight days, and a TRH stimulation test was similarly performed on the ninth day, and TSH response was assessed in three patients (patients 4–6).

For the evaluation of the posterior lobe of the pituitary gland, plasma and urine osmolarity and plasma antidiuretic hormone (ADH) level at 0500, 0600, 0700, and 0800 h were measured after an overnight water restriction.

The measuring methods and the reference ranges of all hormones and antibodies are described in Table 2Go.


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  		Table 2. Measuring methods of the hormones and antibodies and their reference ranges

 
Basal metabolic rate was measured, using Systemic Pulmonary Function System, FUDAC-70 (Fukuda Denshi Co. Ltd., Tokyo, Japan), early in the morning after more than a 1-h bed rest following an overnight fast.

Antipituitary antibody was measured by two different methods: one was a biotin/avidin detection system using rat pituitary cytosol as an antigen described elsewhere (9), whereas the other (10) was the method using Western blotting as described previously by Crock et al. (11). In short, normal human pituitary glands were homogenized in PBS and were centrifuged with 400 x g and then 10 x 104 g. After separating the cytosol and membrane fractions, the former was fractionated onto SDS-polyacrylamide gels by electrophoresis. The separated proteins were transferred to polyvinylidene difluoride membranes and incubated overnight at 4 C with diluted patient’s serum. Reactivity to pituitary proteins was detected using biotin-conjugated goat antihuman IgG antiserum and color reaction with enhanced chemiluminescence detection reagents (Amersham Pharmacia Biotech, Buckinghamshire, UK). There was no positive antihuman pituitary cytosol antibody found in healthy subjects. However, this antibody was detected in 3.6% of postpartum women without pituitary disease and in 15.4% of patients diagnosed with panhypopituitarism other than adenohypophysitis.

All examinations were performed after obtaining the informed consent of the patients according to the Declaration of Helsinki and the permission of the Ethics Committee of Matsunami General Hospital.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal serum levels of TSH, fT3, and free T4 (fT4) (Table 3Go)

Basal serum TSH level was lower than the reference range in all patients. On the other hand, the serum fT3 level was low in four patients and low-normal in another patient. Serum fT4 was within the low-normal range in all patients. Two months after the start of thyroid hormone supplementation, the serum TSH level further decreased to 0.04 or less than 0.04 mU/L in all patients whereas serum fT3 and fT4 levels were still within their respective normal ranges.


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  		Table 3. Serum TSH, fT3, and fT4 levels 2 months after the treatment with levothyroxine sodium

 
Thyroidal 123I uptake (Table 1Go)

123I uptake of the thyroid gland after iodine restriction for 10 days did not elevate in any of the patients (reference range, 10–20%).

Serum TSH, fT3, and plasma {alpha}-subunit responses to TRH administration (Table 4Go and Fig. 1AGo)

The increase of serum TSH was blunted in all patients. Any increase in the response of plasma {alpha}-subunit could not be made clear in any patients. Serum fT3 levels 120 min after administration of TRH were extremely low (Table 4Go), and the rates of increase were also low (Fig. 1AGo). After intramuscular administration of TRH (500 µg daily for 8 days), TRH stimulation still induced an insufficient increase of serum TSH levels in the three patients (patients 4, 5, and 6) examined: from 0.04 to 0.32 mIU/L in patient 4; from 0.18 to 1.00 in patient 5; and from less than 0.04 to 0.13 in patient 6.


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  		Table 4. Response of serum TSH, {alpha}-subunit, and fT3 to TRH stimulation

 


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  		Figure 1. A, Increased ratios of serum fT3 levels at 120 min during TRH stimulation, (value at 120 min - basal value)/basal value, were far less than the reference range. B, Circadian variation of serum TSH level. Nocturnal levels of serum TSH were similar to the levels in the morning; no nocturnal surge of serum TSH level was seen in any of patients. The reference range, shadow area, was referred from the study by Caron et al. (8 ).

 
Nocturnal surge of serum TSH level (Fig. 1BGo)

In all patients, serum TSH levels from 2100 to 0400 h remained low similar to levels measured in the morning; no nocturnal surge of TSH was seen. Only in one patient (patient 4) could a slight increase be seen at 0200 h, but it was still lower than the reference range.

