help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2656
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by van Tijn, D. A.
Right arrow Articles by Vulsma, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Tijn, D. A.
Right arrow Articles by Vulsma, T.
Related Collections
Right arrow Neuroendocrinology and Pituitary
Right arrow Pediatric Endocrinology
Right arrow Thyroid
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 2 410-419
Copyright © 2008 by The Endocrine Society

Role of the Thyrotropin-Releasing Hormone Stimulation Test in Diagnosis of Congenital Central Hypothyroidism in Infants

David A. van Tijn, Jan J. M. de Vijlder and Thomas Vulsma

Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: David A. van Tijn, M.D., Department of Pediatric Endocrinology, Emma Children’s Hospital, G8-205, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: tijn1{at}planet.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency. In the case of congenital hypothyroidism of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency. Therefore, in CH-C, rapid diagnosis is even more urgent than in congenital hypothyroidism of thyroidal origin.

Objective: In the assessment of hypothalamic-pituitary-thyroid function, we considered the pituitary response to iv administration of TRH (TRH test) pivotal. We evaluated the usefulness of the TRH test in a cohort of infants with neonatal congenital hypothyroidism screening results indicative of CH-C by analyzing the results within the framework of investigations of the anatomical and functional integrity of the hypothalamo-hypophyseal system.

Design and Setting: The study was a Dutch nationwide prospective study (1994–1996). Patients were included if neonatal congenital hypothyroidism screening results were indicative of CH-C and patients could be tested within 3 months of birth.

Patients: Ten male and five female infants with CH-C, detected by neonatal screening, and six infants with false-positive screening results, nonthyroidal illness, or transient hypothyroidism, were included in the study.

Main Outcome Measures: Results of TRH tests, within the framework of extensive endocrinological examinations and cerebral magnetic resonance imaging, were measured.

Results: All patients with type 3 TSH responses to TRH had MPHD, and the majority (67%) of patients with type 2 responses had isolated TSH deficiency.

Conclusions: The TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. Abnormal TRH test results, especially a type 3 response, urge immediate assessment of integral hypothalamic-pituitary function because the majority of patients have MPHD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Thyroid hormone is extremely important for normal brain development. A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency (1, 2). In the case of congenital hypothyroidism (CH), the damage appears to be especially related to postnatal T4 deficiency (3). Apparently, central nervous system development can at least be partly preserved by a limited but substantial maternal (transplacental) supply of T4 in the prenatal phase (4). Therefore, to minimize the risk of irreversible cognitive and motor defects in CH patients, postnatal T4 supplementation must be started as early as possible (5, 6, 7). In CH of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD) (8, 9). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency (8, 10). Therefore, rapid diagnosis is even more urgent in cases of CH-C than in cases of CH of thyroidal origin (11). In 1995 the program of the neonatal CH screening in The Netherlands was adapted to improve detection of CH-C. Indeed, in a recent evaluation of the 1995–2000 period (12), we calculated a high detection rate for CH-C (91.6%) and an incidence of 1:16,404 [95% confidence interval (CI) 1:13,174 to 1:21,173], considerably higher than previously reported (13, 14, 15). Formerly considered a rare entity of CH, CH-C was found to make up 13.5% of all cases of permanent CH detected in the 6-yr study period (12). In addition, the adapted CH screening method detects a distinct type of CH-C, secondary to gestational maternal hyperthyroidism, with an estimated incidence of at least 1:35,000 (16, 17).

The improved screening approach thus yields a significant number of young infants suspected of CH-C. As for the majority of these patients the abnormal neonatal screening result is the first sign of a pituitary defect, assessment of hypothalamic-pituitary-thyroid (H-P-T) function is crucial in the identification of these patients. Unlike the situation in CH of thyroidal origin, baseline plasma TSH is only of limited value in the diagnosis of CH-C. Therefore, in the assessment of H-P-T function, we consider the pituitary response to iv administration of TRH (TRH test) pivotal. However, although there is extensive literature on the TRH test regarding dosage, dynamics, and criteria for normalcy in adults (18, 19, 20) and older children (21, 22, 23, 24), there are only a limited number of reports on the performance of this test in neonates and young infants (25, 26). This is possibly due to the fact that throughout the world children with CH-C are only rarely detected by neonatal screening (27). Therefore, to analyze the diagnostic potential of the TRH test in young infants and establish references for this particular age group, we conducted a study, using prospective data from a 2-yr cohort of Dutch infants with neonatal screening results indicative of CH-C (9). To validate the TRH test results in the study population, these subjects were analyzed within the framework of investigations of the anatomical and functional integrity of the thyroid’s regulatory system, following a standardized protocol of endocrine function testing and magnetic resonance imaging (MRI) of the hypothalamus-pituitary region, as previously described (9). A mathematical model and Mann Whitney U tests were used for detailed distinction of the responses between patients and controls.


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

The subjects were participants in a Dutch national prospective study, running from April 1, 1994, to April 1, 1996. Infants with neonatal screening results indicative of CH-C and subsequent plasma free T4 (FT4) concentrations less than 0.93 ng/dl (<12 pmol/liter) and plasma TSH concentrations less than 15 µU/ml (<15 mU/liter) were enrolled in the study. Of 385,042 infants screened during the study period, 26 met the inclusion criteria.

