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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5696-5703
Copyright © 2003 by The Endocrine Society

Is the Thyrotropin-Releasing Hormone Test Necessary in the Diagnosis of Central Hypothyroidism in Children

Ameeta Mehta, Peter C. Hindmarsh, Richard G. Stanhope, Caroline E. Brain, Michael A. Preece and Mehul T. Dattani

London Center of Pediatric Endocrinology and Metabolism and Institute of Child Health, London, United Kingdom WC1N 1EH

Address all correspondence and requests for reprints to: Dr. Mehul Dattani, Pediatric Endocrinology, Institute of Child Health and Great Ormond Street Children’s Hospital, 30 Guilford Street, London, United Kingdom WC1N 1EH. E-mail: mdattani{at}ich.ucl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To determine the value of the TRH test, we analyzed the unstimulated serum T4 and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T4, total T4, and basal TSH concentrations were 0.6 ng/dl, 4.0 µg/dl, and 2.8 µU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase ({Delta}) in TSH, 4.5–17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk ({Delta}TSH, >17.8), absent/blunted ({Delta}TSH, <4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T4 measurements.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE NORMAL SECRETION of T4 depends upon an intact hypothalamo-pituitary-thyroid axis. The thyroid hormones, T4 and T3, are crucial for normal growth and development of the central nervous system. Untreated hypothyroidism is associated with considerable morbidity, in particular, a high incidence of delayed mentation and short stature. Congenital central hypothyroidism (CH), which may be due to isolated deficiency of TSH or, more commonly, combined pituitary hormone deficiency (CPHD), is less common than primary thyroid disorders. Only 60 cases of isolated TSH deficiency have been reported up to 1998 (1). Congenital CH that occurs in combination with other hormone deficiencies is usually due to developmental abnormalities of the pituitary gland or hypothalamus. These may be idiopathic or due to mutations in one of a number of transcription factors (POU1F1 or PIT1, PROP1, HESX1, LHX3, and LHX4) (2, 3).

An inappropriately low serum TSH concentration in the presence of subnormal serum T4 and T3 concentrations is characteristic of CH. However, the diagnosis is not always evident from measurement of unstimulated serum TSH and T4 concentrations. TRH releases preformed TSH from the pituitary into the circulation and also increases TSH synthesis. Administration of TRH in normal individuals produces a consistent rise in serum TSH concentrations, with a peak concentration at 20 min, followed by a decrease in the measured concentrations at 60 min (4). The test has been used as an adjunct in the diagnosis of CH. It has been suggested that differences exist between TSH responses in pituitary and hypothalamic disease. An absent or impaired response is believed to be indicative of primary pituitary disease, and a prolonged lack of TRH in patients with hypothalamic disease has been postulated to result in a delayed rise in serum TSH concentration (5).

Given these data, we aimed first to determine whether TRH tests have a role to play in the diagnosis of congenital CH and second to establish whether this particular test could differentiate between pituitary and hypothalamic disease. We have undertaken a retrospective analysis of unstimulated serum T4 and TSH concentrations in 54 patients with CH. The serum TSH responses to stimulation with TRH were also analyzed in 30 of these patients who underwent a TRH test.


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

A retrospective study of the case records of patients attending the London Centre for Pediatric Endocrinology based at Great Ormond Street Children’s Hospital and University College London Hospitals was undertaken. A diagnosis of CH was made if the serum T4 concentration was subnormal [free T4 (FT4), <0.9 ng/dl (12.0 pmol/liter); total T4 (TT4), <5.0 µg/dl (65 nmol/liter)] with either 1) an inappropriately low serum TSH concentration (<5 µU/ml), thereby ruling out primary hypothyroidism; or 2) biochemical evidence of other pituitary hormone deficiencies. Patients with acquired lesions such as pituitary tumors, cranial irradiation, trauma, or inflammatory pathology were excluded from the study.

