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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3631-3635
Copyright © 2000 by The Endocrine Society

Original Studies

Circulating Thyrotropin Bioactivity in Sporadic Central Hypothyroidism1

Luca Persani, Elisabetta Ferretti, Stefano Borgato, Giovanni Faglia and Paolo Beck-Peccoz

Institute of Endocrine Sciences, University of Milan, Istituto Auxologico Italiano Instituto di Ricovero e Cura a Carattere Scientifico (L.P.), and Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico (S.B., G.F., P.B.-P.), 20145 Milan; and Department of Clinical Science, Endocrinology, University of Rome La Sapienza (E.F.), 00100 Rome, Italy

Address all correspondence and requests for reprints to: Luca Persani, M.D., Ph.D., Laboratorio di Ricerche Endocrinologiche, Istituto Auxologico Italiano Instituto di Ricovero e Cura a Carattere Scientifico, Via Ariosto 13, 20145 Milan, Italy. E-mail: persani{at}auxologico.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The etiopathogenesis of sporadic central hypothyroidism (CH) involves pituitary and hypothalamic lesions. Pituitary CH (pCH) implies a diminished number of functioning thyrotropes, accounting for the quantitative impairment of TSH secretion. Hypothalamic CH (hCH) is characterized by normal or even increased TSH concentrations and qualitative abnormalities of TSH secretion, including a decreased bioactivity of circulating TSH. However, controversy still exists about the actual occurrence of bioinactive TSH among CH patients, and no data are available in pCH. Therefore, we studied 41 CH patients with different hypothalamic-pituitary disorders. Immunoreactive TSH (TSH-I) ranged from 0.08–11.1 mU/L (normal, 0.24–4.0), free T4 (FT4) ranged from 0.6–8.8 pmol/L (normal, 9–18), and FT3 ranged from 1.2–5.4 pmol/L (normal, 4–8). A blunted TSH response to TRH (<4 mU/L), indicating prevalent pCH, was found in 56% of the patients, and a net TSH-I increment >=4 mU/L, indicating prevalent hCH, was found in the remaining 44%. Net TSH-I increments showed significant correlation with basal FT4 (P < 0.02), indicating the relevance of pituitary TSH reserve in the pathogenesis of CH. Circulating TSH was immunoconcentrated and tested in bioassay and in ricin affinity chromatography. The ratio between biological (B) and immunological (I) activities of circulating TSH was reduced (n = 25; TSH B/I, 0.38 ± 0.19) compared to the values recorded in normal subjects (n = 26; TSH B/I, 1.53 ± 0.54; P < 0.001) and primary hypothyroid patients (n = 24; TSH B/I, 0.74 ± 0.31; P < 0.001), but no difference between pCH (n = 9; 0.36 ± 0.16) and hCH (n = 16; 0.39 ± 0.20) was seen. TSH B/I values in CH patients showed a limited overlap with normal values (20%) and a highly significant correlation with the FT3 response to endogenous TRH-stimulated TSH (P < 0.005). The elevated sialylation degree of TSH molecules may explain part of these findings.

In conclusion, the secretion of TSH molecules with reduced bioactivity is a common alteration in the patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of CH.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CENTRAL HYPOTHYROIDISM (CH) is the consequence of an impaired stimulation of an otherwise normal thyroid gland by TSH (1). Abnormalities in TSHß, TRH receptor, Pit-1, and Prop-1 genes have been found in the familial settings of CH (2, 3, 4, 5, 6), whereas huge lesions of the intrasellar or parasellar regions account for most of the sporadic cases of acquired CH, and breech delivery accounts for several sporadic cases of neonatal CH (1, 7, 8). The pathogenesis of sporadic CH involves pituitary and hypothalamic functions that are often concomitantly compromised to a variable extent in single individuals. The pituitary origin (pCH) implies a reduction in the number of functioning thyrotropes, mainly accounting for the quantitative impairment of TSH secretion, as documented by blunted responses of TSH to TRH (1, 7, 8). Differently, the hypothalamic origin (hCH) is characterized by normal or even high serum concentrations of immunoreactive TSH and qualitative abnormalities of TSH secretion, such as decreased bioactivity of circulating molecules, lack of a nocturnal TSH surge, and delayed and/or exaggerated and prolonged TSH responses to TRH injection (1, 7, 8). The decreased bioactivity of circulating TSH explains the discrepancy between the central origin of thyroid function impairment and the normal or even slightly increased serum TSH immunoreactivity (9, 10, 11). An alteration in the carbohydrate moiety probably accounts for the reduced bioactivity of the glycoprotein heterodimer (9, 10, 11). Several studies have documented the secretion of bioinactive TSH in patients with hCH, either indirectly by evaluating the net responses of thyroid hormones to endogenous TRH-stimulated TSH or directly by testing the bioactivity of circulating TSH molecules (12, 13, 14, 15). The hypothalamic origin of such qualitative alteration of TSH secretion has been further supported by the recovery of a normal circulating TSH bioactivity during chronic TRH administration (15). Definitive confirmation of this pathogenetic mechanism was recently provided by studies in knockout mice for the TRH gene, representing a model of hypothalamic (tertiary) hypothyroidism (16). However, controversy still exists about the actual occurrence of bioinactive TSH among CH patients (17), and no data are available for pCH. In the present study we evaluated TSH secretion by means of immunological and biological assays in a large series of patients with hypothalamic-pituitary disorders to elucidate the mechanisms involved in the pathogenesis of sporadic CH.