Anterior pituitary function was assessed primarily by stimulation tests. TRH and CRH tests took place on consecutive days, immediately after referral. Arginine and GnRH tests were performed at the age of 3 months when euthyroid status had been accomplished by T4 supplementation, and, in case of ACTH deficiency, cortisol was supplemented in a physiological dosage (12 mg/m2 per day). In most infants with abnormal TRH results, MRI of the brain (with three-dimensional imaging of the hypothalamus-pituitary region) was also performed at the age of 3 months. Perinatal characteristics and early endocrine test results of these subjects are summarized in Table 1Go. A detailed study design and overview of function test results were published elsewhere (9). In 2001 and 2006–2007, all cases were reevaluated for revised diagnoses, additional morbidity, growth, and treatment data. The study protocol was approved by the Dutch Pediatric Endocrine Society and the Medical Ethics Committees of the participating centers. Parental informed consent was obtained in all cases.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Perinatal data and neonatal screening results

 
Of the 26 infants enrolled in the study, five (subjects 22–26) were excluded from the statistical calculations. One was excluded because of transient CH-C, secondary to gestational maternal hyperthyroidism, as a consequence of untreated Graves’ disease (16). Three, referred after the age of 3 months, were excluded to avoid possible disturbance of the test results by age differences. One infant with neonatal screening results and plasma TSH and FT4 concentrations indicative of CH-C died of cardiorespiratory insufficiency before further endocrine tests could be performed. The five excluded cases are described in detail in the supplemental data published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org.

The remaining 21 subjects underwent a TRH test at a median age of 39 d (range 14–93 d). Six of the children referred to us during the study period (subjects 1–6) turned out to have false-positive screening results, nonthyroidal illness, or possibly transient CH-C. All six had normal (type 0) TRH test results (Table 2Go and Fig. 1AGo), and all had normal baseline FT4 plasma concentrations, i.e. 0.93 ng/dl or greater (≥12 pmol/liter) at the day of testing. All were screened at the appropriate moment and underwent a TRH test at a median age of 44 d (range 14–93 d). After 5 yr of follow-up, none of the four living patients had developed signs or symptoms of pituitary hormone deficiencies. The assumed reasons for the discrepancy between their abnormal screening results and the normal function test results are described in the supplemental data.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Dynamic tests of thyrotropic function and overview of additional endocrine function test results and MRI results

 

Figure 1
View larger version (16K):
[in this window]
[in a new window]

  		FIG. 1. A, Subjects with type 0 responses (patients 1–6; green curves) and subjects with type 2 responses (patients 9, 10, 11, 13, 14, and 18; red curves). The type 2 response is primarily characterized by impaired release of TSH and thus by reduced height of the peak TSH elevation as compared with the type 0 response (Mann-Whitney, P = 0.004). In the patients with a type 2 response, TSH peaks ranged from 4.8–11.2 µU/ml (4.8–11.2 mU/liter); in the controls, TRH peaks ranged from 14.0–37.6 µU/ml (14.0–37.6 mU/liter). B, Subjects with type 3 responses (patients 7, 8, 12, 15, 16, 17, 19, 20, and 21; blue curves). The type 3 response is primarily characterized by delayed timing of the peak TSH elevation and delayed decrease of the TSH plasma concentration after the peak as compared with the type 0 response. C, Subject patient 22: TRH test results at age 17 d (type 2 response; red curve) and 13 months (type 0 response; purple curve).

 
The remaining 15 infants (subjects 7–21) had abnormal TRH test results and were found to have permanent CH-C during 10 yr follow-up. Of those infants, nine (60%) had evidence of glucocorticoid deficiency, 10 (67%) had evidence of GH deficiency, and six (40%) had evidence of gonadotropin deficiency (28). None of the subjects studied had symptoms indicating disturbance of posterior pituitary function to date (9).

Hormone assays

All hormone assays regarding the H-P-T axis were performed in the laboratory of endocrinology of the Academic Medical Center (Amsterdam, The Netherlands). TSH and prolactin (PRL) were measured by immunochemiluminometric assay; T3 and T4 were measured by in-house RIA (29). FT4 was measured by a two-step RIA, and T4-binding globulin (TBG) was measured by single-step RIA. The assays are described in detail in the supplemental data.

TRH tests

Plasma TSH and PRL were measured before and 15, 30, 45, 60, 120, and 180 min after iv administration of TRH (10 µg/kg body mass). On the basis of former studies, an adequate TSH response to TRH (type 0) was characterized by a peak concentration greater than 15 µU/ml (30, 31) and return to baseline within 3 h (32). In response to TRH, CH-C patients either exhibit diminished increase (type 2) or slightly delayed but excessive increase and delayed decrease of the TSH plasma concentration (type 3) (22, 23, 30). Clinicians are accustomed to interpreting TRH tests by plotting the results at several time points after the administration of TRH, looking at the height of the peak TSH elevation and the shape of the curve. We added calculations of the area under the curve (AUC) and ratios of TSH concentrations of several time points of the response curve (expected to be especially discriminative between patients and controls) to be able to test the significance of the visually obvious differences between the different response types (Fig. 1Go).