Subjects

The records of 54 patients [male/female ratio (M/F), 36:18; age range, 0–11 yr] were available for analysis. Clinical information extracted from the case notes included details of birth weight, gestation, neonatal complications, age at presentation, and age at diagnosis of hypothyroidism. Depending on the clinical criteria, the patients were divided into 2 groups: group A, CH patients with isolated hypothalamo-pituitary (H-P) disease; and group B, CH patients with H-P disease and additional midline brain defects, which included optic nerve hypoplasia, corpus callosal or septum pellucidum abnormalities, and/or a forebrain cleavage defect [holoprosencephaly (HPE)]. Within group B, a diagnosis of septo-optic dysplasia (SOD) was made when the patient manifested at least two of the three characteristic features, i.e. optic nerve hypoplasia, pituitary abnormalities, and an abnormality of either the septum pellucidum or the corpus callosum on neuroimaging.

Methods

Endocrine investigations were performed at the time of presentation. Baseline serum concentrations of T4 (free or total) and TSH were measured on the Immulite 2000 analyzer as a chemiluminescent immunometric analysis (Diagnostic Products, Gwynedd, UK). A TRH test, using 7 µg/kg TRH, iv, to a maximum of 200 µg was undertaken in 30 patients who presented more recently. The TRH test was added to the protocol for investigation of children with hypopituitarism to delineate the hypothalamo-pituitary-thyroid axis more clearly, given that several patients with hypopituitarism had unstimulated serum TSH concentrations that were within the normal range. The patients were also evaluated for the presence of CPHD. GH deficiency was diagnosed when a peak GH concentration of less than 6.7 ng/ml (20 µ/liter) was achieved using a single provocation test [glucagon (0.1 mg/kg, im) in children under 12 yr age, insulin (0.15 U/kg, iv) in older children and adolescents] in combination with a poor growth velocity, low concentrations of GH-dependent factors (IGF-I and IGF-binding protein-3), and abnormal neuroradiology. ACTH deficiency was diagnosed when the peak cortisol response was less than 19.8 µg/dl (<550 nmol/liter) in response to stimulation with insulin-induced hypoglycemia, glucagon, or Synacthen (62.5–250 µg depending on age). If the response to glucagon or Synacthen revealed a suboptimal cortisol response, a 24-h cortisol profile was undertaken to support the diagnosis of cortisol insufficiency. Gonadotropin (GN) deficiency was diagnosed by subnormal LH and FSH responses to GnRH (2.5 µg/kg, iv) depending upon the age. Abnormal posterior pituitary function was defined as the presence of diabetes insipidus, confirmed by a water deprivation test in symptomatic patients. The normal range for the basal serum PRL concentration was between 5–25 ng/ml (100–500 mU/liter). Samples for GH, cortisol, LH, FSH, and PRL were also analyzed on the DPC Immulite 2000 analyzer by immunometric analysis.

Patients with visual disturbances underwent a detailed opthalmological evaluation for the presence of optic nerve hypoplasia. Pituitary and hypothalamic morphology were assessed in all patients using magnetic resonance imaging (MRI). Details noted included the size of the adenohypophysis, the position of the posterior pituitary signal, and the presence and morphology of the optic nerves, optic chiasm, pituitary stalk, and midline structures, such as the septum pellucidum and corpus callosum.

Controls

Serum FT4 (or TT4) and unstimulated serum TSH concentrations were also measured in 93 children with no endocrine dysfunction and in 38 newborns with congenital primary hypothyroidism. Of the former group, 30 children with a mean age of 9.9 ± 3.0 yr (M/F, 1:1) also underwent a TRH test.

Statistical analysis

The increase in TSH ({Delta}TSH) was calculated as the difference between the peak and basal serum TSH concentrations. The 10th-90th percentiles of the {Delta}TSH in controls were arbitrarily selected to delineate a normal range to obtain as tight a normal range as possible for the control population. Based on these percentiles [10th percentile ({Delta}TSH, 4.5) and 90th percentile ({Delta}TSH, 17.8)], the serum TSH responses observed in our patients (n = 30) were divided into four groups: 1) absent or blunted ({Delta}TSH, <4.5) response with peak serum TSH concentration at 20 min, 2) normal response ({Delta}TSH, 4.5–17.8) with peak serum TSH concentration at 20 min, 3) brisk response ({Delta}TSH, 17.8) with peak serum TSH concentration at 20 min, and 4) delayed response with peak serum TSH concentration at 60 min. Given the difference in mean age between the control group and our patient group, caution should be exercised in comparing the responses to TRH. However, to our knowledge there are no data to support age-related changes in TRH testing in this population.

