Abstract
TRH to test dynamic response of the hypothalamic–pituitary–thyroid axis continues to be needed when baseline tests, even with the current sensitive thyrotropin (TSH) assays, are not clearly diagnostic for mild primary or central hypothyroidism (3,4). The need is particularly great for newborns in whom baseline TSH levels are only mildly elevated with normal or low normal thyroxine and triiodothyronine values. The case has been made that even mild or transient hypothyroidism in premature, as well as term, neonates may be associated with adverse neurodevelopmental consequences (5). The dilemma for pediatric endocrinologists is trying to balance the need for an urgent decision to treat as soon as possible with the imperative of making a clear diagnosis before committing an infant to treatment for the 3-year phase of thyroxine-sensitive neurological development. In sick and/or premature infants, transient hypothyroxinemia and immaturity of the hypothalamic–pituitary axis are common (6,7) and may lead to ambiguous results on the newborn thyroid screening tests (8). Use of TRH tests have been shown to aid management of newborns with various forms of hypothyroidism. Early reports supported the use of TRH to aid in treatment decisions for newborns with slight elevations of TSH in whom hyperresponsiveness to TRH suggested the need for treatment, even if transiently (9). Later reports confirmed the existence of mild hypothyroidism that persists even after reevaluation after 3 years of age (10 –12).
Recent studies highlight genetic causes in a small percentage of patients with congenital hypothyroidism (13), with TRH testing of heterozygotes or mildly affected infants being very useful (14). Mild or transient cases of congenital hypothyroidism may have detectable genetic etiologies. Mutations in the TSH receptor gene (TSHR) demonstrated in Japanese infants with congenital hypothyroidism (15) may have a heterozygous form of “compensated hypothyroidism” demonstrated by the TRH test (16). Transient congenital hypothyroidism was noted in subjects with heterozygous mutations leading to the loss of activity of the thyroid oxidase 2 gene (dual oxidase 2; DUOX2) (17,18).
Central hypothyroidism can be diagnosed by TRH stimulation tests, thus allowing recognition of other pituitary hormone deficiencies, a common concomitant occurrence (19,20). Early detection may lead to lower morbidity and mortality in such infants (21).
TRH stimulation tests are also useful for supporting the diagnosis of hypothyroidism in adults with depression and the elderly (22) and have been used as a predictor of response to antidepressants (23).
While TRH stimulation tests alone may not completely resolve many of the preceding diagnostic dilemmas, we believe their use may substantially contribute to improving clinical care and further clinical investigation. Therefore, we would respectfully urge that efforts be expanded by individuals, as well as organizations such as the American Thyroid Association, to reacquire TRH for testing in the United States.