Elevated Plasma TSH and Hypothyroidism in Children with Hypothalamic Hypopituitarism RUTH ILLIG, HELENA KRAWCZYNSKA,* T. TORRESANI, AND A. PRADER Department of Pediatrics, University of Zurich, Kinderspital, CH-8032, Zurich, Switzerland ABSTRACT. Basal TSH levels were found to be elevated in 6 patients with documented growth hormone deficiency and hypothyroidism. TRH (200 /xg/m2 administered intravenously) led to an exaggerated TSH response. This is in contrast to the results in other GH-deficient children with either a delayed rise of TSH (hypothalamic hypothyroidism due to TRH deficiency, n = 22), an absent TSH response (pituitary hypothyroidism due to TSH deficiency, n = 7), or a normal increase of TSH (isolated GH deficiency, n = 20).
S
YNTHETIC thyrotropin-releasing hormone (TRH) given intravenously to healthy subjects consistently produces arise of plasma thyroid-stimulating hormone (TSH). Since this effect is mediated by a direct action on the pituitary gland, TRH administration allows an assessment of pituitary function with respect to TSH secretion. It also facilitates distinguishing between a hypothalamic disorder and pituitary failure as reported in adults (1-11) and in children (12-15). In an attempt to differentiate the cause of hypopituitarism we have performed TRH tests in more than 50 children with growth hormone (GH) deficiency. We found a normal TSH response in all patients with isolated GH deficiency. In patients with multiple hormone deficiencies and signs of hypothyroidism, the TSH response was low or delayed. Some of these patients, however, showed elevated basal TSH levels and an exaggerated TSH response to TRH. These rather unexpected findings are preReceived February 25, 1975. Supported by the Schweizerische Nationalfonds zur Forderung der Wissenschaftlichen Forschung Grant No. 3.678.71. * Fellow of the Roche-Studienstiftung, from Warsaw, Poland. Reprints: Dr. Ruth Illig, Kinderspital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Elevated plasma TSH in the presence of hypothyroidism as seen in 6 of our patients with idiopathic hypopituitarism or craniopharyngioma, indicates an intact feedback action between the pituitary and the thyroid gland. TSH, however, seems to be inadequate for the maintenance of normal thyroid function. It is suggested that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form. (J Clin Endocrinol Metab 41: 722, 1975)
sented together with the results from our other patients with GH deficiency.1 Materials and Methods Methods Blood samples for basal TSH values were obtained before thyroid therapy. In some patients the determinations were repeated after treatment with thyroid hormone as indicated below. The TRH test was performed by iv injection of TRF-Roche" in a dose of 200 fig/m2 body surface area. Blood samples were taken at 0, 20, and 60 min. The heparinized blood was centrifuged at 4 C and the plasma stored at —20 C until analyzed. TSH was determined radioimmunologically (17) using reagents provided by the NIAMDD, Bethesda, Md. USA. The results are expressed as fxU of hTSH standard 68/38 of the British Medical Research Council. Standards were measured in TSH-free human plasma. The sensitivity of our assay system is 0.5 fiU/ml plasma; the range of highest precision is between 0.5 and 10 /LtU/ml; the interassay variation coefficient is 7%, 8.7%, and 9.6% for 3.0, 6.0, and 15.0 fjXJ/ml plasma, respectively. The TSH results from the TRH test in 97 endocrinologically normal children and adolescents, 1-20 years old, are given in Table 3; the maximum TSH 1
This study has been reported in part at the Annual Meeting of the European Society of Pediatric Endocrinology (16).
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TSH AND HYPOTHALAMIC HYPOTHYROIDISM TABLE 1. Thyroid status in 16 patients with GH deficiency and elevated plasma TSH levels Bone Patients
Age
age
yrs.
years
Idiopathic hypopituitarism 2y2 Hi. 6 8 3V2 Mil. 4 Mi. 9Vfe St. 24 17 24 17 Cu. Craniopharyngioma Sh. 8
6V2
TSH jtU/ml
T4 fig/100
Cholest. Reflexogramm*
/Llg/lOO
t
9.6 9.4
3.8 3.3 3.6 3.9 1.9
T
184 295 221 308 266
7.4
2.6
t
263
5.2 6.4 6.1
ml
T T
t
ml
AT4 after TRH
AT3 after TSH**
+44% +36%
+33% +47% !31 I #
+52%
* Achilles tendon reflex time. ** Measured 18 h after 10 IU bovine TSH im. # Radioiodine uptake increased after TSH.