All data are expressed as the mean ± SD. Between-group comparisons were performed using a t test for large groups and the {chi}2 test for a 2 x 2 group comparison. Correlation analysis was performed using Pearson’s correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 54 CH patients, 24 had isolated H-P disease (group A; patients 1–24), whereas in 30 patients, midline brain defects were associated with hypopituitarism (group B; patients 25–54). Of the latter, 28 were diagnosed with SOD, and 2 patients had HPE (patients 27 and 34). In 52 of the 54 patients, TSH deficiency was associated with CPHD, whereas 2 patients had isolated TSH deficiency (patients 16 and 34). A TRH test was performed in 15 children within each group. The clinical data, basal serum hormone concentrations, TRH test results, and MRI findings of patients with CH in group A are shown in Table 1Go, whereas Table 2Go shows similar data for CH patients in group B.


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  		TABLE 1. Clinical, biochemical, and MRI findings in CH patients with isolated H-P disease (group A)

 

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  		TABLE 2. Clinical, biochemical, and MRI findings in CH patients with H-P disease and midline brain defects (group B)

 
Patient characteristics

The sex distribution and perinatal details of patients within groups A and B are shown in Table 3Go. There was a greater M/F preponderance in group A, although the difference was not statistically significant. The mode of delivery was known in 18 patients in group A (normal vaginal delivery, 50%; forceps delivery, 5.5%; emergency lower segment caesarian section, 44.5%) and in 24 patients in group B, with fewer assisted instrumental deliveries in the latter group (normal vaginal delivery, 62.5%; forceps delivery, 8.3%; ventouse delivery, 8.3%; emergency section, 20.9%). Perinatal complications occurred in 17 patients (70.8%) from group A (hypoglycemia, n = 14; persistent jaundice, n = 7; seizures, n = 2; feeding difficulties, n = 4; recurrent sepsis, n = 4; hyponatremia, n = 2) and in 22 patients (73.3%) from group B (hypoglycemia, n = 18; persistent jaundice, n = 13; seizures, n = 7; feeding difficulties, n = 5; recurrent sepsis, n = 4; hyponatremia, n = 2). Genital abnormalities, such as microphallus and undescended testes, were noted in 52.8% of all males at birth (group A, 9 of 18; group B, 10 of 18).


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  		TABLE 3. Clinical characteristics of patients: group A (isolated H-P disease) and group B (H-P disease and associated midline defects)

 
All but two patients had evidence of CPHD. Patient 16 (group A) with isolated TSH deficiency presented with growth failure in infancy and, apart from an absent serum TSH response to TRH stimulation, had normal anterior pituitary function. He responded to T4 treatment and continued to have profound TSH deficiency on retesting in adulthood. There were no abnormalities on neuroimaging. Patient 34 with HPE (group B) has isolated TSH deficiency and, to date, has not developed any other hormone deficiency.

GH deficiency was the most common associated hormone abnormality. Provocative testing had been performed in 21 patients in group A and 28 patients in group B. The remainder (n = 5) have normal growth to date and have not undergone provocation tests. All patients were investigated for ACTH deficiency and hypocortisolemia. GN function was tested in 18 patients in group A and 24 patients in group B, and deficiency was confirmed in 55.5% and 62.5% of those tested, respectively. Of the patients not tested for GN deficiency, an additional 4 patients are likely to be deficient given the presence of genital abnormalities at birth (bilateral undescended testes and microphallus). Posterior pituitary dysfunction was demonstrated only in patients with midline defects (n = 7). The basal serum PRL concentrations were significantly (P = 0.05) higher in patients with midline brain defects [range, 4.9–147.3 ng/ml (98–2947 mU/liter); mean, 46.2 ± 38.1 ng/ml (923.7 ± 38.1 mU/liter)] compared with those in group A [range, 0.7–94.2 ng/ml (14–1887 mU/liter); mean, 25.8 ± 26.5 ng/ml (516.4 ± 530.3 mU/liter)].

