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Nongenomic effects of estradiol vs. the birth control estrogen ethinyl estradiol on signaling and cell proliferation in pituitary tumor cells, and differences in the ability of R-equol to neutralize or enhance these effects.

  • Saraf, Manish Kumar1
  • Jeng, Yow-Jiun1
  • Watson, Cheryl S2
  • 1 Department of Biochemistry & Molecular Biology, University of Texas Medical Branch Galveston, TX 77555-0645, United States. , (United States)
  • 2 Department of Biochemistry & Molecular Biology, University of Texas Medical Branch Galveston, TX 77555-0645, United States. Electronic address: [email protected] , (United States)
Published Article
Publication Date
Apr 01, 2021
DOI: 10.1016/j.steroids.2019.01.008
PMID: 31132367


Ethinyl estradiol (EE2, the active component of many birth control formulations) persists in treated waste waters and it has become a concerning endocrine-disrupting contaminant throughout the world. Previous studies have not examined the behavior of EE2 in nongenomic signaling pathways and the subsequent functional responses (either alone or in mixtures) or conducted comparisons with the physiological estrogen estradiol (E2). In this study, mitogen-activated protein kinases (MAPKs), ERK, and JNK were activated in pituitary tumor cells by fM EE2, but p38 activation was insensitive to <nM doses. Both E2 and EE2 (10 fM to 10 nM) caused cell proliferation as well as triggering intracellular calcium increases and GTP charging of Gαi. E2 was more effective at causing prolactin release. Previously, we reported that the soy-based diadzein synthetic metabolite R-equol (R-eq) activated nongenomic responses in pituitary cells and impaired the actions of E2, thereby affecting both prolactin release and cell proliferation. In the present study, as expected, R-eq activated all MAPKs in a dose-dependent manner at concentrations ranging from fM to 100 nm, and it also modified the effects of environmentally and therapeutically relevant levels of EE2. The physiological/therapeutic doses of E2/EE2 that activated p38 were most effectively challenged by R-eq at ≥fM concentrations. R-eq did not alter the proliferative response to E2 but it elevated the cell numbers induced by EE2 at all concentrations of added R-eq. The more pronounced ability of R-eq to inhibit the cell-killing mechanisms associated with p38-induced inflammatory responses may explain its capacity to increase the numbers of EE2-stimulated pituitary tumor cells. Thus, widespread exposure to persistent pharmaceutical estrogens that imperfectly mimic endogenous estrogens may exacerbate cell proliferation in these responsive cells. Copyright © 2019. Published by Elsevier Inc.

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