Progesterone antagonizes estrogen in FMD 1 1 2 Short-term oral progesterone administration antagonizes the effect of transdermal 3 estradiol on endothelium-dependent vasodilation in young healthy women 4 5 6 7

32 Background. Very few studies have explored the cardiovascular effects of progesterone in 33 premenopausal women. This study aimed to examine the short-term effects of oral progesterone34 only, transdermal estrogen-only, and progesterone and estrogen combined on flow-mediated 35 dilation (FMD) in healthy reproductive-aged women. 36 Methods. We suppressed endogenous estrogens and progesterone in 17 premenopausal women 37 for 10-12 days using a gonadotropin-releasing hormone antagonist (GnRHa). On day 4 (hormone 38 suppression condition), subjects were tested (n=17) and then were supplemented with either 200 39 mg micronized progesterone (n=8) orally or 0.1 mg estradiol (n=9) transdermally per day. On 40 day 7 (progesterone-first or estradiol-first condition) subjects were tested and began 41 supplementation with both hormones (n=17), and were tested again on day 10 (combined 42 hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, 43 combined with synchronized Doppler analysis. 44 Results. Significant differences in FMD were observed between hormone suppression 45 (7.85±1.06%) and estrogen-first conditions (10.14±1.40%; p<0.05). The estradiol-induced 46 increase was abolished when oral progesterone was also supplemented (6.27±0.96%). In 47 contrast, we observed a trend toward a decrease in FMD with unopposed progesterone 48 administration, but no statistically significant differences were found between the progesterone49 first (6.66±1.23%), hormone suppression (7.80±1.23%), and combined hormone conditions 50