Patients with midline defects presented significantly (P = 0.02) earlier than those with isolated H-P disease. They were also diagnosed with CH at an earlier age. A significantly (P = 0.05) greater number of group B patients (40%) were diagnosed with CH and other hormone deficiencies within the first month of life compared with those in group A (12.5%). A further 12 patients, 6 within each group, were diagnosed in the first year of life due to symptoms of hypoglycemia, recurrent infections, genital abnormalities, or visual impairment. Short stature with a poor growth velocity was the primary mode of presentation in the 13 individuals in group A who presented between the ages of 1 and 11 yr. A late diagnosis of SOD was made in 6 patients after infancy, up to 4.5 yr of age.

Evolving TSH deficiency was evident in eight individuals, two in group A (patients 13 and 18) and six in group B (patients 25, 29, 38, 46, 49, and 53), up to 11.78 yr after the initial presentation. All patients had normal serum T4 concentrations at initial presentation with H-P disease, but evolved into hypothyroidism over time. A TRH test was performed in five of eight cases. Patient 13 was initially diagnosed with deficiencies of GH, ACTH, LH, and FSH at 0.2 yr of age, at which stage he had normal thyroid function. On repeat testing 3.4 yr later, he had subnormal serum T4 concentrations, with an absent TSH response to TRH. Patient 18 presented at 10 yr with growth failure and documented GH and ACTH deficiencies, but normal thyroid function tests. At 16 yr of age, on repeat evaluation, he was found to have hypothyroidism, with a blunted serum TSH response to stimulation. Of the six patients from group B, a TRH was performed in three at the time of hypothyroidism. A normal serum TSH response ({Delta}TSH, 8.6) was demonstrated in patient 53, a blunted serum TSH response ({Delta}TSH, 1.0) in patient 25, and a brisk serum TSH response ({Delta}TSH, 18.7) in patient 46.

Basal hormonal profile

Serum FT4 (n = 44), TT4 (n = 10) and basal serum TSH concentrations were 0.6 ± 0.1 ng/dl (7.7 ± 1.8 pmol/liter), 4.1 ± 0.8 µg/dl (53.6 ± 9.8 nmol/liter), and 2.5 ± 1.5 µU/ml in patients in group A and 0.7 ± 0.1 ng/dl (8.6 ± 1.5 pmol/liter), 3.9 ± 0.7 µg/dl (50.8 ± 9.1 nmol/liter), and 3.1 ± 2.5 µU/ml in patients in group B, respectively. There were no statistical differences between the serum concentrations in both groups. Although the majority (90.7%) of patients had basal serum TSH concentrations less than 5 µU/ml, an elevated concentration (>5 µU/ml) was observed in five patients (patients 22, 32, 40, 52, and 54), four of whom had SOD. The relationship between serum FT4 and basal serum TSH concentrations was shifted to the left compared with that in euthyroid individuals (Fig. 1Go). A similar relationship was observed between serum TT4 and the basal serum TSH concentration (data not shown). Patients with primary hypothyroidism had markedly elevated serum TSH concentrations at diagnosis (Fig. 1Go). There were no significant differences in the basal serum TSH concentrations between males and females in both patients and controls.



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  		FIG. 1. Relationship between baseline serum FT4 and log-transformed serum TSH concentrations in patients with CH (n = 44; •) and primary hypothyroidism (n = 38; X) and in controls (n = 63; {triangleup}).

 
TRH test

A TRH test was performed in 30 patients and 30 controls. Of the 30 patients, 15 belonged to group A and an equal number to group B. The remainder (24 of 54) did not undergo a TRH test and were started on T4 treatment based upon low serum FT4 or TT4 concentrations. The serum TSH responses to stimulation are illustrated in Fig. 2Go. Males and females did not respond differently to TRH stimulation.



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  		FIG. 2. TRH test. The {Delta}TSH values in CH patients with isolated H-P disease (group A) and in those with H-P disease and midline brain defects (group B) were compared with the 10th and 90th percentiles of the {Delta}TSH values in the controls. •, Patients with a peak serum TSH concentration at 20 min; {circ}, patients with a peak serum TSH concentration at 60 min.

