title: Beta-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 DS-associated 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 beta-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 beta-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 isoproterenol-stimulated cAMP levels were significantly higher in the hTSH group than in the nTSH group and control subjects (45 +/- 30 versus 22 +/- 9 and 21 +/- 9 pmol . 10(6) cells(-1) . 10 min(-1), respectively; p = 0.02). Four patients in the DS hTSH subgroup had impaired sexual development. We found hyperresponsiveness of PMCs to a beta-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.
authors.affiliation: Pediatric Endocrine Unit, Kaplan Medical Center/Hadassah Medical School, Hebrew University of Jerusalem, Rehovot 76100, Israel. amzung2@bezeqint.net
authors.forename: Amnon
authors.initials: A
authors.lastname: Zung
authors.forename: Ayala
authors.initials: A
authors.lastname: Yaron
authors.forename: Yehudith
authors.initials: Y
authors.lastname: Altman
authors.forename: Zvi
authors.initials: Z
authors.lastname: Zadik
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000527:Alprostadil / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002772:Cholera Toxin / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004314:Down Syndrome / Q000150:complications* / Q000196:embryology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006058:Gonadal Disorders / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000150:complications / Q000378:metabolism*; D007223:Infant; D007545:Isoproterenol / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood; D013997:Time Factors
chemical_list: D011943:Receptors, Adrenergic, beta; D013963:Thyroid Hormones; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil; D007545:Isoproterenol