β-Adrenergic Hyperresponsiveness in Compensated Hypothyroidism Associated with Down Syndrome

Abstract

Although compensated hypothyroidism (CH) is the most common thyroid impairment in Down syndrome (DS), its pathogenesis remains elusive. Because primary gonadal failure is another DSassociated endocrinopathy, we hypothesized that an impaired signal-transduction pathway shared by several organs may provide a unifying explanation for both endocrinopathies. We assessed two possible transduction-pathway components associated with CH in DS: the G-protein adenylate-cyclase (AC) system and ␤-adrenergic responsiveness, previously reported to be enhanced in DS fibroblasts. Twenty-one DS patients and 14 control subjects were studied. Peripheral mononuclear cells (PMCs) were incubated with G-protein modulators [prostaglandin E1 (PGE1) and cholera toxin (CTx)], an AC stimulator (forskolin), and a ␤-adrenergic agonist (isoproterenol), and cAMP levels were determined. All participants had normal plasma thyroid hormone levels, but 11 of the DS patients had elevated TSH levels (hTSH), whereas in the 10 others, they were normal (nTSH). cAMP levels in response to forskolin, PGE1, and CTx were similar in all groups, whereas isoproterenolstimulated cAMP levels were significantly higher in the hTSH group than in the nTSH group and control subjects (45 Ϯ 30 versus 22 Ϯ 9 and 21 Ϯ 9 pmol · 10 6 cells Ϫ1 · 10 min Ϫ1, respectively; p ϭ 0.02). Four patients in the DS hTSH subgroup had impaired sexual development. We found hyperresponsiveness of PMCs to a ␤-adrenergic agonist in a subgroup of DS patients with CH. If this observation is applicable to the thyroid gland, then it may reflect a mechanism in which negative effects on cell growth or responsiveness to TSH lead to CH. Many studies over the past several decades have found an increased prevalence of various types of thyroid dysfunction in individuals with Down syndrome (DS), including congenital hypothyroidism (1) and thyroid autoimmune disease (2-5). However, the most prevalent thyroid disorder in this population is compensated hypothyroidism (CH), characterized by mildly elevated TSH in the absence of signs of thyroid autoimmunity or clinical hypothyroidism. Its prevalence in DS has been reported to be in the range of 14 to 63% (3,5-8), but its cause remains elusive.A decreased threshold in the pituitary gland to thyroxin in CH, postulated in some studies (3,5), seems unlikely because low-dose thyroxin treatment rapidly brings TSH to normal levels, suggesting that the thyroxin-TSH negative feedback mechanism is preserved (5). Others have suggested the presence of immunologically competent but biologically less active TSH (3,9,10). However, this hypothesis was ruled out recently by Konings et al. (10), who postulated that CH derives from an impaired signal-transduction pathway involved in thyroid hormonogenesis. The presence of hypogonadism in some of our DS patients with CH led us to hypothesize that hypothyroidism is just one aspect of multiple hormone resistance in DS.Gonadal impairment in DS is manifested by hypogonadism with subsequent elevation of LH and FSH levels but with no...

Pediatric endocrinology through syndromes

“…In some patients, however, neonatal hypothyroidism is transient and follow-up is always recommended (Fort et al, 1984). In the light of the increased presence of beta-adrenergic receptors on circulating monocytes in the subset of DS patients with congenital hypothyroidism, one of the possible mechanisms could be associated to the increase in beta adrenergic receptors on thyrocytes, which may result in down regulation of the TSH receptor and therefore hypothyroidism (Zung et al, 2005).…”