Antithyoglobulin antibody, antiperoxidase antibody, TRab, TSab, anti-TSH antibody, and anti-T4 antibody

In all patients, TRab, TSab, anti-TSH antibody, and anti-T4 antibody were negative. Antithyroglobulin antibody and antiperoxidase antibody were negative in five patients (patients 1–3, 5, and 6), although they were positive, 100 U/mL and 30.0 U/mL, respectively, in the other patient (patient 4).

Antipituitary antibody

Using a biotin/avidin detection system, no antipituitary antibody against rat pituitary cytosol was detected in any patients. In addition, using a Western blotting system, antipituitary antibody against rat pituitary cytosol was detected in only one patient (patient 5). However, antipituitary antibody against human pituitary cytosol was detected in five (patients 2–6) of the six patients.

Other pituitary hormones (Table 5Go)

In all patients, the responses of plasma ACTH, GH, PRL, LH, and FSH to their respective hypothalamic-stimulating hormones were normal considering their age and sex. Plasma {alpha}-subunit clearly increased when GnRH was administered in all patients. The plasma ADH level and urinary osmolarity after overnight water restriction were normal in all patients.


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  		Table 5. Responses of anterior pituitary hormones to the respective hypothalamic hormone stimulation

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The complaints of all six patients investigated were unclear and nonspecific. Particularly in patients 1–4, the period from their first consultation to confirmation of the correct diagnosis in our hospital required 3–6 yr. In these patients, the underlying symptoms, which would identify the disease, remained undiagnosed. However, following the successful diagnosis of central hypothyroidism in patient 1, it became relatively easier to identify it in the others. Following the diagnosis of these patients, we actively sought this disease. In retrospect, the symptoms of these six patients were compatible with hypothyroidism, but the physical and general laboratory examinations did not always indicate the disease. Not only serum TSH level but also serum fT3 and fT4 levels were low-normal or slightly lower than the reference range. Then, low-normal or low basal metabolic rate and thyroidal 123I uptake were consistent with hypothyroidism. However, plasma sex hormone-binding globulin (SHBG) was not always low in all patients. The plasma SHBG level parallels the plasma thyroid hormone level, but the absolute value of plasma SHBG does not always reflect true thyroid function. Serum TSH level was rather low compared with serum fT3 and fT4 levels and showed a blunted increase after TRH administration. In this series, serum fT4 levels were relatively high when compared with serum fT3 levels. However, no anti-T4 antibodies were detected in any of the patients. It is unlikely that owing to the presence of autoimmunity in these patients, interference of anti-T4 antibodies in fT4 assay led to an overestimation of the actual fT4 concentration.

The symptoms of all our patients ameliorated by treatment with levothyroxine. However, the target of serum fT4 levels for the therapy in central hypothyroidism proposed by Ferretti E et al. (12) was higher than those achieved in our patients. Substitution doses of levothyroxine in our patients may have to be increased. We were unable to clarify the reason why there was a slight increase in the size of the thyroid gland under conditions where the deficit of TSH secretion in three patients.

Alterations in the tests for thyroid function can occur commonly in patients with nonthyroidal illness; in many of whom the serum concentrations of both fT3 and fT4 are low and serum TSH level may also be low (13). The term "nonthyroidal illness" is used for such abnormalities resulting from variable, usually reversible, disturbances in hypothalamo-pituitary-thyroid hormones, and/or thyroid hormone metabolism. These patients usually suffer from a critical systemic illness and internal abnormalities of corticosteroids and/or catecholamines. Administration of drugs including glucocorticoids (14), dopamine (15), and anticonvulsants (16) can influence the hypothalamo-pituitary-thyroid axis. Nocturnal TSH surge often decreases in this state, but TSH responses to TRH stimulation remain normal (17). Continuous TRH infusion to patients with severe nonthyroidal illness increased TSH 2- to 5-fold, T4 by 40–50%, and T3 by 52–116% (18). These results may suggest that patients with nonthyroidal illness have acquired transient central hypothyroidism (13). However, in our patients, no critical systemic illness was found, plasma levels and urinary secretion of cortisol were normal, and no drugs affecting the hypothalamo-pituitary-thyroid axis were being administered. Therefore, a diagnosis of nonthyroidal illness was inappropriate for our patients.