Statistical analysis

Descriptive statistics were computed for all variables. The Mann-Whitney U test and Pearson correlation test were used to compare median values. For all analyses, a two-tailed P < 0.05 was considered statistically significant. SPSS 10.1 (SPSS Inc., Chicago, IL) was used for statistical computations. AUC was calculated using the program provided by Allan Chang (Department of Obstetrics and Gynaecology, Chinese University of Hong Kong) (33).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
For reasons briefly described in Subjects and Methods and in more detail in the supplemental data, five of the children referred to us during the study period (subjects 22–26) were excluded from the statistical calculations. Of the remaining 21 infants, six (subjects 1–6) turned out to have false-positive screening results, nonthyroidal illness, or possibly transient CH-C. The assumed reasons for the discrepancy between their abnormal screening results and the normal function test results can also be found in the supplemental data.

Fifteen infants (subjects 7–21) had type 2 or 3 response curves, depicted in Fig. 1Go, A and B. Baseline FT4 plasma concentrations were abnormal [i.e. < 0.93 ng/dl (<12 pmol/liter)] (34) at the day of testing. TRH tests took place at a median age of 36 d (range 15–56 d). Of the 15 subjects, 13 were born at term, two (13%) were prematurely born. Ten were boys (67%). One child had a birth body mass (BBM) below the third percentile and one above the 97th percentile. Four (27%) were born in breech position; two (13%) were born by cesarean section, four (27%) were born by vacuum or forcipal extraction. The most frequently encountered perinatal problems were pathological neonatal jaundice or elevated plasma concentrations of the transaminases (40%), hypoglycemia (33%), and persistent vomiting (20%). CH screening took place at a median age of 6 d (range 5–15 d). For 12 infants (80%), the CH screening provided the first indication of CH-C. TSH concentrations in heel puncture blood ranged from 1 to 7 µU/ml (1–7 mU/liter), total T4 concentrations ranged from 2.7 to 11.3 µg/dl (35–145 nmol/liter), and TBG concentrations ranged from 14.1 to 25.4 µg/dl (261–470 nmol/liter). Fourteen patients (93%) had heel puncture blood T4 to TBG ratios below the cutoff level of 8.5, used in the Dutch screening program for discrimination of CH-C patients from false positives (35). Patient 16 was referred on the basis of low screening T4 and a consecutive plasma FT4 concentration less than 0.93 ng/dl (<12 pmol/liter) and plasma TSH concentration less than 15 µU/ml (<15 mU/liter) (Table 1Go). At further testing, 12 of the subjects (80%) were found to have MPHD (9) (Table 2Go).

Mathematic representation of TRH test results

TSH response to TRH The analysis, of which the results are listed in Table 3Go, was driven by the preestablished hypothesis that TRH test results would differ between CH-C patients (n = 15) and false positives (n = 6). This null hypothesis was tested in two ways: 1) by comparison of the AUC between the different response types and 2) by calculation of ratios of TSH concentrations of several time points of the TRH response curve, each representing a certain stretch of the curve, together describing the shape of the response curve.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Ratios between TSH concentrations at four points of the TRH response curve expected to be especially discriminative between response types 0, 2, and 3 (see text), as calculated by Mann-Whitney tests (subjects 1–21)

 
The ratios between the TSH plasma concentrations 15 and 30 min after TRH administration [(TSH)15 and (TSH)30, respectively] vs. the baseline value [(TSH)0] were used as markers of the velocity and magnitude of the increase of the TSH concentration to its peak; the last three ratios [(TSH)30 to (TSH)60, (TSH)30 to (TSH)180, and (TSH)180 to (TSH)0] were used as markers of the decrease of the TSH concentration after the peak.

The type 2 response is primarily characterized by impaired release of TSH and thus by reduced height of the peak TSH elevation as compared with the type 0 response. This is especially reflected in the first (ascending) part of the curve and thus in the first two ratios (P = 0.025 and P = 0.016).

The type 3 response is primarily characterized by delayed timing of the peak TSH elevation and delayed decrease of the TSH plasma concentration after the peak as compared with the type 0 response. This is especially reflected in the second (descending) part of the curve and thus in the last three ratios (P = 0.004, P = 0.003, and P = 0.002). Also, the AUCs of the types 2 and 3 TSH responses were significantly different from those of the type 0 responses (Mann-Whitney, P = 0.004 and P = 0.007, respectively). The height of the peak TSH elevation was significantly different between the type 2 vs. type 0 responses (Mann-Whitney, P = 0.004) but not between the type 3 vs. type 0 responses (P = 0.059).

In the patients with type 2 response, TSH peaks ranged from 4.8 to 11.2 mU/liter; in the controls (with type 0 response), TSH peaks ranged from 14.0 to 37.6 mU/liter. Hence, the cutoff between the types 2 and 0 responses could be estimated at 14 µU/ml (14 mU/liter).

