Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

Abstract

Miner JA, Martini ER, Smith MM, Brunt VE, Kaplan PF, Halliwill JR, Minson CT. Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endotheliumdependent vasodilation in young healthy women. Am J Physiol Heart Circ Physiol 301: H1716 -H1722, 2011. First published August 19, 2011; doi:10.1152/ajpheart.00405.2011.-Very few studies have explored the cardiovascular effects of progesterone in premenopausal women. This study aimed to examine the short-term effects of oral progesterone alone, transdermal estrogen alone, and progesterone and estrogen combined on flow-mediated dilation (FMD) in healthy reproductive-aged women. We suppressed endogenous estrogens and progesterone in 17 premenopausal women for 10 -12 days using a gonadotropin-releasing hormone antagonist. On day 4 (hormone suppression condition), subjects were tested (n ϭ 17) and were then supplemented with either 200 mg micronized progesterone (n ϭ 8) orally or 0.1 mg estradiol (n ϭ 9) transdermally per day. On day 7 (progesterone-first or estradiol-first condition), subjects were tested and began supplementation with both hormones (n ϭ 17) and were tested again on day 10 (combined hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, combined with synchronized Doppler analysis. As a result, significant differences in FMD were observed between hormone suppression (7.85 Ϯ 1.06%) and estrogen-first conditions (10.14 Ϯ 1.40%; P Ͻ 0.05). The estradiol-induced increase was abolished when oral progesterone was also supplemented (6.27 Ϯ 0.96%). In contrast, we observed a trend toward a decrease in FMD with unopposed progesterone administration, but no statistically significant differences were found between the progesterone-first (6.66 Ϯ 1.23%), hormone suppression (7.80 Ϯ 1.23%), and combined hormone conditions (7.40 Ϯ 1.29%). In conclusion, these data suggest that short-term oral micronized progesterone administration antagonizes the beneficial effect of transdermal estradiol on FMD.flow-mediated vasodilation; endothelial function; sex hormones; birth control WITH OVER 73% OF childbearing-aged women in the United States taking exogenous hormones for contraceptive and gynecological purposes (49a), the exploration of how exogenous hormones affect cardiovascular health is imperative. Although research on sex hormones has mainly focused on the effects of estrogens and manufactured progestins, there is relatively little known regarding the effect of progesterone on the vasculature. With progesterone production occurring naturally within the body and its bioidentical exogenous form being one of the most frequently prescribed progestogens, the need to understand the influence of progesterone on cardiovascular health is great.One of the primary methods used to investigate the effect of sex hormones on vascular health is via flow-mediated dilation (FMD). FMD, measured as the percent change in brachial artery diameter in response to an increase in shear stress, has been widely used as a nonin...

Oral Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women

“…47 For example, physiological concentrations of progesterone can oppose estrogen’s vasodilating effects on the endothelium when measured via flow-mediated dilation. 48 It is important to note that synthetic progestins not only have activity at the progesterone receptor but also at other steroid receptors to have androgenic, glucocorticoid, antiandrogenic, and antimineralocorticoid effects. A progestin’s influence on blood pressure regulation will be highly dependent on its composition and concentration.…”

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

“…This was surprising, given the common link between female sex hormones and greater NOS expression in both skeletal muscle and endothelium (Fadel et al 2003; Gavin et al 2009). Estradiol levels increase through the luteal phase and increasing levels of estrogen may create a NOS-mediated rise in exercise vasodilation, although progesterone may offset estrogen-mediated enhancements (Miner et al 2011). Similarly to Parker et al (2007) we studied women in days 1–5 of the menstrual cycle, to minimize sex differences in hormones.…”

“…It is possible that larger sex differences in exercise vascular conductance could be observed during the luteal phase that are NOS or COX mediated. However, progesterone can counter many vascular effects of estrogen in humans (Miner et al 2011). …”

Lack of effect of ovarian cycle and oral contraceptives on baroreceptor and nonbaroreceptor control of sympathetic nerve activity in healthy women

“…Our current finding that baroreceptor sensitivity remains intact during the ML phase supports the notion that the increase in MSNA during the high hormone phase may be in response to an increase in estrogen-mediated vasodilation. Miner and colleagues (26) recently reported that the addition of exogenous progesterone to exogenous estrogen antagonized flow-mediated vasodilatation in the presence of exogenous estrogen alone. Such differences may potentially explain the lack of increase in SNA during the high hormone (high exogenous estrogen and progesterone) phase in OCP users.…”