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

Twenty-six healthy volunteers and 24 patients with primary hypothyroidism (PH) served as control groups in TSH bioactivity and glycosylation studies. Blood was always drawn during the morning. The data for these subjects have been reported previously (18).

Patients with CH

Forty-one patients with different hypothalamic-pituitary disorders (22 pituitary macroadenomas, 8 craniopharyngiomas or other suprasellar tumors, 3 cranial irradiation, 1 hypophysitis, and 6 patients with a history of breech delivery and neonatal pituitary insufficiency) were studied. All patients gave their informed consent to the study. All patients had had a previous diagnosis of CH and were negative for the presence of circulating antithyroglobulin and antithyroperoxidase autoantibodies. On physical examination, thyroid glands were normal or hypotrophic. All patients were studied during appropriate replacement therapy for concomitant pituitary deficiencies, with the exception of GH, and after a mean 60-day period of L-T4 therapy discontinuation (19). The period of L-T4 therapy discontinuation was sufficient to induce clinical and biochemical hypothyroidism [free T4 (FT4) levels were low in all patients; see Results] and to restore levels of measurable TSH from the undetectable TSH concentrations observed during substitutive L-T4 therapy (19). The patients were also studied during a TRH stimulation test (200 µg, iv). The TRH test was performed to assess 1) the hypothalamic or pituitary origin of CH [blunted TSH responses (<4 mU/L) were considered indicative of a prevalent pituitary involvement; normal/exaggerated TSH responses (>=4 mU/L) were considered indicative of a prevalent hypothalamic lesion], and 2) the net FT4 and FT3 increments observed 2–3 h after TRH injection (n = 32). Blood for the evaluation of circulating TSH bioactivity was drawn at baseline.

Immunoassays

Immunoreactive TSH (TSH-I) was measured by a third generation immunofluorometric assay (Delfia, Pharmacia, Milan, Italy), using a two-step procedure and TSH International Reference Preparation 80/558 as reference. The sensitivity of the TSH immunoassay is 0.007 mU/L, normal values range from 0.24–4.0 mU/L. Serum FT3 and FT4 levels were measured by direct back-titration methods, using Delfia technology (Pharmacia). Normal values for FT3 and FT4 immunoassays range between 4–8 pmol/L and 9–20 pmol/L, respectively. The interassay coefficient of variation is less than 5.0% in both cases. cAMP in incubation buffers was measured by commercial RIA (RIANEN, DuPont Co., Billerica, MA).

TSH bioassays

Immunoconcentration of circulating TSH. As human serum contains several factors that interfere in the TSH bioassay response, circulating TSH was immunopurified using polystyrene tubes coated with a monoclonal antibody directed against a conformational epitope, as previously described (20). The minimal amount of TSH (before immunoconcentration) necessary to perform a reliable estimation of its biological activity is 30 µU. The total volume of CH serum samples varied from 5–52 mL depending on the immunoreactive TSH concentrations. The recovery before the concentration step was 88–98%, whereas final recovery ranged between 52–68%; the discrepancy was due to nonspecific losses and not to selection of particular molecular forms of TSH (20). Furthermore, the possible presence in the purified samples of non-TSH substances able to alter cAMP production in the bioassays was ruled out by the observation of unmodified basal cAMP accumulation after incubation of the cells with the immunopurified material from a Graves’ patient with suppressed TSH secretion (18).