PRL response to TRH The PRL response was monitored simultaneously with the TSH response. The PRL response, expressed as AUC or multiple (i.e. ratio between peak and baseline value), was not significantly different between infants with either type 2 or type 3 responses and those with type 0 TSH responses (Mann-Whitney; type 2, P = 0.855 and P = 0.749; type 3, P = 0.465 and P = 0.606 for AUC and multiple, respectively; data not shown). The PRL response between infants with type 2 and those with type 3 responses was not significantly different either (Mann-Whitney; P = 0.253 and P = 0.366 for AUC and multiple, respectively; data not shown).

Thyroid hormone response to TRH Our data showed significant correlations between the TSH response to TRH (AUC) and the increases in T3 and T4 plasma concentrations 3 h after the administration of TRH (Pearson, r = 0.613, P = 0.020, n = 14; r = 0.539, P = 0.038, n = 15, respectively). Twenty-four hours after the administration of TRH, the correlations had lost statistical significance (r = 0.727, P = 0.164, n = 5; r = 0.616, P = 0.141, n = 7, respectively). The increases in T3 and T4 plasma concentrations ({Delta}T3 and {Delta}T4) were not significantly different between infants with type 2 vs. type 0 TSH responses ({Delta}T3, P = 0.221; {Delta}T4, P = 0.602) or between infants with type 3 vs. type 0 TSH responses ({Delta}T3, P = 0.116; {Delta}T4, P = 0.295).

MRI of the brain

Fourteen patients underwent MRI of the brain, around the age of 3 months. Eight (57%) had posterior pituitary ectopia (PPE), a picture characterized by a hypoplastic anterior pituitary lobe, located in the sella turcica; invisible or very thin pituitary stalk; and an ectopic posterior pituitary lobe, located at the median eminence in the floor of the third ventricle. Six patients (43%) had additional cerebral abnormalities, such as agenesis of the corpus callosum, bilateral periventricular nodular heterotopia, and/or hydrocephalus (9). All patients with PPE had MPHD (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Considering the relatively high prevalence of 1:16,400 recently established in The Netherlands (12) and the evidence that early detection and treatment may substantially reduce morbidity and mortality (8, 10), CH-C is a disorder for which it is worth screening (36). After the institution of an effective screening approach for detection of CH-C in The Netherlands (9, 12, 17, 34), there was an urgent need for a rapid and reliable procedure to verify the diagnosis in infants with screening results indicative of CH-C. The data presented here show that the TRH test plays a pivotal role in the diagnosis of CH-C in young infants.

In response to TRH, CH-C patients show either diminished increase (type 2 response) or slightly delayed but excessive increase and delayed decrease (type 3 response) of the TSH plasma concentration, in comparison with controls (with a type 0 response). Until recently the TSH responses termed types 2 and 3 responses in this paper were generally considered to reflect disturbance at the pituitary and hypothalamic level, respectively. Consequently, the clinical entities associated with these responses were termed secondary (pituitary) and tertiary (hypothalamic) hypothyroidism. In our study, seven of eight patients with type 3 (hypothalamic) responses who underwent MRI were found to have PPE, a pituitary malformation. In contrast, five of six patients with a type 2 (pituitary) response did not show PPE or any other pituitary malformation on MRI. These findings confirm the statement in other reports that the distinction of secondary and tertiary hypothyroidism is improper (37, 38, 39) and therefore call for a new categorization of TRH test results. Our findings also illustrate the clinical relevance of the distinction of types 0, 2, and 3 responses (type 1 being the response type in primary/thyroidal hypothyroidism): all patients with type 3 TSH responses had MPHDs, whereas the majority of patients with type 2 responses (67%) had isolated TSH deficiency. Thus, guided by the TRH test results, the patients at risk for potentially life-threatening ACTH and GH deficiencies can be timely identified among the infants detected by neonatal screening. Obviously, subsequent establishment of deficiencies in other hypothalamus-pituitary-target organ axes and/or demonstration, e.g. by MRI, of malformations of the hypothalamus-pituitary regulatory unit, as in most CH-C patients, further enhances the diagnostic value of the TRH test results.

The factors that give rise to developmental disorders of the pituitary are still largely unknown. The hallmarks of PPE, nonjunction of adenohypophyseal and neurohypophyseal tissue and development of an ectopic posterior pituitary lobe, presumably reflect the lack of reciprocal inductive signals between the diencephalon and Rathke’s pouch during pituitary ontogeny. Normal development, functional specialization with formation of the portal circulatory system, and differentiation of the hormone-secreting pituitary cells probably require direct contact with the hypothalamus (40). Most likely, PPE is a polygenetic developmental disorder, involving distinct genes coding for signaling molecules of which the majority still has to be discovered (38). At present, we can only speculate on the similarities and differences between patients with different TSH response types, with and without PPE. Therefore, a purely descriptive categorization as used in this paper seems to suit the current knowledge best.

