AJR 2003; 181:577-582
© American Roentgen Ray Society
MR Imaging Features of Thyrotropin-Secreting Pituitary Adenomas at Initial Presentation
Nicholas J. Sarlis1,2,
Loukas Gourgiotis1,
Christian A. Koch3,4,
Monica C. Skarulis5,
Françoise Brucker-Davis6,
John L. Doppman7,8,
Edward H. Oldfield9 and
Nicholas J. Patronas7
1 Clinical Endocrinology Branch, National Institutes of Diabetes, Digestive and
Kidney Diseases, National Institutes of Health, Rm. 8D04, Bldg. 10, 10 Center
Dr., Bethesda, MD 20892.
2 Present address: Department of Endocrine Neoplasia and Hormonal Disorders, The
University of Texas M. D. Anderson Cancer Center, Unit 435, 1515 Holcombe
Blvd., Houston, TX 77030-4009.
3 Pediatric and Reproductive Endocrinology Branch, National Institute of Child
Health and Human Development, National Institutes of Health, Rm. 9D42, Bldg.
10, 10 Center Dr., Bethesda, MD 20892.
4 Present address: Department of Medicine III, University of Leipzig,
Phillip-Rosenthal-Str. 27, Leipzig, D-04103, Germany.
5 Division of Intramural Research, National Institutes of Diabetes, Digestive
and Kidney Diseases, National Institutes of Health, Rm. 8D12C, Bldg. 10, 10
Center Dr., Bethesda, MD 20892.
6 Department of Endocrine Medicine and Diabetes, Centre Hospitalier de
l'Université de Nice (CHUN), Nice, Cedex 01, F-06002, France.
7 Department of Radiology, Warren G. Magnuson Clinical Center, National
Institutes of Health, Rm. 1C635, Bldg. 10, 10 Center Dr., Bethesda, MD
20892.
8 Deceased.
9 Surgical Neurology Branch, National Institute of Neurological Diseases and
Stroke, National Institutes of Health, Rm. 5D37, Bldg. 10, 10 Center Dr.,
Bethesda, MD 20892.
Received August 28, 2002;
accepted after revision January 30, 2003.
Presented in part at the second meeting of the Section of
Neuroendocrinology of the German Society of Endocrinology, Göttingen,
Germany, October 1999.
This article is dedicated to the memory of John L. Doppman, who was a
pioneer in research involving imaging techniques in endocrinology and, more
specifically, endocrine oncology.
Address correspondence to N. J. Sarlis.
Abstract
OBJECTIVE. We report the MR imaging characteristics of
thyrotropin-producing pituitary adenomas at their initial presentation and
also report the role of MR imaging in predicting surgical outcome in these
rare tumors.
MATERIALS AND METHODS. We reviewed the records and MR images of 21
patients with thyrotropin-producing pituitary adenomas from 1984 to 1999. The
imaging features of these tumors were examined, including enhancing
characteristics and tumor volumes. A staging system of tumor invasion was
designed by grading cavernous and sphenoid sinus invasion and suprasellar
extension. A cumulative invasion score was then used as a predictor of
short-term surgical outcome.
RESULTS. Twenty patients had macroadenomas, and one patient had a
microadenoma. In 17 of 21 patients, the thyrotropin-producing pituitary
adenoma was clearly visualized as a hypoenhancing mass compressing the normal
pituitary gland. Conversely, in four patients, the pituitary gland was not
discernible because of complete distortion by the adenoma.
Thyrotropin-producing pituitary adenomas were large and showed a tendency to
invade surrounding structures. Tumor volume ranged from 0.42 to 94.2
cm3 (mean ± SD, 16.0 ± 17.8 cm3). The mean
score of tumor invasion was 4.77 ± 2.06 of a maximal possible value of
9.0. A high staging score was found to be predictive of an unfavorable
response to surgery.
CONCLUSION. Thyrotropin-producing pituitary adenomas are usually
large tumors at initial presentation with hypoenhancing features compared with
normal pituitary tissue; they tend to be invasive. Greater amounts of invasion
correlate with incomplete surgical removal of the tumor and continued hormonal
secretion.