Chinese hamster ovary cells expressing human TSH receptor (CHO-R). The CHO-R strain JP-26 (supplied by Dr. G. Vassart, Brussels, Belgium) was used (21). Three different dilutions of immunoconcentrated TSH were bioassayed in triplicate, as was TSH standard. Extracellular cAMP was measured in the medium collected at the end of the incubation. The sensitivity of this system is 1.6 ± 0.25 mU/L. The other characteristics of the assay are similar to those previously reported (18, 20). The accumulation of cAMP was exclusively due to the stimulation of transfected TSH receptor in strain JP-26, as no stimulation was observed when immunopurified samples were tested in the control cells not expressing the TSH receptor (strain JP-02) (18).

As our experiments fulfilled the criteria illustrated by Chappel (22), i.e. the same reference preparation was always employed, and parallelism between immunoconcentrated sample dilutions and the TSH standard curve was observed in both immuno- and biological assays, the results of the TSH bioassay are expressed as the biological (B) to immunological (I) ratio (B/I) of immunoconcentrated TSH samples (mean ± SD; n = 9), thus giving an estimation of the biological potency of immunopurified materials.

Ricin lectin affinity chromatography

This investigation was performed as previously described (18, 23). Briefly, columns containing 1 mL Ricinus communis insolubilized on beaded agarose (RCA 120, Sigma, St. Louis, MO) were equilibrated with phosphate buffer (PB; pH 7.4) and 0.05% BSA. Specimens (25 µL immunopurified samples and 100 µL PB, pH 6.6) with or without neuraminidase (NAM) treatment (10 mU, 4 h at 37 C) were loaded onto the column and allowed to interact for 1 h at room temperature. Unbound TSH was collected by repeated centrifugation (20 times with 1 mL PB-BSA). Bound fractions were eluted using the same procedure with PB-BSA containing 200 mmol/L galactose (Sigma). Unbound and bound fractions were pooled and dried under vacuum (Speed-Vac, Jouan, A.L.C. International, Cologno Monzese, Italy); dried samples were solubilized in 1 mL PB-BSA, and TSH was measured by immunoassay. The final recovery was always above 77%. Ricin lectin specifically binds to exposed galactose or N-acetylglucosamine residues, whereas NAM treatment specifically removes terminal sialic acid, thus exposing the underlying galactose residue. The difference between the percentages of TSH bound to ricin before and after NAM treatment represents an estimation of the amount of sialylated molecules (18, 23).

Statistical analysis

Data were analyzed by Student’s t test and ANOVA, as appropriate. Differences were considered statistically significant if P < 0.05. Results are expressed as the mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline biochemical evaluation

In the CH patients, immunoreactive TSH (TSH-I) ranged between 0.08–11.1 mU/L (mean ± SD, 2.6 ± 3.1; normal, 0.24–4.0), FT4 ranged between 0.6–8.8 pmol/L (4.3 ± 2.6; normal, 9–18), and FT3 ranged between 1.2–5.4 pmol/L (3.1 ± 1.1; normal, 4–8). Antithyroid autoantibodies (antithyroperoxidase and antithyroglobulin) were absent in all cases. No correlation between basal TSH and FT4 values was found (Fig. 1Go).



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  		Figure 1. Lack of correlation between immunoreactive TSH and FT4 serum levels in CH. The vertical dotted lines indicate lower and upper limits of the normal TSH-I range. The horizontal dotted line indicates the lower limit of the normal FT4 range. Note that serum TSH levels can be low, normal, or high.

 
TRH test

An absent/impaired TSH response to TRH (net TSH-I increment, <4.0 mU/L), indicating a prevalent pCH, was found in 56% of the patients (1.16 ± 1.02 mU/L; 0.06–3.84); in these cases serum FT4 was 4.9 pmol/L or less. Net TSH-I increments of 4.0 mU/L or more, indicating a prevalent hCH, were found in the remaining 44% (10.3 ± 4.4 mU/L; 4.0–18.0). Serum FT3 and FT4 increments in response to TRH-stimulated endogenous TSH were absent/impaired (<1.1 pmol/L) in the large majority of CH patients (78%). Net TSH-I increments after TRH injection showed significant correlations with baseline TSH-I (r = 0.423; P < 0.02) and FT4 (r = 0.376; P < 0.02) concentrations (Fig. 2Go).