All patients with abnormal TRH test results had baseline FT4 plasma concentrations less than 0.93 ng/dl (<12 pmol/liter) at referral. The differences in TRH test results between CH-C patients (type 2 or type 3 response) and controls (type 0 response) were tested in three ways: 1) by comparison of the peak TSH elevation in response to TRH between the different response types, 2) by comparison of the AUC between the different response types, and 3) by comparison of ratios of TSH concentrations of several time points of the TRH response curve, each representing a certain stretch of the response curve.

The type 2 response is primarily characterized by impaired release of TSH and thus by reduced height of the peak TSH elevation as compared with the type 0 response (Mann-Whitney, P = 0.004). This is especially reflected in the first (ascending) part of the curve and thus in the first two ratios (P = 0.025 and P = 0.016). Also, the AUC of the type 2 responses was significantly different from that of the type 0 response (Mann-Whitney, P = 0.004). In the patients with a type 2 response, TSH peaks ranged from 4.8 to 11.2 µU/ml (4.8–11.2 mU/liter); in the controls, TRH peaks ranged from 14.0 to 37.6 µU/ml (14.0–37.6 mU/liter). Hence, the cutoff between type 2 and type 0 responses in the study cohort was about 14 µU/ml (14 mU/liter). Hopefully, in the near future, reports of similar investigations in young infants will validate our results.

The type 3 response is primarily characterized by delayed timing of the peak TSH elevation and delayed decrease of the TSH plasma concentration after the peak as compared with the type 0 response. This is especially reflected in the second (descending) part of the curve and thus in the last three ratios (P = 0.004, P = 0.003, and P = 0.002). Also, the AUC of the type 3 TSH response was significantly different from that of the type 0 response (Mann-Whitney, P = 0.007). The height of the peak TSH elevation was (just) not significantly different between the type 3 vs. type 0 responses (Mann-Whitney, P = 0.059). Because next to the (TSH)30 to (TSH)60 ratio, especially the (TSH)30 to (TSH)180 and (TSH)180 to (TSH)0 ratios, were highly discriminative between the type 3 and type 0 responses, it is recommended that the TRH test lasts 3 h for optimal discrimination.

Remarkably throughout the study, a type 2 response was seen in male infants only. This might point to a separate disease entity occurring exclusively or predominantly in males. We presume this is a reflection of the mode of inheritance of this particular entity, rather than an indication of a sexual dimorphism or an effect of the prenatal or perinatal (sex) hormonal status. At present, X-linked (or mitochondrial) genes that could be implicated in this entity have not been identified. Interestingly, all infants with isolated TSH deficiency secondary to gestational maternal hyperthyroidism had type 2 responses, too (16). Among the infants with a type 3 response (and PPE), there was no male preponderance: four were males and five were females. To estimate the influence sex (hormones) and the thyroid hormone status might have had on the TSH response curves, Pearson correlation tests were performed. None of the main determinants of the response curves (peak TSH elevation, AUC, TSH ratios) was significantly correlated with sex or FT4 concentration on the day of testing (data not shown).

Several authors have reported decreased or excessive PRL secretion in response to TRH in central hypothyroidism (41, 42). However, in our patients the PRL response, expressed as AUC or multiple (i.e. ratio between peak and baseline value) was not significantly different between infants with either type 2 or type 3 responses vs. those with type 0 TSH responses. Neither was there a significant difference between infants with type 2 vs. those with type 3 responses. Thus, estimation of the PRL response to TRH did not enhance the sensitivity of the TRH test. Also, impaired rise of T3 and T4 plasma concentrations in response to TRH infusion is reported in patients with central hypothyroidism as compared with normal subjects (43). Indeed, we did not observe any rise of total T4 or T3 in CH-C patients, neither with a type 3 response nor a type 2 response. However, in our patients the T3 and T4 responses were not significantly different between infants with either type 2 or type 3 responses vs. those with type 0 TSH responses. Therefore, we conclude that measurement of T4 and T3 during the TRH test does not enhance the test’s sensitivity substantially.

PPE is usually associated with multiple pituitary hormone deficiency (44, 45, 46). Indeed, all infants with PPE in our study had deficiencies of one or more pituitary hormones besides TSH. In fact, the emergence of a second deficiency of anterior pituitary function was predicted by the finding of PPE (and a type 3 TSH response) in patient 16, who initially was considered TSH deficient only. This also draws attention to the fact that in patients diagnosed with isolated TSH deficiency, additional pituitary hormone deficiencies might emerge over time (47). These findings are of particular importance because MPHD is a condition with complex morbidity and high mortality (8, 10). Therefore, especially the finding of a type 3 TSH response and/or PPE on MRI urge immediate testing for additional, potentially life-threatening, pituitary hormone deficiencies.

