J. Michael McMillin

Resistance To Thyroid Hormone: Implications for Neurodevelopmental Research On the Effects of Thyroid Hormone Disruptors

Thyroid hormones are essential for normal behavioral, intellectual, and neurological development. Congenital hypothyroidism, if not treated, can result in irreversible mental retardation, whereas thyroid diseases with more moderate impairment of thyroid function, such as resistance to thyroid hormone, cause less severe intellectual and behavioral abnormalities, including attention deficit hyperactivity disorder. There is increasing evidence that exposure to certain synthetic compounds, including dioxins and polychlorinated biphenyls (PCBs), during the perinatal period can also impair learning, memory, and attentional processes in offspring. Animal and human studies suggest that exposure to these environmental toxicants impair normal thyroidfunction. Although the precise mechanisms of action of the adverse effects these toxicants have on neurodevelopment have not yet been elucidated, it is possible that they are partially or predominantly mediated by alterations in hormone binding to the thyroid hormone receptor. The convergence of studies that examine the neurodevelopmental consequences of moderate impairment of thyroid function, such as is found in resistance to thyroid hormone, with those studies that demonstrate the adverse behavioral and cognitive effectsof perinatal exposure to dioxins and PCBs serves to generate new hypotheses to test in a research setting. Such studies may provide new insights into the basic pathogenesis of developmental neurotoxicity following exposure to thyroid-disrupting synthetic compounds.

Coexistent Hypothyroidism, Psychosis, and Severe Obsessions in an Adolescent: A 10-Year Follow-up

UNLABELLED This is the first longitudinal report on possible psychosis resulting from the juvenile onset of hypothyroidism. A 10-year follow-up in the case of a 13-year-old boy published in this journal in 1993 is presented. The patient presented with a diagnostic dilemma. Although psychosis resulting from hypothyroidism was the most parsimonious explanation of his symptoms (new-onset auditory hallucinations, severe obsessions, and severe hypothyroidism), a primary psychiatric disorder (obsessive-compulsive disorder [OCD] or psychotic depression) aggravated by hypothyroidism could not be excluded. The aim of this study was to illustrate that the diagnosis and clinical interrelationships can be clarified by longitudinal data. FOLLOW-UP DATA: The patients symptoms responded optimally to a combination of fluvoxamine, risperidone, and levothyroxine (LT4, 300 microg daily). He was free from severe symptoms until age 21, when he discontinued all psychotropic medications while continuing with LT4. Over 2 months later, he was hospitalized for thoughts of hurting himself or others. In the hospital, his LT4 was discontinued and propranolol was started. He was discharged on multiple psychotropic medications, and was rehospitalized 6 days later for suicide risk. When LT4 (200 microg daily) was added to his psychotropic regimen, he partially responded and was discharged. The optimal response to treatment occurred only after he was placed on a combination of fluoxetine, risperidone, and LT4 (300 microg daily). The patient remained stable for up to 12 months of follow-up. CONCLUSIONS This chronology suggests that the optimal treatment in this patient probably required three components: a Selective Serotonin Reuptake Inhibitor, (SSRI) risperidone, and LT4 (300 g daily). Each component was apparently necessary but not sufficient individually for the optimal response. The relapse after the discontinuation of fluvoxamine and risperidone (but not LT4) suggests the presence of a primary psychiatric disorder (OCD with depression). The failure to improve without an adequate dosage of LT4 suggests that hypothyroidism was probably an aggravating factor. This case illustrates the diagnostic difficulty in distinguishing between obsessions, depressive ruminations, and delusions in children and the need to consider hypothyroidism in the differential diagnosis of the sudden worsening of OCD, or in cases of new-onset psychosis in children and adolescents.

469 SERUM PROLACTIN IS ELEVATED IN CHILDREN WITH CONGENITAL GROWTH HORMONE DEFICIENCY ASSOCIATED WITH PERINATAL COMPLICATIONS

Children with idiopathic congenital growth hormone deficiency (ICGHD) frequently have a history of significant perinatal complications. We have investigated the hypothesis that children with perinatal complications represent a discreet etiologic subset of children with ICGHD characterized by abnormalities of prolactin secretion. Thirty-two children with newly diagnosed ICGHD were studied by measuring the prolactin response to TRH. Fifteen normal children were studied as controls. Children were classified as ICGHD on the basis of documented growth hormone deficiency, growth records compatible with a congenital onset and absence of findings suggesting an acquired or definable lesion. Sixteen of the ICGHD children had a history of significant complications during the perinatal period. Mean baseline prolactin in this group was 22.0 ± 4.2 ng/ml (Mean ± SEM). This was significantly greater than the baseline prolactin in children with ICGHD and normal perinatal histories (11.4 ± 1.7 ng/ml) and normal children (8.7 ± 1.6 ng/ml, p < .03, Students t-test). There was no significant difference in peak prolactin concentration 15 minutes after TRH injection in the three groups (51.7 ± 7.3, 52.1 ± 7.8 and 45.8 ± 4.7 ng/ml, p > .05). We conclude that hypothalamic compromise associated with perinatal complications is the etiology of growth hormone deficiency in a subset of children with ICGHD. Vigorous follow-up of at-risk children is recommended.