On the other hand, Jaffiol et al. (19) reported a patient with hypersensitivity to thyroid hormone, in which serum thyroid hormones and TSH level and its response to TRH administration were low in the same manner as described in our patients. However, the results of thyroidal radioactive iodine uptake and basal metabolic rate in our patients indicated the presence of hypothyroidism, and not hypersensitivity to thyroid hormones, hyperthyroidism. Central hypothyroidism was consistent with the symptoms and endocrine results found in our patients.

Hypothalamic (tertiary) hypothyroidism more frequently shows a normal, prolonged, or delayed pattern of the response curve of serum TSH to TRH stimulation (1, 20). Conversely, absent or impaired TSH responses have often been encountered in hypothyroid patients having pituitary lesions (21). However, several controversial results regarding TSH responses to TRH stimulation have been reported (4, 21, 22). Based on these findings, the TSH response pattern to TRH stimulation is not beneficial for distinguishing between hypothalamic and pituitary hypothyroidism. Serum TSH increase was blunted in all of our patients during TRH stimulation. Increase of the serum fT3 level and its rate of increase during TRH stimulation were severely impaired in all patients. Even when serum TSH level normally or markedly increases during TRH stimulation in patients with central hypothyroidism, the serum fT3 rate of increase is blunted (23, 24). The immunoreactive TSH in such cases might have reduced or obscured biologic activity (20, 25, 26, 27).

TSH secretion shows a diurnal rhythm with a surge late in the evening in healthy subjects (6, 28). This pattern seems to be under hypothalamic control and disappears in patients with central hypothyroidism (6, 28, 29, 30, 31). Nocturnal surge of TSH was absent in all of our patients. However, this evidence alone is not efficacious in distinguishing pituitary from hypothalamus disease, either. A TRH stimulation test was performed after intramuscular administration of TRH at a dose of 500 µg subsequently, daily, for 8 days in three patients (patients 4, 5, and 6). The response in serum TSH was, however, still blunted similarly to the results of the TRH stimulation test without pretreatment of TRH, which may indicate pituitary disease, at a minimum, in these patients.

Usually, central hypothyroidism is associated with impairment of other pituitary hormones (1). Pituitary macroadenoma, hemorrhage, infiltrative diseases, irradiation, or surgery can lead to central hypothyroidism. LH, FSH, and GH are more vulnerable to impairment than TSH and ACTH, although ACTH is most frequently impaired in lymphocytic adenohypophysitis (32). One patient (patient 3) in our series had a microadenoma 4 mm in diameter. It is not uncommon with pituitary neoplasmas to find isolated deficiencies of GH, LH, or FSH, but isolated deficiencies of ACTH or TSH are rare (33). It is unlikely that such a microadenoma could have caused impairment of TSH secretion.

A congenital deficit of Pit-1, which is the tissue-specific POU-domain transcription factor, results in hypopituitarism with deficiencies in GH, PRL, and TSH (34). The inactivating mutations of the PROP-1 gene result in a gene product with reduced DNA-binding and transcriptional activating ability and result in combined deficiencies of pituitary hormones, GH, gonadotropins, PRL, and TSH (35). TRH-receptor defect, caused by an inactivating mutation in the TRH-receptor gene, can cause a deficit of not only TSH but also PRL secretion and shows hypothyroidism (36). These genetic defects are an unlikely cause of isolated impairment of TSH secretion, which occurs rather in combination with other pituitary hormones. Rare genetic mutations of TSH-ß subunit have been reported in several Japanese (37) and Greek families (38). Clinical and biochemical features of hypothyroidism in such patients are much more severe than found in our patients. In the present series, unfortunately, we could not measure TSH-ß subunit, although the mutant protein may escape detection with anti-TSH-ß antibodies. {alpha}-Subunit measured in this study is common among pituitary glycoprotein hormones, TSH, LH, and FSH. The antibody of the TSH measuring system recognizes TSH-ß-subunit but not {alpha}-subunit. During TRH stimulation, the increase of plasma {alpha}-subunit was blunted together with TSH in all patients. However, it clearly increased during GnRH stimulation in the same manner as plasma LH and FSH in all patients. From these results, neither an {alpha}-subunit nor a TSH-ß-subunit only in thyrotrophs was secreted normally. Isolated TSH deficiency associated with pseudohypoparathyroidism was reported in a patient (39). The serum calcium level and PTHint in all of our patients were normal (data not shown), which is inconsistent with the patients reported.