Although there is extensive literature on the TRH test regarding dosage, dynamics, and criteria for normalcy in adults (18, 19, 20) and older children (21, 22, 23, 24), there are only a limited number on the performance of this test in neonates (25, 26). Zabransky et al. (26) provide an overview of the results of different TRH dosages on TSH stimulation in children. From their data 2 µg TRH per kilogram body mass seems to be the lowest dose that gives a maximal TSH response. However, these data were acquired in healthy normal children, a minority of whom were neonates. In normal adults, Snyder and Utiger (32) estimated an optimal test dosage of 400 µg TRH, thus about 6 µg TRH per kilogram body mass. If we consider the differences in distribution volume between adults and neonates (1:1.55) (48), this compares with about 10 µg TRH per kilogram body mass in neonates. Because the risk of provoking an exaggerated response in normal subjects when using a supraphysiological dosage is small (32), compared with the risk of false-negative results in patients with (long-standing) TRH deficiency when the dosage is too low, we administered TRH in a dosage of 10 µg/kg body mass in all subjects.

Recently Mehta et al. (38) stated that a TRH test is not essential in assessment of central hypothyroidism and that the diagnosis should be made by serial T4 measurements. This British group retrospectively studied a cohort of 54 patients, who had a median age of 1.75 yr at diagnosis of hypothyroidism, some evolving into TSH deficiency at a still later age. Most patients had severe midline brain defects, such as septooptic dysplasia (n = 28) and holoprosencephaly (n = 2). The majority of these patients will be referred on the basis of their neurodevelopmental disorder rather than endocrine dysfunction. Many of the septooptic dysplasia patients exhibited slowly evolving central hypothyroidism. Consequently, in this particular entity of CH-C, serial T4 measurement might be the optimal strategy rather than neonatal screening. However, in contrast to the British study, for 12 of the 15 infants in our study, the CH screening result provided the first clue toward pituitary hormone deficiency. Up to now, 11 of those 15 infants (79%) have been diagnosed with MPHD. Because the improved method of screening in The Netherlands results in detection of a significant number of sporadic cases of CH-C/MPHD, early establishment of H-P-T function is crucial in the identification of patients at risk. We emphasize that in our rather extensive experience with the performance of the TRH test in children of different ages, the vast majority of tests is conclusive and proves reliable at long-term follow-up, provided that the TSH response to TRH is monitored for (at least) 180 min.

In conclusion, our data show that the TRH test is an essential tool in the diagnosis of CH due to TRH and/or TSH deficiency in young infants, as detected by neonatal screening. Abnormal TRH test results (especially a type 3 response) urge immediate assessment of integral hypothalamic-pituitary function and morphology because the majority of patients have MPHD and malformations of the hypothalamus-pituitary regulatory unit and/or other cerebral structures.


   Acknowledgments
 
We are indebted to the patients and their parents; the referring pediatricians and pediatric endocrinologists; Erik Endert (head of the Endocrinology Laboratory, Academic Medical Center, University of Amsterdam) for sharing his thorough expertise in thyroid matters with us; Brenda Wiedijk (Department of Pediatric Endocrinology, Emma Children’s Hospital AMC) for her indispensable assistance in collection of the data from all over the country; Caren Lanting and Paul Verkerk (TNO Prevention and Health, Department of Social Pediatrics and Child and Youth Health Care, Leiden, The Netherlands) for sharing epidemiological data with us; and Heather Houlihan for review of the English syntax.


   Footnotes
 
This work was supported by Grant 28-1060-2 (to J.J.M.d.V. and T.V.) from The Netherlands Organization for Health Research and Development (ZON-MW, the Hague, The Netherlands).

Disclosure Summary: The authors have nothing to disclose.

First Published Online November 13, 2007

Abbreviations: AUC, Area under the curve; BBM, birth body mass; CH-C, congenital hypothyroidism of central origin; FT4, free T4; H-P-T, hypothalamic-pituitary-thyroid; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; PPE, posterior pituitary ectopia; PRL, prolactin; TBG, T4-binding globulin.

Received December 1, 2006.