 
The mean basal serum TSH concentrations in patients with an absent/blunted response, a normal response, a brisk response, or a delayed response and those in controls were 2.1 ± 1.1, 1.8 ± 0.8, 3.0 ± 0.9, 3.0 ± 1.5, and 2.0 ± 0.8 µU/ml, respectively (Fig. 3Go). Patients with brisk or delayed responses had significantly higher basal serum TSH concentrations compared with those who had absent/blunted or normal responses (P = 0.02) or controls (P = 0.003).



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  		FIG. 3. Basal serum TSH concentrations in patients and controls who underwent the TRH test (horizontal line represents the mean).

 
A normal TRH test ({Delta}TRH, 4.5–17.8) was observed in a total of 7 patients (23.3%) despite subnormal serum T4 concentrations. Such a serum TSH response was evident in both patients with (patients 4, 6, and 19) and those without (patients 34, 36, 47, and 53) associated midline defects. An abnormal TRH test was demonstrated in a total of 23 patients. Seven patients (46.7%; patients 12, 13, 16, 18, 20, 21, and 24) in group A demonstrated an absent or blunted response compared with only 2 patients (13.3%; patients 25 and 42) in group B. Patient 16 with idiopathic isolated TSH deficiency had an absent response. A total of 5 patients (16.7%) had a brisk response with a {Delta}TSH of more than 17.8. Of these, the majority (80%) had midline brain defects (patients 28, 46, 48, and 51). A delayed serum TSH peak was observed in 9 patients (30%), 4 in group A (patients 7, 9, 11, and 14) and 5 in group B (patients 31, 37, 43, 50, and 52). Such a response was observed in a significantly (P = 0.05) higher number of patients compared with controls (6.7%). The mean basal serum PRL concentration [63.5 ± 48.8 ng/ml (1270.9 ± 976.8 mU/liter)] was significantly (P = 0.01) higher in patients with the delayed serum TSH response compared with the serum PRL concentrations [24 ± 21.4 ng/ml (481 ± 429 mU/liter)] in patients with other responses.

Among the five patients who demonstrated elevated basal serum TSH concentrations, a TRH test had been performed in only one case, and he had a delayed serum TSH response.

Neuroimaging

MRI scan was normal in only three patients (patients 10, 15, and 16). The scan was normal in the single patient with idiopathic isolated TSH deficiency (patient 16). The other two patients (patients 10 and 15) had CPHD due to isolated H-P disease. The abnormalities included a small anterior pituitary (n = 39), an undescended posterior pituitary (n = 24), an absent or thin septum pellucidum or corpus callosum (n = 22), an absent or thin stalk (n = 21), optic nerve hypoplasia (n = 23), and HPE (n = 2).

The basal serum TSH concentration or the {Delta}TSH did not differ significantly between patients with a small or normal anterior pituitary. Of the patients who had anterior pituitary hypoplasia without any midline or stalk abnormalities, only 50% had an absent/blunted serum TSH response. No correlation was observed between serum TSH concentrations in response to TRH and the height or volume of the anterior pituitary. This lack of correlation may be due to the small percentage of the anterior pituitary that is composed of thyrotrophs. A delayed serum TSH rise was demonstrated in 41.7% of cases with stalk abnormalities, but also in 22.2% of patients who had a normal stalk; this difference was not statistically significant. The mean serum PRL concentration was 54.4 ± 41.5 ng/ml (1087 ± 829.2 mU/liter) in those with an absent/thin stalk compared with 25 ± 19.5 ng/ml (500.9 ± 389.6 mU/liter) in those with a normal stalk, but, again, this difference did not reach statistical significance (P = 0.06). Only 7.7% of patients with defects of the septum pellucidum or corpus callosum (n = 13) demonstrated an absent/blunted serum TSH response compared with 47% of patients without such a defect (n = 17; P = 0.05).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Pulsatile and circadian TSH secretion is controlled predominantly by TRH (6). A normal serum TSH response to TRH stimulation is best described as a normal unstimulated serum TSH concentration with a peak concentration within 30 min, followed by a decline in the serum TSH concentration, subsequently reaching the unstimulated value (4, 7, 8). Several studies (9, 10, 11) have attempted to differentiate patients with CH based on the serum TSH response to TRH stimulation. Pituitary hypothyroidism strictly implies a quantitative abnormality by which a diminished number of functioning thyrotrophs are associated with a low TSH secretion and an absent or blunted response to stimulation with TRH. Hypothalamic CH is postulated to be a qualitative abnormality due to a prolonged lack of TRH resulting in reduced pituitary TSH content and a delayed rise in serum TSH concentration. However, there is still considerable controversy surrounding this differentiation (9, 12, 13, 14).

