A dose-response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism.

OBJECTIVE: Young hypogonadal women appear to have an increased risk of cardiovascular disease. We studied the influence of increasing doses of hormone replacement therapy (HRT) on markers of metabolism and vascular physiology. DESIGN: Nine-month sequential dose-ranging study. PATIENTS: A total of 25 young hypogonadal women (Turner Syndrome, n = 14; 46,XX gonadal dysgenesis, n = 9), hypogonadotrophic hypogonadism (n = 2), mean age 31.9 years (range 18.5-42.2). All subjects sequentially received oral 17beta-oestradiol 1,2 and 4 mg daily in a cyclical formulation for 12 weeks each. MEASUREMENTS: Metabolic markers and vascular physiology measurements to assess intima media thickness (IMT); arterial stiffness: pulse wave velocity (PWV) and augmentation index (AIx); endothelial function: flow-mediated dilatation (FMD). Results Increasing doses of oestrogen resulted in a reduction in IMT (0.63 +/- 0.06 vs. 0.58 +/- 0.06 vs. 0.56 +/- 0.06 mm at 1 mg, 2 mg and 4 mg 17beta-oestradiol, respectively, P = 0.001). RESULTS: were similar in women with Turner Syndrome and normal karyotype. High-density lipoprotein (HDL) cholesterol concentrations increased (1.9 +/- 0.4 vs. 2.0 +/- 0.5 vs. 2.2 +/- 0.4 mmol/l, P = 0.001) and plasma glucose (4.8 +/- 0.4 vs. 4.7 +/- 0.3 vs. 4.6 +/- 0.6 mmol/l, P = 0.038) decreased slightly with the increasing dose of HRT. There was no correlation between the changes in IMT and HDL. Increasing HRT dose had no significant impact on blood pressure, weight, other lipid parameters, insulin, C-reactive protein, interleukin-6 and fibrinogen concentrations or FMD, PWV and AIx. CONCLUSIONS: Increasing doses of HRT result in a reduction in carotid IMT in young hypogonadal women, along with increased serum HDL and decreased plasma glucose. This study raises the possibility that exogenous oestrogen may be cardioprotective in young women, but this observation needs to be balanced against a prothrombotic effect which is predominant in postmenopausal women.

Adipokine dysregulation in turner syndrome: comparison of circulating interleukin-6 and leptin concentrations with measures of adiposity and C-reactive protein.

Women with Turner syndrome (TS) have increased risks of atherosclerosis, diabetes mellitus, and obesity. We hypothesized that women with TS have adverse metabolic or inflammatory markers for cardiovascular disease compared with normal women and estrogen-deficient controls. This was a cross-sectional study conducted at University College London Hospitals, UK. One hundred seventeen estrogen-treated women with TS and normal fasting blood glucose were compared with 30 age-matched normal controls and 31 estrogen-treated women with 46,XX premature ovarian failure (POF). The main outcome measures were markers of the metabolic syndrome, including the adipokines IL-6 and leptin, and C-reactive protein (CRP). TS women were more obese than controls (waist circumference, 79.9 +/- 12.4, 73.5 +/- 6.9, and 74.7 +/- 8.6 cm in TS, normal subjects, and POF controls, respectively; P = 0.005; body mass index, 26.8 +/- 5.8, 23.7 +/- 3.2, and 22.9 +/- 3.4 kg/m2; P < 0.001). This obesity was associated with increased CRP (2.9 +/- 1.5, 0.8 +/- 1.0, and 1.2 +/- 0.9 mg/liter; P < 0.001) and IL-6 concentrations (1.5 +/- 0.7, 1.0 +/- 1.5, and 1.2 +/- 0.5 pg/ml; P = 0.014), but lower fasting serum insulin (4.7 +/- 2.3, 6.3 +/- 3.0, and 6.9 +/- 2.9 mIU/ml; P = 0.004), glucose (83 +/- 11, 90 +/- 7, and 90 +/- 7 mg/dl; P < 0.001), and leptin (10.2 +/- 6.3, 14.4 +/- 7.6, and 14.8 +/- 8.1 ng/ml; P = 0.048). Triglyceride concentrations were similar in TS and POF women and were greater than in normal controls (97 +/- 53, 97 +/- 53, and 71 +/- 27 mg/dl; P = 0.024). We conclude that women with TS have various physical and biochemical features suggestive of the metabolic/insulin resistance syndrome, but there is a discrepancy among CRP, IL-6, and leptin, with leptin and fasting insulin concentrations being lower than expected for the degree of obesity. Obesity and estrogen therapy do not fully explain these findings. Women with TS may have specific metabolic defects contributing to cardiovascular risk.

Excess visceral and hepatic adipose tissue in Turner syndrome determined by magnetic resonance imaging: estrogen deficiency associated with hepatic adipose content.

Obesity, predominantly centrally distributed, is common in women with Turner syndrome (TS) and is thought to contribute to the increased risk of atherosclerosis; however, insulin concentrations are unexpectedly low. To explore this discrepancy, we assessed fat content and distribution by magnetic resonance imaging (MRI) and bioelectrical impedance (BI). Six nondiabetic, estrogen-treated women with TS were compared with six age-matched normal controls of similar body mass index. Clinical history, anthropometric measurements, biochemical markers, and MRI and BI measures of adiposity were assessed. TS women had increased intrahepatocellular lipids (IHCL) on MRI. After height adjustment, they also had an excess of total and visceral compared with sc adipose tissue (AT) than controls, without elevated insulin concentrations. BI and MRI measures correlated strongly for total and sc, but not visceral, AT in TS. IHCL was associated with cumulative estrogen-deficient years (r = 0.928; P = 0.008). Women with TS depart from the classical picture of metabolic syndrome despite an excess of total and visceral AT on MRI. Elevated IHCL in TS is associated with estrogen deficiency. BI may be useful to estimate total body fat, but does not reliably localize fat depots in TS.