Introduction
Thyrotropin-secreting pituitary adenomas are rare tumors, resulting in
central hyperthyroidism. In conjunction with biochemical parameters and
dynamic endocrine testing, imaging evaluation of the pituitary gland and sella
turcica is mandated for establishing the correct diagnosis
[1]. Despite a high resolution
achieved by CT scans with current technology, MR imaging of the pituitary
gland has become the method of choice for the initial evaluation of pituitary
tumors. Pituitary MR imaging is more sensitive than CT in identifying
pituitary microadenomas and can better define the relationship of pituitary
tumors to normal surrounding structures
[2,
3].
The role of MR imaging in the initial evaluation and diagnosis of
thyrotropin-producing adenomas has been suggested in the only original
clinical cohort report from the National Institutes of Health
[4] and three literature
reviews [1,
5,
6]. This study reports our
single-institution experience in the evaluation of 21 patients with
thyrotropin-producing pituitary adenomas and describes the MR imaging features
of these rare tumors. Finally, it also assesses the role of MR imaging in the
management of thyrotropin-producing pituitary adenomas, especially regarding
its ability to predict neurosurgical outcome in patients with these rare
tumors.
Materials and Methods
We retrospectively reviewed the clinical records and MR images of 21
patients with thyrotropin-producing pituitary adenomas from the time of their
initial evaluation. The mean age of patients was 45.8 ± 15.4 years
(mean ± SD) (range, 23–80 years). These patients were enrolled in
a long-term clinical protocol focusing on the natural history of
"inappropriate thyrotropin secretory states" and constituted part
of a large database spanning 15 years (1984–1999) at our institution.
The study protocol was approved by the institutional review board and informed
consent was obtained for the use of clinicolaboratory and imaging data derived
from all patients.
MR images were obtained using a 0.3-T magnet in one, 0.5-T in seven, and
1.5-T in 13 patients. T1-weighted images were obtained before and after IV
administration of contrast agent (0.01 mmol/kg of body weight of gadolinium,
Magnevist, Berlex Laboratories, Montville, NJ). All scans were reviewed by a
neuroradiologist and three endocrinologists, and the findings of the studies
were assessed by consensus agreement among all four physicians. We measured
the anteroposterior, vertical, and transverse diameters of the pituitary
adenomas using precision calipers. Moreover, we calculated the tumor volume by
using the formula for an ellipsoid approximation, 
/6 x (A
x B x C), where A, B, and C
are the anteroposterior, vertical, and transverse diameters of the pituitary
adenomas, respectively. Depending on their enhancement characteristics, tumors
were classified as hypo- or isoenhancing, with respect to the normal pituitary
gland, when it was visible. Finally, we described the anatomic relationship of
the tumors with the surrounding structures and reported any extension to or
invasion of the cavernous sinus, sphenoid sinus, or suprasellar space. The
staging system used specifically for these tumors is shown in Appendix 1 and
is schematically depicted in Figure
1. A cumulative score was calculated for each tumor, as the sum of
the three scores in our staging system—that is, cumulative score =
cavernous sinus invasion score + sphenoid sinus invasion score + suprasellar
extension score. The maximal cumulative score possible with this system is
9.0.
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Fig. 1. —Drawing shows staging system for thyrotropin-producing pituitary
adenomas used in our study. ICA = internal carotid artery, CSI = cavernous
sinus invasion, SSI = sphenoid sinus invasion, SSE = suprasellar
extension.
|
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With regard to follow-up of biochemical indexes, serum thyroid function
tests, including thyrotropin and the serum thyrotropin response to
thyrotropin-releasing hormone stimulation, were performed approximately 6
months after removal of the thyrotropin-producing adenoma. The values of these
three parameters at the time of the initial presentation (i.e., before
neurosurgery) have been previously reported in 17 of 21 patients by
Brucker-Davis et al. [4]. We
considered as evidence of early favorable postoperative tumor response to
surgery a normal or low baseline serum thyrotropin level accompanied by a
normal thyrotropin response after thyrotropin-releasing–hormone
stimulation. To assess the predictive value of MR imaging features of
thyrotropin-producing adenomas regarding early surgical outcome, we correlated
the cumulative score of tumor invasion, as gauged by our staging system at the
time of the patient's initial presentation, with the restoration of normal
biochemistry after surgical excision of the adenoma.
Results
MR imaging features of thyrotropin-producing pituitary adenomas at the time
of the initial presentation were the following: One patient had a microadenoma
(7 x 7 x 6 mm) (Fig.