Only 30% of our patients had an absent or blunted serum TSH response suggestive of pituitary disease. A further 30% of cases had a delayed hypothalamic response, and a brisk serum TSH response was present in 16.7% of patients. The majority (77.8%) of patients who had a delayed serum TSH peak had exaggerated stimulated concentrations ({Delta}TSH, >17.8). Our data suggest that this differentiation between pituitary and hypothalamic disease may be rather simplistic, as only 50% of patients with anterior pituitary hypoplasia and no stalk or midline deficits demonstrated an absent or blunted response. Stalk disruption suggestive of H-P disconnection, and hence hypothalamic disease, was evident in a total of 12 of 30 patients who underwent the TRH test. Of these, a delayed response was observed in only 41.7%; it was also observed in 22.2% of patients who did not have stalk disruption. Interestingly, a similar delayed response was present in 2 controls. Additionally, Cohen et al. (15) reported 2 patients with CH due to mutations within PIT1, 1 of whom demonstrated a delayed TSH rise. A similar response was reported in a patient with CH due to a mutation within PROP1 (16). Both PIT1 and PROP1 are pituitary-specific transcription factors and are certainly not associated with a hypothalamic phenotype. Hence, a pituitary cause of CH cannot be ruled out on the basis of a delayed serum TSH response.

Seven of our patients had a normal serum TSH response ({Delta}TSH between the 10th-90th percentiles of our control population) despite subnormal serum T4 concentrations. Previous studies (14, 17, 18, 19) have demonstrated similar normal responses in 30–90% of patients with CH. Evaluation of the nocturnal serum TSH surge has been suggested that it is a more sensitive marker for the diagnosis of CH in such patients (19, 20). The nocturnal surge in spontaneous TSH secretion is altered not only in patients with CH, but also in euthyroid patients with suprasellar extensions of pituitary lesions (21). It has been suggested that nocturnal serum TSH profiling, possibly in combination with a TRH test, may be more useful in the diagnosis of CH, particularly when basal serum TSH concentrations are normal or elevated.

Unstimulated serum TSH concentrations ranged from 0.04–11.0 µU/ml in our study compared with 1.0–3.8 µU/ml in controls. In contrast to previous studies (22), the unstimulated serum TSH concentration in our group did not correlate with the {Delta}TSH. The serum FT4 concentrations were also highly variable, ranging from 0.4–0.9 ng/dl (5.0–11.5 pmol/liter). There was no significant relationship between either unstimulated serum T4 or serum TSH concentrations and the age at diagnosis of CH.

Of our five patients who had elevated unstimulated serum TSH concentrations, an absent pituitary stalk suggestive of hypothalamic disease was documented in only one case. The exact mechanism underlying the elevated unstimulated serum TSH concentrations remains unknown, although it has been postulated that the TSH measured in these patients is biologically inactive (9, 17, 18, 23, 24). This explanation may also apply in those individuals who demonstrate normal serum TSH responses.