Accepted November 6, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Fisher DA 1991 Management of congenital hypothyroidism. J Clin Endocrinol Metab 72:523–529[Free Full Text]
  2. Kooistra L, Laane C, Vulsma T, Schellekens JMH, Van der Meere JJ, Kalverboer AF 1994 Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr 124:903–909[CrossRef][Medline]
  3. Kempers MJE, Van der Sluijs Veer L, Nijhuis-van der Sanden MWG, Kooistra L, Wiedijk BM, Faber I, Last BF, De Vijlder JJM, Grootenhuis MA, Vulsma T 2006 Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 91:418–424[Abstract/Free Full Text]
  4. Vulsma T, Gons, MH, De Vijlder JJM 1989 Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321:13–16[Abstract]
  5. Porterfield SP, Henrich CE 1993 The role of thyroid hormones in prenatal and neonatal neurological development—current perspectives. Endocr Rev 14:94–106[Abstract/Free Full Text]
  6. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, Brown RS, Public Health Committee, Lawson Wilkins Pediatric Endocrine Society, Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK 2006 Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 117:2290–2303[Abstract/Free Full Text]
  7. Derksen-Lubsen G, Verkerk PH 1996 Neuropsychologic development in early-treated congenital hypothyroidism: analysis of literature data. Pediatric Res 39:561–566[Medline]
  8. Vulsma T, Delemarre HA, de Muinck Keizer SMPF, Wiedijk BM, Gons MH, Verkerk PH, De Vijlder JJM 1989 Detection and classification of congenital thyrotropin deficiency in the Netherlands. In: Drexhage HA, De Vÿlder JJM, Wiersinga WM, eds. The thyroid gland, environment and autoimmunity. Amsterdam: Excerpta Medica, International Congress Series; 896:343–346
  9. van Tijn DA, De Vijlder JJM, Verkerk PH, Verbeeten Jr B, Vulsma T 2005 Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab 90:3350–3359[Abstract/Free Full Text]
  10. Hintz RL 1996 Eternal vigilance -Mortality in children with growth hormone deficiency. J Clin Endocrinol Metab 81:1691–1692 (Editorial)
  11. Asteria C, Persani L, Beck-Peccoz P 2001 Central hypothyroidism: consequences in adult life. J Pediatr Endocrinol Metab 14(Suppl 5):1263–1269
  12. Lanting CI, Van Tijn DA, Loeber JG, Vulsma T, De Vijlder JJM, Verkerk PH 2005 Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics 116:168–173[Abstract/Free Full Text]
  13. Fisher DA, Dussault JH, Foley Jr TP, Klein AH, LaFranchi S, Larsen PR, Mitchell ML, Murphey WH, Walfish PG 1979 Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr 94:700–705[CrossRef][Medline]
  14. Fisher DA, Klein AH 1981 Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 304:702–712[Medline]
  15. Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH 1986 Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program. J Pediatr 109:959–964[CrossRef][Medline]
  16. Kempers MJE, Van Tijn DA, Van Trotsenburg ASP, De Vijlder JJM, Wiedijk BM, Vulsma T 2003 Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 88:5851–5857[Abstract/Free Full Text]
  17. Kempers MJE, Lanting CI, Van Heijst AFJ, Van Trotsenburg ASP, Wiedijk BM, De Vijlder JJM, Vulsma T 2006 Neonatal screening for congenital hypothyroidism based on T4, TSH and TBG measurement: potentials and pitfalls. J Clin Endocrinol Metab 91:3370–3376[Abstract/Free Full Text]
  18. Hollander CS, Mitsuma T, Shenkman L, Woolf P, Gerschengorn MC 1972 Thyrotropin-releasing hormone: evidence for thyroid response to intravenous injection in man. Science 175:209–210[Abstract/Free Full Text]
  19. Faglia G, Beck-Peccoz P, Ferrari C, Ambrosi B, Spada A, Travaglini P, Paracchi S 1973 Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders. J Clin Endocrinol Metab 37:595–601[Abstract/Free Full Text]
  20. Hershman JM 1974 Clinical application of thyrotropin-releasing hormone. N Engl J Med 290:886–890
  21. Foley Jr TP, Owings J, Hayford JT, Blizzard RM 1972 Serum thyrotropin response to synthetic thyrotropin-releasing hormone in normal children and hypopituitary patients. J Clin Invest 51:431–437[Medline]
  22. Gruñeiro de Papendieck L, Iorcansky S, Rivarola MA, Heinrich JJ, Bergadá C 1982 Patterns of TSH response to TRH in children with hypopituitarism. J Pediatr 100:387–392[CrossRef][Medline]
  23. Illig R, Krawczynska H, Torresani T, Prader A 1975 Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. J Clin Endocrinol Metab 41:722–728[Abstract/Free Full Text]
  24. Dutau G, Augier, Bayard F, Rochiccioli P 1975 Le test au TRH avec dosage de la triiodothyronine (T3) et de la thyréostimuline (TSH) plasmatiques. Ann Pédiatr 22:309–314
  25. Jacobsen BB, Andersen H, Dige-Petersen H, Hummer L 1976 Thyrotropin response to thyrotropin-releasing hormone in full-term, euthyroid and hypothyroid newborns. Acta Paediatr Scand 65:433–438[Medline]
  26. Zabransky S, Cunow E, Lengle D 1981 Optimale TRH-testdosis bei Kindern: 1 µg TRH/kg (i.v.). Pädiatr Pädol 16:335–341[Medline]
  27. Dussault JH 1999 The anecdotal history of screening for congenital hypothyroidism. J Clin Endocrinol Metab 84:4332–4334[Free Full Text]
  28. Van Tijn DA, Schroor EJ, Delemarre-van de Waal HA, De Vijlder JJ, Vulsma T 2007 Early assessment of hypothalamic-pituitary-gonadal function in patients with congenital hypothyroidism of central origin. J Clin Endocrinol Metab 92:104–109[Abstract/Free Full Text]
