Publications

The renin-angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT)(2/3), and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT)(2/3) and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P=0.001) and (CT)(2) (OR 6.2, P=0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dose-dependent associations between the ACE I/D (P=0.003), ACE (CT)(2/3) (P=0.005) and Atg M235T (P=0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.

OBJECTIVE

To investigate uterine effects of unopposed ultralow-dose transdermal estradiol administered to postmenopausal women for 2 years.

METHODS

Postmenopausal women (n = 417), aged 60-80 years, with a uterus and with bone mineral density that was normal for age (z score >or=-2.0) were randomly assigned to receive unopposed transdermal estradiol (14 microg per day) or identical placebo patch. We evaluated effects on endometrial histology, vaginal bleeding, and vaginal epithelial cell maturation.

RESULTS

At baseline, estradiol and placebo groups were similar in age (67 +/- 5 years) and in median baseline serum estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/mL). In the estradiol group, median estradiol level increased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, P < .001). In the estradiol group, focal atypical endometrial hyperplasia developed in 1 woman, and adenosarcoma of the uterus developed in 1 woman. The placebo group had no endometrial hyperplasia. Endometrial proliferation occurred in 8.5% of the estradiol group and in 1.1% of the placebo group (P = .06). Incidence of vaginal bleeding was 12.4% in the estradiol group and 8.6% in the placebo group (P = .3). Vaginal epithelial cells showed greater maturation in the estradiol group than in the placebo group (P < .001) but less than typically observed with standard doses of estrogen.

CONCLUSION

During 2 years of treatment with ultralow-dose unopposed estradiol, treatment and placebo groups had similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding. This therapy apparently causes little or no endometrial stimulation.

LEVEL OF EVIDENCE

I.