Sex hormones have been shown to influence levels of adiponectin. Furthermore, testosterone has been shown to alter the subform distribution of adiponectin, whereas the effects of oestradiol are equivocal. We investigated the impact of sex hormone replacement therapy (HRT) on circulating adiponectin and its subforms, fasting lipids and measures of insulin sensitivity in Turner syndrome (TS) and Klinefelter syndrome (KS) respectively. We compared eight young TS patients on and off 2 months of HRT vs. eight age- and body mass index (BMI) matched healthy females as well as 19 untreated KS patients vs. 20 testosterone treated KS patients vs. 20 age and BMI matched healthy males. Total adiponectin and adiponectin subforms separated by fast protein liquid chromatography were measured using an in-house assay. In addition, fasting levels of insulin, glucose and homeostasis model assessment estimates were determined. In TS, total adiponectin levels were 10.5 +/- 3.1 (mean +/- SD) vs. 12.8 +/- 3.5 mg L(-1) (P = 0.02) and high molecular weight (HMW) adiponectin 5.8 +/- 2.7 and 6.8 +/- 1.9 mg L(-1) (P = 0.02) on and off HRT respectively. Irrespective of HRT, total adiponectin and HMW adiponectin were similar to control values. In KS, total adiponectin levels were 6.5 (3.0-24.2) (median and range) and 9.3 (4.3-14.3) mg L(-1) (P = NS) and HMW adiponectin was 2.5 (0.5-16.0) and 4.6 (1.3-8.6) mg L(-1) (P = NS) with and without testosterone treatment respectively, and similar to controls. Short time HRT suppressed HMW and total adiponectin levels in TS patients. Testosterone treatment in KS patients had no effect on these parameters. In both groups of patients either adiponectin or the HMW subform seems to play no greater role in reflecting or mediating insulin sensitivity. Our data indicates that in patients with TS and KS, sex hormones have different effects on circulating adiponectin and its HMW subform than previously reported in other sex hormone deficient patients and healthy subjects.