  29. Wiersinga WM 1979 The peripheral conversion of thyroxine (T4) into triiodothyronine (T3) and reverse triiodothyronine (rT3), academic thesis, University of Amsterdam.
  30. Okuno A, Taguchi T, Nakayama K, Takimoto M 1979 Kinetic analysis of plasma TSH after TRH stimulation. Horm Metab Res 11:293–295[Medline]
  31. Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, Horlick M, Goldstein S, Dimartino J, Saenger P 1993 Thyrotropin-releasing hormone stimulation tests in infants. J Clin Endocrinol Metab 77:889–894[Abstract]
  32. Snyder PJ, Utiger RD 1972 Response to thyrotropin releasing hormone in normal man. J Clin Endocrinol Metab 34:380–385[Abstract/Free Full Text]
  33. Chang A, Statistics tool box. Available at web site of Department of Obstetrics and Gynecology, The Chinese University of Hong Kong: http://department.obg.cuhk.edu.hk/researchsupport/area_under_curve.asp
  34. Vulsma T 1991 Etiology and pathogenesis of congenital hypothyroidism. Evaluation and examination of patients detected by neonatal screening in The Netherlands, academic thesis, University of Amsterdam
  35. Verkerk PH, Loeber JG, Vulsma T, De Vijlder JJM 1995 [The benefit of extension of the CH-screening procedure by determination of thyroxine-binding globulin (Dutch). Leiden, The Netherlands: Nederlandse Organisatie voor toegepast-natuurwetenschappelijk onderzoek TNO (TNO publication PG 95.062)
  36. Fisher DA 2005 Next generation newborn screening for congenital hypothyroidism? J Clin Endocrinol Metab 90:3797–3799 (Editorial)
  37. Cohen LE, Wondisford FE, Salvatoni A, Maghnie M, Brucker-Davis F, Weintraub BD, Radovick S 1995 A "hot spot" in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates. J Clin Endocrinol Metab 80:679–684[Abstract]
  38. Mehta A, Hindmarsh PC, Stanhope RG, Brain CE, Preece MA, Dattani MT 2003 Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children? J Clin Endocrinol Metab 88:5696–5703[Abstract/Free Full Text]
  39. Vieira TC, Dias da Silva MR, Cerutti JM, Brunner E, Borges M, Arnaldi LT, Kopp P, Abucham J 2003 Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay. J Clin Endocrinol Metab 88:38–44[Abstract/Free Full Text]
  40. Mitchell LA, Thomas PQ, Zacharin MR, Scheffer IE 2002 Ectopic posterior pituitary lobe and periventricular heterotopia: cerebral malformations with the same underlying mechanism? AJNR Am J Neuroradiol 23:1475–1481[Abstract/Free Full Text]
  41. Foley Jr TP, Jacobs LS, Hoffman W, Daughaday WH, Blizzard RM 1972 Human prolactin and thyrotropin concentrations in the serums of normal and hypopituitary children before and after the administration of synthetic thyrotropin releasing hormone. J Clin Invest 51:2143–2150[Medline]
  42. Frisch H, Herkner K, Schober E, Stögman W, Waldhauser F, Weissel M 1982 Prolactin and thyrotrophin response to thyrotrophin-releasing hormone in growth hormone deficiency. Arch Dis Child 57:769–773[Abstract/Free Full Text]
  43. Faglia G, Ferrari C, Paracchi A, Spada A, Beck-Peccoz P 1975 Triiodothyronine response to thyrotrophin releasing hormone in patients with hypothalamic-pituitary disorders. Clin Endocrinol (Oxf) 4:585–590[Medline]
  44. Triulzi F, Scotti G, Di Natale B, Pellini C, Lukezic M, Scognamiglio M, Chiumello G 1994 Evidence of a congenital midline brain anomaly in pituitary dwarfs: a magnetic resonance imaging study in 101 patients. Pediatrics 93:409–416[Abstract/Free Full Text]
  45. Chen S, Leger J, Garel C, Hassan M, Czernichow P 1999 Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between the visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function. J Clin Endocrinol Metab 84:2408–2413[Abstract/Free Full Text]
  46. Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS, Leite CC, Estefan V, Mendonca BB, Arnhold IJ 2002 Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 87:5076–5084[Abstract/Free Full Text]
  47. Böttner A, Keller E, Kratzsch J, Stobbe H, Weigel JF, Keller A, Hirsch W, Kiess W, Blum WF, Pfäffle RW2004 PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab 89:5256–5265
  48. Jouvet P, Hubert P, Saudubray JM, Rabier D, Man NK 2005 Kinetic modeling of plasma leucine levels during continuous venovenous extracorporeal removal therapy in neonates with maple syrup urine disease. Pediatr Res 58:278–282[CrossRef][Medline]
  49. Klasson A, Ericson A, Freyer JG, Karlberg J, Lawrence C, Karlberg P 1991 An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977–1981). Acta Paediatr Scand 80:756–762[Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
D. A. van Tijn, J. J. M. de Vijlder, and T. Vulsma
Role of Corticotropin-Releasing Hormone Testing in Assessment of Hypothalamic-Pituitary-Adrenal Axis Function in Infants with Congenital Central Hypothyroidism
J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3794 - 3803.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
H. Filipsson, E. Nystrom, and G. Johannsson
Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism
Eur. J. Endocrinol., August 1, 2008; 159(2): 153 - 160.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by van Tijn, D. A.
Right arrow Articles by Vulsma, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Tijn, D. A.
Right arrow Articles by Vulsma, T.
Related Collections
Right arrow Neuroendocrinology and Pituitary
Right arrow Pediatric Endocrinology
Right arrow Thyroid

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals