Botanical derived progestins and their impact on women's health

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Botanical dietary supplement use has skyrocketed over the last ten years. One significant portion of this market is herbal supplements targeted toward women, who commonly use them to treat their gynecological ailments, not only for their cost-effective advantage or affordability, but also for their health benefits. Progesterone is an endogenous hormone and synthetic progestins are used therapeutically for a variety of conditions including prevention of uterine hyperplasia, which increases the risk of uterine cancer, uterine bleeding, endometriosis, and prevention of preterm birth. Selective progesterone receptor (PR) modulators are also used in the treatment of prevention of fibroids, which occur in 80% of women. At a national level, treating benign gynecological conditions is expensive, with an annual cost of between $13–$22 billion. Thus, studying alternative therapies that women are already widely consuming is significant. However, a major technological and scientific gap exists: while botanicals are being widely consumed and contain compounds that are relatively safe, these compounds have not been identified or rigorously biologically evaluated, which is an area of emphasis for NCCIH (NOT-AT-21-006) that is specifically addressed in this application. Phytoprogestins need to be identified and studied in order to apply them for safe and effective use in uterine disorders. To address this, our team laid the groundwork for this new subfield of chemodietary prevention through the identification and biological characterization of molecules from dogwood, vitex, red clover, and yucca, as these contained compounds that modified PR signaling. In the current proposal our goal is to identify the structures of compounds in several other commonly consumed botanicals that modify PR signaling so that they can be examined for safety and efficacy in preclinical chemodietary prevention models, including prevention of fibroids, preterm birth and uterine hyperplasia. We aim to test our hypothesis that commonly consumed botanicals used to improve women’s health contain compounds that regulate PR signaling via three integrated aims. We will 1) Isolate and characterize the structures of phytoprogestin natural products from validated plant material through use of a cell-based PRE- luciferase assays and measure active compound abundance in commercial products; 2) Confirm that isolated compounds bind to a receptor, determine if they function as agonists, antagonists, or potentiators, determine if they modify off-target receptors, and refine their genome-wide transcriptional action using RNA seq; and 3) Confirm that chemodietary prevention using phytoprogestin-containing botanicals reduces preterm birth, uterine hyperplasia or blunts fibroid growth. Since little is known about phytoprogestin content and their associated biological activities from botanicals widely consumed by women, this study presents a profound opportunity to inform the treatment of gynecologic disorders and increase awareness in those consuming these botanicals already. Further, because women are already consuming these botanicals, studies should be conducted to understand their progesterone-modifying properties even if synthetic compounds exist.