2), whereas the remaining 20 patients had macroadenomas, of which
the largest measured 52 x 50 x 41 mm. The average dimensions of
the tumors were as follows: anteroposterior diameter, 17.7 ± 6.5 mm;
vertical diameter, 16.2 ± 5.8 mm; and transverse diameter, 16.9
± 6.1 mm. The MR imaging appearance of the adenomas after gadolinium
administration was hypoenhancing with respect to the normal pituitary gland in
17 (81%) of 21 patients. In the remaining four patients, the adenoma could not
be clearly distinguished from the pituitary gland because either they both
showed similar enhancing patterns or the pituitary anatomy was completely
distorted.
The grading of the invasive features of the tumors, as assessed by our
staging system, can be summarized as follows: Regarding cavernous sinus
invasion, findings in five of 21 patients showed invasion grade 0, eight
showed grade 1, two showed grade 2, and six showed grade 3. Regarding sphenoid
sinus invasion, eight of 21 patients had invasion grade 0, five had grade 1,
one had grade 2, and seven had grade 3. Regarding suprasellar extension of the
thyrotropin-producing adenomas, five of 21 patients were assigned grade 0;
seven, grade 1; four, grade 2; and five, grade 3. Furthermore, the MR imaging
features of representative cases of thyrotropin-producing pituitary adenomas
with various degrees of extrasellar extension are shown in Figures
3,
4,
5,
6A,
6B,
6C. Tumor volume ranged from
0.42 to 94.2 cm3 (mean, 16.0 ± 17.8 cm3). The
mean score of tumor invasion was 4.77 ± 2.06 of a maximal possible
value of 9.0. As expected, a strong positive log-linear correlation between
tumor volume and the cumulative staging score for each tumor was also noted
(r = 0.8496, p < 0.002)
(Fig. 7).
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Fig. 5. —50-year-old woman with thyrotropin-producing pituitary adenoma. MR
image shows grade 3 suprasellar tumor extension and significant distortion of
normal pituitary anatomy (arrows) (capping).
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Fig. 6A. —48-year-old woman with thyrotropin-producing pituitary adenoma. MR
image obtained in coronal plane shows grade 3 tumor invasion in both
suprasellar space (black arrowheads) and sphenoid sinus (white
arrowhead).
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Fig. 6B. —48-year-old woman with thyrotropin-producing pituitary adenoma. MR
image obtained in lateral plane shows grade 3 tumor invasion in both
suprasellar space (black arrowhead) and sphenoid sinus (white
arrowheads).
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Fig. 6C. —48-year-old woman with thyrotropin-producing pituitary adenoma. MR
image obtained in coronal plane (more posteriorly located than A) shows
grade 3 tumor invasion in all three axes: suprasellar space (black
arrowhead), cavernous sinuses bilaterally (black arrows), and
sphenoid sinus (white arrows).
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Fig. 7. —Graph shows correlation between tumor volume in cubic centimeters
and cumulative score according to staging system used in our study. As
expected, strong positive log-linear correlation is evident, along with 95%
confidence interval curves for this correlation.
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To assess the validity of our staging system in these rare tumors, we
investigated the correlation of the cumulative score of tumor invasion on MR
imaging (at the time of initial clinical presentation in our institution) with
postoperative changes in biochemical indexes at the time of the patient's
first postoperative follow-up evaluation. We noted the following findings:
none (0%) of the six patients with cumulative scores of less than or equal to
2.0 had evidence of residual tumoral thyrotropin hypersecretion; only one
(12.5%) of eight patients with a cumulative score between 3.0 and 5.0 had
persistently abnormal biochemical indexes; all (100%) of the eight patients
with cumulative staging scores equal to or greater than 6.0 continued to have
evidence of tumoral thyrotropin hypersecretion. All patients with continued
evidence of abnormal thyrotropin dynamics eventually required further
treatment, which consisted of either repeated neurosurgery, external beam
radiotherapy, or long-acting somatostatin analogues. Thus, a high cumulative
staging score, as assessed by our grading system (which was based on MR
imaging morphology), was a strong predictor of a noncurative surgical
outcome.
Finally, with regard to the degree of distortion of normal pituitary
anatomy, in the 17 patients in whom at least part of the pituitary gland could
be distinguished from the adjacent thyrotropin-producing adenoma, we observed
significant displacement of the pituitary gland outside the sella (capping) in
only three patients (17.6%); a representative case of this effect is shown in
Figure 5.