The relationships among empty sella, antipituitary antibody, and pituitary function are controversial. Empty sella is an anatomical syndrome in which the arachnoidal space occupies the sella turcica. It can be caused by a defect in the diaphragma sellae allowing liquor pressure to enlarge the sella (primary empty sella), or it can be caused by a mass enlarging the sella, which is surgically removed, infarction, or radiation. Although the pituitary function of adult subjects with empty sella is usually intact, some subjects manifest varying severity of hypopituitarism. Buchfelder et al. (40), in a review of the literature, reported that 57 of 199 patients with empty sella, including their 52 cases, had panhypo- or partial hypopituitarism. In some patients with panhypopituitarism or isolated pituitary hormone deficiency, empty sella can be revealed (40, 41, 42). Isolated TSH deficiency associated with empty sella has been reported (43, 44, 45, 46) in the manner as isolated ACTH deficiency (42). In our study, three of six patients had empty sella. On the other hand, Komatsu et al. (47) reported that antipituitary antibody is positive in many patients with empty sella and suggested that antipituitary antibody may play a role in the development of empty sella. They reported that antibodies reacting with ACTH-secreting mouse AT-T20 cells and with PRL-secreting rat GH3 cells were found in 75% and 47%, respectively, of 32 patients with empty sella. Sugiura et al. (41) and Kajita et al. (42) reported that patients with isolated ACTH deficiency frequently have antipituitary antibody. Antipituitary antibody may be related to morphological anomalies such as empty sella and pituitary tumor or to functional anomalies such as panhypopituitarism, isolated ACTH (41, 42), or GH (11) deficiency. In addition, all but one of the patients with isolated TSH deficiency in this study had antihuman pituitary cytosol antibody. In our series, two of five patients having antihuman pituitary cytosol antibody, had empty sella, one had pituitary microadenoma, and two had no morphological anomalies of the pituitary as revealed on MRI. Only one patient, not having antipituitary cytosol antibody, had empty sella.

No patient with isolated TSH deficiency having antipituitary antibodies has been reported, to our knowledge. Peacy et al. (44) reported a patient with isolated TSH deficiency having partial empty sella, in whom antipituitary antibodies could not be proven. Lymphocytic adenohypophysitis may be an autoimmune disease, which frequently shows transient or permanent hypopituitarism of varying severity (32). In the later stages of lymphocytic adenohypophysitis, the pituitary may atrophy, leaving an empty sella and hypopituitarism (48), as occurs in Sheehan’s syndrome. Antipituitary antibodies reactive to a 49-kDa pituitary cytosolic protein were found in 70% of patients with lymphocytic adenohypophysitis (49). Etiologically, the thyrotrophs of some of our present patients might have been destroyed autoimmunologically, because of empty sella and/or positive antihuman pituitary cytosol antibody. However, we could not examine the antihuman thyrotroph antibodies in this study. No studies on antithyrotrophs antibody have been reported, although a study on anti-TSH antibody is available (50). Autoimmune damage against the thyrotroph should be investigated in greater detail in the future.

Rose et al. (4) have suggested that most prior studies failed to accurately identify many patients with central hypothyroidism because of diagnostic criteria that require thyroid hormone levels below the reference range in addition to a low TSH level. They studied 208 pediatric cancer survivors to determine how often central hypothyroidism remained undetectable by routine outpatient tests of thyroid hormones. Using TRH stimulation and TSH-nocturnal surge, they found central hypothyroidism of various degrees in 57 of 208 patients examined. Furthermore, 15 (24%) of them showed no impairment of any other pituitary hormone. In these pediatric cancer survivors, irradiation and/or chemotherapy were the major factors influencing hormone deficiency. The author further reported that 30 of 181 children with apparent idiopathic short stature and without GH deficiency and primary hypothyroidism had a blunted TSH surge, isolated central hypothyroidism (31).

It is conceivable that idiopathic isolated deficit of TSH secretion is not so rare, based on the results of our study. From only routine tests of serum basal thyroid hormone and TSH levels, such patients will be missed. When considering hypothyroidism through clinical symptoms, routine examination of thyroid function is not sufficient. Serum TSH and fT3 response to TRH stimulation and nocturnal surge of serum TSH should also be examined.

Received August 4, 2000.

Revised October 25, 2000.

Accepted November 6, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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