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  		Figure 2. Significant correlation between net increments in immunoreactive TSH after TRH injection at a maximal effective dose (200 µg, iv) and basal FT4 concentrations in patients with CH.

 
Circulating TSH bioactivity

Whenever the absolute amount of basal TSH-I was sufficient (n = 25), we carried out the immunoextraction of TSH molecules to test the immunopurified samples in the CHO-hTSHR bioassay. In the CH patients, circulating TSH B/I was significantly reduced (range, 0.10–0.73; mean, 0.38 ± 0.19) compared to the values recorded in normal subjects (n = 26; 1.53 ± 0.54; P < 0.001) and primary hypothyroid patients (n = 24; 0.74 ± 0.31; P < 0.001), but no difference between pCH (n = 9; basal TSH-I: range, 0.8–2.3; median, 0.9 mU/L; net TSH-I increments after TRH: range, 0.27–3.84; median, 1.30 mU/L) and hCH (n = 16; basal TSH-I: range, 1.7–11.1; median, 3.30 mU/L; net TSH-I increments after TRH: range, 4.0–18.02; median, 10.55 mU/L) was seen (TSH B/I: pCH, 0.36 ± 0.16; hCH, 0.39 ± 0.20; P = NS; Fig. 3Go). The TSH B/I values of CH patients showed a limited overlap (20%) with the normal range and a highly significant correlation with the net FT3 response to the stimulation of endogenous TSH after TRH injection (r = 0.673; P < 0.005; Fig. 4Go).



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  		Figure 3. The TSH B/I in CH patients with secondary or tertiary defect ({circ}, single cases; •, mean ± SD) and in control subjects (mean ± SD; {diamondsuit}, normal subjects; {blacktriangleup}, primary hypothyroid patients). The dotted line indicates the lower limit of the normal range. Both groups of CH patients have B/I ratios significantly lower than those observed in normal or primary hypothyroid controls.

 


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  		Figure 4. Significant correlation between circulating TSH B/I and net increments in serum FT3 levels after stimulation of endogenous TSH with TRH. The dotted lines indicate the lower limit of the normal ranges.

 
Ricin lectin affinity chromatography

In five patients, the amount of immunopurified TSH was sufficient to perform this analysis. They showed low ricin binding for untreated TSH molecules, as in normal (n = 8) and PH (n = 10) controls, whereas an increased amount of total TSH was bound to ricin after NAM treatment, indicating an increased sialylation degree of carbohydrate chains compared to normal or primary hypothyroid controls [CH, 63 ± 12%; vs. normal subjects, 24 ± 6% (P < 0.01); or vs. PH, 45 ± 8% (P < 0.01); Table 1Go].


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  		Table 1. Clinical data, thyroid function tests, and results of TRH test and TSH bioassay in the five patients with ricin lectin analysis of TSH carbohydrate moiety

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study to evaluate the in vivo and in vitro biological activities of circulating TSH in a large series of nonselected patients with sporadic CH. The use of a sensitive bioassay allowed the demonstration that secretion of TSH with reduced biological activity is a frequent finding in patients with CH, accounting for 80% of the cases. Unexpectedly, the reduced bioactivity of circulating TSH is also present in patients with prevalent pituitary damage. Therefore, in association with the impairment of pituitary TSH reserve, the low bioactivity of circulating TSH molecules generally contributes to the pathogenesis of CH in patients with hypothalamic-pituitary lesions.

In CH, the secretion of TSH with low bioactivity accounts for the lack of correlation between immunoreactive TSH and free thyroid hormone concentrations, and the absent/impaired increments in free thyroid hormone after acute stimulation of endogenous TSH by TRH (despite normal or even exaggerated TSH responses in patients with prevalent hypothalamic defects). In contrast, it is well known that bovine TSH administration was rapidly effective in stimulating thyroid hormone secretion and iodide uptake in patients with CH (1, 2, 9, 10, 11, 12, 13, 14, 15). The present findings are consistent with those obtained by means of different bioassays in a small number of selected patients with hypothalamic hypothyroidism (13, 14, 15, 24). Indeed, the relevant contribution of the low TSH bioactivity to determining CH in the majority of the patients with hypothalamic-pituitary disease is highlighted by the direct correlation between the circulating TSH B/I values and the net FT3 responses. It is conceivable that such a correlation could be even more significant if TSH B/I was measured 60–180 min after acute TRH injection. Interestingly, the recovery of a normal TSH B/I after acute TRH treatement was obtained in only one CH patient of six tested (15, 20). On the contrary, acute TRH administration to normal subjects was reported to release TSH isoforms with varied oligosaccharide structure (25) and lower bioactivity (26).

