Treatment of Endometriosis Patients with Selective Estrogen Receptor Modulator & Conjugated Estrogen Negatively Impacts Microvascular Function

Cardiovascular disease (CVD) is the leading cause of death in women. Endometriosis, an estrogen-dependent systemic inflammatory disease, and hot flashes during the menopausal transition are both female-specific risk factors for CVD. Bazedoxifene, a selective estrogen receptor modulator (SERM), with conjugated estrogen (BZE/CE) has been successful in treating menopause-related hot flashes; the SERM protecting breast and uterine tissue from developing abnormalities while the conjugated estrogen is proposed to treat the vasomotor dysfunction. In pre-clinical models of endometriosis BZE/CE has been successful in preventing endometriosis lesions and preliminarily improves endometriosis-related symptoms (i.e., pain) in patients. However, the impact of BZE/CE treatment on the vasculature of women with endometriosis has yet to be investigated. We hypothesized that 30 days of BZE/CE treatment, through estrogen’s vasoprotective actions on the vasculature, would improve vascular endothelial dysfunction, characterized by reduced nitric oxide (NO)-mediated vasodilation, in women with endometriosis. Endometriosis patients (n = 6, 36 ± 9 years) were tested pre-/post-30 days BZE/CE treatment. Two intradermal microdialysis fibers were placed in the forearm. Local heaters and laser-Doppler flowmetry probes were placed over the fibers to record red blood cell flux. Increasing doses of acetylcholine (ACh; log [-10] M to log [-1] M) were perfused to induce endothelium-dependent vasodilation. In one fiber, NO synthase was continuously inhibited with NG-nitro-L-arginine methyl ester (LNAME), while the other perfused ACh alone (Control). Maximal vasodilation was then induced (heat 43ºC + sodium nitroprusside) at each site to allow normalization of cutaneous vascular conductance (CVC; CVC = flux/mean arterial pressure) to site-specific maximums. NO-mediated dilation was calculated as the area between the dose-response curves of the control site and the LNAME site. Flow-mediated dilation (FMD) was used (n = 5) to assess macrovascular endothelial function. Brachial artery diameter was continuously recorded with ultrasound imaging, the artery was occluded for 5 min and then reperfused. FMD is calculated as the % change of brachial artery diameter from baseline to post-occlusion. There was a significant effect of site (p = 0.02) and interaction of site*treatment (p < 0.01). LNAME was significantly lower than the control site during the baseline visit (p < 0.01), and the control site was different following BZE/CE treatment (p = 0.02) while LNAME was not altered after BZE/CE treatment (p = 0.06). LNAME was not different from the control site following BZE/CE treatment (p = 0.29). The NO-mediated dilation was reduced (p = 0.03) from baseline (144 ± 56 AU) after BZE/CE treatment (-83 ± 158 AU). FMD was not altered (6.0 ±2.0% pre-, 6.0 ± 3.3% post- BZE/CE; p = 0.97). These findings indicate that 30 days of BZE/CE treatment induces further microvascular endothelial dysfunction in women with endometriosis. As a SERM, bazedoxifene antagonizes some and agonizes other estrogen receptors. Endometriosis is estrogen-dependent, primarily via estrogen receptor β, and the combined effect of estrogen receptor β agonization and conjugated estrogen delivery may alter systemic inflammation and/or directly impair endothelial function. NIH Grants 1F31HL170616-01 (ACW), R01 HL161000-02S2 (VGC), R01 HL16100 (LMA) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process. Information & Authors Information Published In Physiology Volume 40 • Issue S1 • May 2025 Copyright Copyright © 2025 Int. Union Physiol. Sci./Am. Physiol. Soc. History Published in print: May 2025 Published online: 12 May 2025

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