Discussion
Thyrotropin-producing pituitary adenomas represent only 2% of pituitary
tumors [1,
5,
6]. Typically, patients present
with symptoms and signs of thyrotoxicosis, although some patients remain
clinically euthyroid despite significant increases in serum thyroid hormone
levels—presumably because of down-regulation of thyroid hormone
receptors of peripheral tissues
[5]. These rare tumors exhibit
an interesting combination of biochemical findings consisting of elevated
serum thyroid hormone levels in the presence of inappropriately normal or
frankly elevated serum thyrotropin levels
[4]. The differential diagnosis
of thyrotropin-producing adenomas is limited and includes the syndrome of
resistance to thyroid hormone and hypothyroidism-induced pituitary thyrotroph
hyperplasia (the latter occurring in selected patients with hypothyroidism and
intermittently poor compliance to thyroid hormone replacement therapy)
[7]. Although the gross
structural characteristics of these tumors may seem superficially similar to
those of other, much more prevalent pituitary adenomas (such as prolactinomas,
growth hormone–secreting adenomas, and nonfunctioning adenomas), the
degree of microscopic invasion and intra- and peritumoral fibrosis observed
with the thyrotropin-producing adenomas is remarkable and may be related to
basic fibroblast growth factor expression—and possibly other growth
factors—in these tumors
[8]. It has been shown that
thyrotropin-producing pituitary adenomas are less easily cured by surgery than
other types of pituitary adenomas, even when matched for size, because of the
invasive features that the former may attain during the delay between the time
of initial diagnosis and neurosurgery
[9].
In addition to the measurement of serum thyrotropin and thyroid hormone
levels, assessment of several other biochemical parameters—for example,
serum 
-subunit and the -subunit to thyrotropin molar ratio;
dynamic endocrine testing, such as the thyrotropin-releasing hormone
stimulation test [4]; the acute
liothyronine (T3) suppression test
[10]; and the octreotide
suppression test
[11]—can also help
diagnostically. Within the context of the results of these hormonal tests, the
presence of a pituitary adenoma on central nervous system imaging usually
confirms a thyrotropin-producing tumor.
CT and MR imaging are currently used for the evaluation of pituitary and
parasellar abnormalities and masses. Although both are equally diagnostic in
cases of macroadenomas, MR imaging should be the initial scan of choice for
microadenomas because of heightened sensitivity of MR imaging for detection of
pituitary disease [3,
12]. Furthermore, MR imaging
has the additional advantage of better delineating the relationship of
pituitary tumors to surrounding structures
[2].
Our study showed that in the majority (20/21) of cases,
thyrotropin-producing adenomas are large. Furthermore, they frequently invade
surrounding structures such as the cavernous and sphenoid sinuses; they also
extend suprasellarly and may compress the optic chiasm. Therefore, early
diagnosis is highly desirable in maximizing the probability of cure by surgery
alone. The pattern of growth of these tumors is aggressive; hence,
thyrotropin-producing adenomas mimic true pituitary carcinomas or metastatic
malignant deposits to the sella. Finally, with regard to their initial MR
imaging appearance, most thyrotropin-producing adenomas are hypoenhancing
after gadolinium administration.
Our data also show a strong and statistically significant positive
log-linear correlation between tumor volume and the extension of the adenoma
beyond the confinements of the sella, as assessed by our staging system. In
locally aggressive growth hormone–producing adenomas, cavernous sinus
invasion has been shown to be an independent factor influencing early
postoperative outcome [13].
Because of the previously mentioned data and the fact that persistence of
microscopic lateral dural invasion after neurosurgery represents a common
cause of treatment failure in locally invasive pituitary adenomas
[3], we devised a staging
system that includes cavernous sinus invasion as a possible predictor of
outcome. Our findings suggest that the initial MR imaging features of
thyrotropin-producing adenomas predict, at least in part, their response to
transsphenoidal or transfrontal surgery and, hence, the likelihood of
subsequent need for additional treatment—that is, conventional external
beam radiotherapy, gamma knife radiotherapy, or administration of somatostatin
analogs (e.g., octreotide or lanreotide)
[9,
14]. The fact that all
patients with cumulative staging scores between 3.0 and 5.0 (some of them
corresponding even to grade 2 cavernous sinus invasion) still had favorable
early surgical outcomes could be explained by two factors that are not
mutually exclusive: the possibility that MR imaging may overestimate tumor
burden in patients in whom the dura is simply displaced but not frankly
infiltrated by the tumor (pressure effect) and the fact that our data pertain
to a tertiary referral center setting, which may not be representative of the
general neurosurgical community in all instances.