An animal model for hypothalamic hypothyroidism was recently generated by homologous recombination (16). As in our patients with hCH, the TRH knockout mice have blunted T3 responses to endogenous TRH-stimulated TSH despite exaggerated TSH increments and have elevated immunoreactive TSH levels in serum, a finding in contrast with the reduced number of thyrotropes in their pituitaries (16). The relevance of the impaired pituitary TSH reserve in the determination of CH in our patients is supported by the significant direct correlation between net immunoreactive TSH responses to TRH and basal FT4 concentrations; a similar finding was reported by Horimoto et al. (17), studying seven patients with CH of different origin. Interestingly, TRH treatment restored the normal number of thyrotrope cells in TRH knockout mice (16). In humans with hypothalamic hypothyroidism, daily administration of TRH for 1–4 months was transiently effective in restoring the secretion of bioactive TSH and euthyroidism (16, 27). A quantitative modification of the residual thyrotrope population might also occur in CH patients during chronic TRH.

Interestingly, the increased sialylation degree of TSH carbohydrate chains observed in CH patients is even higher than that previously found in primary hypothyroid patients (18) and may partially explain the diminished bioactivity of circulating molecules. Moreover, the terminal sialylation results in prolongation of the half-life of the hormone (9, 10, 11), which may justify the exaggerated and prolonged TSH responses to TRH and the maintenance of normal/high immunoreactive concentrations of TSH in hCH despite a reduction of producing cells. This finding is in agreement with data indicating that the transcription of some glycosyltransferases, such as sialyltransferase, is up-regulated in hypothyroidism (28). The increased sialylation degree may thus be a consequence of the hypothyroid state at the thyrotrope levels, but the mechanism accounting for the severe impairment of intrinsic TSH bioactivity in CH remains to be completely elucidated. It is likely that the synthesis and secretion rate of TSH are markedly increased in the remaining thyrotropes, resulting in a subversion of the posttranslational processing that is worsened by the concomitant impairment of TRH action (29, 30). In agreement, we and others (23, 31), have observed an increased amount of poorly processed TSH molecules with high mannose carbohydrate chains in the serum of some patients with hypothalamic hypothyroidism.

In conclusion, the secretion of TSH molecules with reduced bioactivity is a common alteration in patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of sporadic CH.


   Acknowledgments
 
We are indebted to Miss V. Giammona for her skillful technical assistance.


   Footnotes
 
1 This work was supported in part by funds from Ricerca Corrente of the Istituto Auxologico Italiano IRCCS (Milan, Italy; to L.P.) and by MURST (Rome, Italy) Grant 9806243848. Back

Received December 27, 1999.

Revised March 17, 2000.

Accepted June 30, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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W. T. Gibson, I. S. Farooqi, M. Moreau, A. M. DePaoli, E. Lawrence, S. O'Rahilly, and R. A. Trussell
Congenital Leptin Deficiency Due to Homozygosity for the {Delta}133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4821 - 4826.
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A. Mehta, P. C. Hindmarsh, R. G. Stanhope, C. E. Brain, M. A. Preece, and M. T. Dattani
Is the Thyrotropin-Releasing Hormone Test Necessary in the Diagnosis of Central Hypothyroidism in Children
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5696 - 5703.
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L. Alberti, M. C. Proverbio, S. Costagliola, R. Romoli, B. Boldrighini, M. C. Vigone, G. Weber, G. Chiumello, P. Beck-Peccoz, and L. Persani
Germline Mutations of TSH Receptor Gene as Cause of Nonautoimmune Subclinical Hypothyroidism
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2549 - 2555.
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M. Bonomi, M. C. Proverbio, G. Weber, G. Chiumello, P. Beck-Peccoz, and L. Persani
Hyperplastic Pituitary Gland, High Serum Glycoprotein Hormone {{alpha}}-Subunit, and Variable Circulating Thyrotropin (TSH) Levels as Hallmark of Central Hypothyroidism due to Mutations of the TSH{beta} Gene
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