Although compensated hypothyroidism (CH) is the most common thyroid impairment in Down syndrome (DS), its pathogenesis remains elusive. Because primary gonada l failure is another DS-associated endocrinopathy,we hypothesized that an impai red signal-transduction pathway shared by several organs may provide a unifying explanation for both endocrinopathies. We assessed two possible transduction-p athway components associated with CH in DS: the G-protein adenylate-cyclase (A C) system and β-adrenergic responsiveness, previously reported to be enhanced in DS fibroblasts. Twenty-one DS patients and 14 control subjects were studied. Peripheralmononuclear cells (PMCs)were incubated with G-proteinmodulators [pro stag-landin E1 (PGE1) and cholera toxin (CTx)], an AC stimulator (forskolin), and a β-adrenergic agonist (isoproterenol), and cAMP levels were determined. All pa rticipants had normal plasma thyroid hormone levels, but 11 of the DS patients h ad 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 isoprotereriol-stimulated cAMP levels were significantly higher in th e hTSH group than in the nTSH group and control subjects (45 ±30 versus 22 ±9 and 21 ±9 pmol ·106 cells-1 ·10 min-1, respectively; p = 0.02). Four patien ts in the DS hTSH subgroup had impaired sexual development. We found hyperrespon siveness of PMCs to a β-adrenergic agonist in a subgroup of DS patients with C H. If this observation is applicable to the thyroid gland, then it may reflect a mechanismin which negative effects on cell growth or responsiveness to TSH lead to CH. Although compensated hypothyroidism (CH) is the most common thyroid impairment in Down syndrome (DS), its pathogenesis remains elusive. Because primary gonada l failure is another DS-associated endocrinopathy, we hypothesized that an impai red signal-transduction pathway shared by several organs may provide a unifying explanation for both endocrinopathies. We assessed two possible transduction-p athway components associated with CH in DS: the G-protein adenylate-cyclase (AC) system and β-adrenergic responsiveness, previously reported to be enhanced in DS fibroblasts. Twenty-one DS patients and 14 control subjects were studied. Peripheralmonuclear cells (PMCs) were incubated with G-protein modulators [pro stag-landin E1 (PGE1) and cholera toxin (CTx)], an AC stimulator (forskolin) All participants had normal plasma thyroid hormone levels, but 11 of the DS patients h ad elevated TSH levels (hTSH), while in the 10 others, they were normal (nTSH). CAMP levels in response to forskolin, PGE1, and CTx were similar in all groups, while isoprotereriol-stimulated cAMP levels were significantly higher in th hTSH group than in the nTSH group and control subjects (45 ± 30 versus 22 ± 9 and 21 ± 9 pmol · 106 cells-1 · 10 min-1, respectively; p = 0.02). Four patien ts in the DS hTSH subgroup had impaired sexual development. We found that hyperresponsiveness of PMCs to a β-adrenergic agonist in a subgroup of DS patients with C H. If this observation is applicable to the thyroid gland, then it may reflect a mechanismin which negative effects on cell growth or responsiveness to TSH lead to CH.