values were observed, without exception, 20 min after TRH injection. There was no statistically significant difference between boys and girls, either before or during puberty, and no statistically significant difference between age groups. Thyroid function was assessed by clinical evaluation as well as by measuring basal T4, and T4 after stimulation with TRH (200 fig/m2 iv, or 20-30 mg per os) and/or T3 after stimulation with bovine TSH (10 IU AmbinonR im) (Table 1). T4 was determined with a proteinbinding method (18), T 3 radioimmunologically (19). In one boy the increment of 131iodine uptake following TSH stimulation was measured. Plasma growth hormone (GH) was measured radioimmunologically after stimulation with insulin and arginine as described previously (20). All 54 children had a deficient GH response (peak values
S
YNTHETIC thyrotropin-releasing hormone (TRH) given intravenously to healthy subjects consistently produces arise of plasma thyroid-stimulating hormone (TSH). Since this effect is mediated by a direct action on the pituitary gland, TRH administration allows an assessment of pituitary function with respect to TSH secretion. It also facilitates distinguishing between a hypothalamic disorder and pituitary failure as reported in adults (1-11) and in children (12-15). In an attempt to differentiate the cause of hypopituitarism we have performed TRH tests in more than 50 children with growth hormone (GH) deficiency. We found a normal TSH response in all patients with isolated GH deficiency. In patients with multiple hormone deficiencies and signs of hypothyroidism, the TSH response was low or delayed. Some of these patients, however, showed elevated basal TSH levels and an exaggerated TSH response to TRH. These rather unexpected findings are preReceived February 25, 1975. Supported by the Schweizerische Nationalfonds zur Forderung der Wissenschaftlichen Forschung Grant No. 3.678.71. * Fellow of the Roche-Studienstiftung, from Warsaw, Poland. Reprints: Dr. Ruth Illig, Kinderspital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Elevated plasma TSH in the presence of hypothyroidism as seen in 6 of our patients with idiopathic hypopituitarism or craniopharyngioma, indicates an intact feedback action between the pituitary and the thyroid gland. TSH, however, seems to be inadequate for the maintenance of normal thyroid function. It is suggested that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form. (J Clin Endocrinol Metab 41: 722, 1975)
sented together with the results from our other patients with GH deficiency.1 Materials and Methods Methods Blood samples for basal TSH values were obtained before thyroid therapy. In some patients the determinations were repeated after treatment with thyroid hormone as indicated below. The TRH test was performed by iv injection of TRF-Roche" in a dose of 200 fig/m2 body surface area. Blood samples were taken at 0, 20, and 60 min. The heparinized blood was centrifuged at 4 C and the plasma stored at —20 C until analyzed. TSH was determined radioimmunologically (17) using reagents provided by the NIAMDD, Bethesda, Md. USA. The results are expressed as fxU of hTSH standard 68/38 of the British Medical Research Council. Standards were measured in TSH-free human plasma. The sensitivity of our assay system is 0.5 fiU/ml plasma; the range of highest precision is between 0.5 and 10 /LtU/ml; the interassay variation coefficient is 7%, 8.7%, and 9.6% for 3.0, 6.0, and 15.0 fjXJ/ml plasma, respectively. The TSH results from the TRH test in 97 endocrinologically normal children and adolescents, 1-20 years old, are given in Table 3; the maximum TSH 1
This study has been reported in part at the Annual Meeting of the European Society of Pediatric Endocrinology (16).
722
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 November 2015. at 22:45 For personal use only. No other uses without permission. . All rights reserved.
723
TSH AND HYPOTHALAMIC HYPOTHYROIDISM TABLE 1. Thyroid status in 16 patients with GH deficiency and elevated plasma TSH levels Bone Patients
Age
age
yrs.
years
Idiopathic hypopituitarism 2y2 Hi. 6 8 3V2 Mil. 4 Mi. 9Vfe St. 24 17 24 17 Cu. Craniopharyngioma Sh. 8
6V2
TSH jtU/ml
T4 fig/100
Cholest. Reflexogramm*
/Llg/lOO
t
9.6 9.4
3.8 3.3 3.6 3.9 1.9
T
184 295 221 308 266
7.4
2.6
t
263
5.2 6.4 6.1
ml
T T
t
ml
AT4 after TRH
AT3 after TSH**
+44% +36%
+33% +47% !31 I #
+52%
* Achilles tendon reflex time. ** Measured 18 h after 10 IU bovine TSH im. # Radioiodine uptake increased after TSH.
values were observed, without exception, 20 min after TRH injection. There was no statistically significant difference between boys and girls, either before or during puberty, and no statistically significant difference between age groups. Thyroid function was assessed by clinical evaluation as well as by measuring basal T4, and T4 after stimulation with TRH (200 fig/m2 iv, or 20-30 mg per os) and/or T3 after stimulation with bovine TSH (10 IU AmbinonR im) (Table 1). T4 was determined with a proteinbinding method (18), T 3 radioimmunologically (19). In one boy the increment of 131iodine uptake following TSH stimulation was measured. Plasma growth hormone (GH) was measured radioimmunologically after stimulation with insulin and arginine as described previously (20). All 54 children had a deficient GH response (peak values