With regard to potential weaknesses of our study, the following points are
pertinent: Our patient data reflect observations made over 15 years. During
this time, the broader use of third-generation (ultrasensitive) assays for the
measurement of serum thyrotropin, the inclusion of determinations of free
thyroxine levels along with thyrotropin in serum chemistry panels
[15], and the progressively
more astute recognition by endocrinologists of inappropriate thyrotropin
secretion states [16] have
probably increased the ability of clinicians to suspect thyrotropin-producing
adenomas and have led to the detection of these tumors at an earlier stage
during their natural history. Hence, the expansile and invasive MR imaging
features of thyrotropin-producing adenomas—at their initial
presentation—described in our series may not be as prominent in future
studies of newly diagnosed patients with these tumors. Furthermore, at least
theoretically, it could be possible to characterize the MR imaging signal
features of thyrotropin-producing adenomas compared not with the pituitary
gland but with another adjacent structure with similar signal
features—for example, the pons. In this fashion, one could always
comment on the hypo- or hyperenhancing appearance of these tumors, even if the
pituitary gland is completely obliterated or invisible. However, we have not
attempted such comparisons in our study. Because of the extreme rarity of
thyrotropin-producing adenomas, the relatively low number of cases in our
series, and the variable technologies used over time for MR imaging in our
cohort (instruments with field intensities ranging from 0.3 to 1.5 T), we
could not correlate MR imaging signal intensity or pattern features of
thyrotropin-producing adenomas with the degree of invasion shown by them.
Finally, we accept the fact that our staging scale of invasion needs further
validation in future studies in the realm of either thyrotropin-producing
adenomas or other pituitary macroadenomas. Although cavernous sinus invasion
is definitely associated with poorer surgical outcome in macroadenomas in
general [13], it should not be
regarded as the only determinant of such outcome. In several instances,
difficult access to neurosurgical exploration via a heavily infiltrated
sphenoid sinus can also lead to surgical failure. Similarly, the presence of
significant suprasellar extension, especially when it involves the optic
chiasm and the temporoparietal lobes, can also represent a significant
surgical dilemma. If validated by future studies, our proposed integrated
scale assessing tumor extension in all three axes may offer a better predictor
of outcome rather than only the degree of lateral cavernous sinus invasion by
the tumor.
In conclusion, our analysis of the MR imaging characteristics of
thyrotropin-producing pituitary adenomas before initial medical or
neurosurgical intervention showed that these tumors—most often
presenting as hypoenhancing (after gadolinium administration) pituitary
lesions in comparison with the normal pituitary gland—are mostly of
moderate-to-large size with a mean diameter in any axial dimension of 1.7 cm;
are prone to surrounding tissue invasion; and, when they invade the
surrounding structures to a significant degree, are unlikely to be cured by
surgery alone.
APPENDIX 1. Staging System for Assessment of Anatomic Relationship of
Thyrotropin-Producing Pituitary Adenomas with Their Surrounding
Structures
Cavernous Sinus Invasion
Grade 0 = no involvement of internal carotid artery circumference Grade 1 =
tumor abutment of less than 50% of internal carotid artery circumference Grade
2 = encasement by tumor of equal to or greater than 50% of internal carotid
artery circumference Grade 3 = tumor extension into the middle cranial fossa
with compression of temporal lobe
Sphenoid Sinus Invasion
Grade 0 = no erosion or remodeling of sellar floor Grade 1 = minimal
erosion and remodeling of sellar floor by tumor Grade 2 = tumor extension into
sphenoid sinus, occupying less than 50% of its height Grade 3 = tumor
extension into sphenoid sinus, occupying equal to or greater than 50% of its
height
Suprasellar Extension
Grade 0 = tumor superior border at or below diaphagma sellae Grade 1 =
tumor extending above diaphragma sellae but not abutting optic chiasm Grade 2
= tumor abutting, but not displacing, optic chiasm Grade 3 = tumor displacing
and compressing optic chiasm
Acknowledgments
We thank Jacob Robbins and Paul M. Yen, National Institutes of Diabetes,
Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,
for their thorough review of the manuscript, as well as constructive comments
and suggestions.
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Abstract
Introduction