Neuroimaging was performed in all of our patients and was abnormal in 94.4%. Patients with midline brain defects, particularly those with SOD, are known to have a complex phenotype that is highly variable and evolving (25, 26). Hypothalamic dysfunction is also commonly associated with SOD (27, 28). Four of our 5 patients (80%) with elevated unstimulated serum TSH concentrations at diagnosis had SOD. A TRH test was performed in 14 patients with SOD. Of these, an absent/blunted serum TSH response was present in 2 patients, a normal serum TSH response was present in 3 patients, a brisk response was present in 4 patients, and a delayed rise in serum TSH was present in 5 patients, although the latter was also observed in patients without midline defects. Of the 4 patients with elevated unstimulated serum TSH concentrations, only 1 had been investigated using a TRH test, the response to which was delayed. Patients with SOD who had abnormalities of the septum pellucidum and/or corpus callosum were less likely to demonstrate an absent/blunted response (7.7%) than those without these abnormalities (47%). Although hypothyroidism evolved in patients with and without midline defects, this phenomenon was more common in those with SOD (75%). Serum PRL concentrations were elevated in patients in both groups, but were significantly higher in those with midline defects than in those without. Measurement of random and TRH-stimulated serum PRL concentrations has been shown to provide a means of distinguishing pituitary from hypothalamic disease (29). Posterior pituitary dysfunction was only noted in patients with SOD. Of the 7 patients with diabetes insipidus, a TRH test had been performed in 4 cases, all of which were abnormal.

It is clear from both previous reports and our data that a normal TRH test (23.3% of our patients) does not exclude abnormalities in the hypothalamic-pituitary-thyroid axis (10). It has been suggested that a combination of nocturnal serum TSH measurements together with the TRH test is necessary to identify all patients with CH, because abnormal TRH-TSH dynamics may precede CH (30).

Isolated TSH deficiency was observed in only two of our patients. Of these, one patient had idiopathic isolated TSH deficiency, and the other had HPE. The etiology of idiopathic isolated TSH deficiency is still unclear in many reported cases, although genetic mutations of the TSHß gene (31, 32) or of the TRH receptor gene (33) may account for some cases. Our patient with idiopathic isolated TSH deficiency had no rise in serum TSH concentration in response to TRH, as previously reported (34). More commonly, TSH deficiency occurs in combination with a number of other pituitary hormone deficiencies. Among our patients, GH deficiency was the most common associated endocrine abnormality; it was present in 88.9% of patients. ACTH and GN deficiencies were present in 77.8% and 46.3% of patients, respectively. Posterior pituitary dysfunction was evident in 13% of patients, all of whom had SOD. The high incidence of CPHD in patients with CH highlights the need to investigate the H-P axis carefully for other endocrine abnormalities. There was also a high prevalence (72.2%) of neonatal complications [perinatal hypoglycemia (59.2%), persisting neonatal jaundice (37%), sepsis (14.8%), feeding difficulties (16.7%), seizures (16.7%), and hyponatremia (7.4%)]. However, in only 27.8% of patients was the diagnosis of CH made during the neonatal period.

We conclude that a TRH test may be of limited use in those patients in whom other biochemical or neuroradiological H-P abnormalities have been demonstrated, particularly in light of the occasional discomfort to the patients resulting from the administration of TRH (nausea and flushing). Regular evaluation of serum FT4 or TT4 concentrations may reveal the diagnosis, which is usually made in the presence of a low serum T4 concentration in the face of a low, normal, or even modestly elevated unstimulated serum TSH concentration. Additionally, there is considerable overlap between patients with pituitary disease and those with hypothalamic disease in terms of the serum TSH response to TRH. Patients with midline defects on neuroimaging, particularly SOD, have a more complex phenotype characterized by elevated basal serum TSH concentrations, often with brisk or delayed responses to TRH, and evolving disease. Indeed, a delayed response can occur both in patients and in the normal population. On the other hand, a normal TRH test does not rule out CH, and the pathogenesis of CH in patients demonstrating such normal responses is still unclear.


   Footnotes
 
This work was supported by Medical Research Council Career Establishment Grants (to M.T.D. and A.M.) and a grant from Novo Nordisk, United Kingdom (to A.M.).

Abbreviations: CH, Central hypothyroidism; CPHD, combined pituitary hormone deficiencies; FT4, free T4; GN, gonadotropin; H-P, hypothalamo-pituitary; HPE, holoprosencephaly; M/F, male/female ratio; MRI, magnetic resonance imaging; {Delta}TSH, increase in TSH; SOD, septo-optic dysplasia; TT4, total T4.

Received June 2, 2003.

Accepted September 11, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hashimoto K 1998 The etiology of isolated thyroid stimulating hormone deficiency. Intern Med 37:231–232[Medline]
  2. Dattani MT, Robinson IC 2000 The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet 57:337–346[CrossRef][Medline]
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