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Original Studies |
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
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Abstract |
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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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)
Five women and one man with a mean age of 46.2 yr were
investigated. The complaints of the patients are listed in Table 1, 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 1. 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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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 
-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 -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 2.
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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.
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Results |
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)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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)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 -subunit responses to TRH
administration (Table 4 and Fig. 1A)
The increase of serum TSH was blunted in all patients. Any
increase in the response of plasma -subunit could not be made clear
in any patients. Serum fT3 levels 120 min after
administration of TRH were extremely low (Table 4), and the rates of
increase were also low (Fig. 1A). 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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)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 5)
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 -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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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
-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 -subunit. During
TRH stimulation, the increase of plasma -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 -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.
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References |
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subunit of the pituitary glycoprotein hormones. Am J
Clin Pathol. 94:417–421.[Medline]
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