Phytotherapy for Endometriosis

ABSTRACT/SUMMARY
Endometriosis is an inflammatory gynecological disease of reproductive-age women. The two major symptoms
are chronic pelvic pain and infertility, which profoundly affect reproductive health and life quality. The pro-
inflammatory microenvironment of the endometriotic lesions, endometrium, and the peritoneal cavity are the
hallmarks of endometriosis, which leads to chronic pelvic pain and infertility. Emerging evidence suggests that
pelvic pain in endometriosis is a combination of visceral inflammatory and neuropathic pain. The long-term
goals are to understand the molecular and cellular pathogenesis of endometriosis and identify non-steroidal
therapy for endometriosis. Withania somnifera, an ancient medicinal plant, has been used to treat inflammatory
disorders, neurological diseases/disorders, neuropathic and inflammatory pain, and cancers. A wide range of
therapeutic effects of Withania somnifera is exerted through its active steroidal lactone Withaferin-A. However,
no studies have investigated the role of Withania somnifera/Withaferin-A in endometriosis. The proposed timely
needed hypothesis-driven novel preclinical research is focused on the therapeutic effects of Withaferin-A in
endometriosis. Overarching Hypothesis: Treatment of Withaferin-A suppresses the growth and survival of
endometriotic lesions, ameliorates pelvic pain, and restores the endometrial microenvironment to support fertility.
Objectives: Determine the therapeutic effects of Withaferin-A on (i) growth and survival of the endometriotic
lesions, (ii) pro-inflammatory state of the peritoneal cavity, endometriotic lesions, and pain-brain areas, (iii) pro-
inflammatory and hormonal microenvironment of the endometrium, (iv) epithelial and stromal cell-specific gene
signatures in the endometriotic lesions and endometrium, (v) ascending and descending pain pathway and
central sensitization and the underlying molecular and cellular mechanisms, and (vi) pelvic pain threshold and
spontaneous pain. Specific Aim-1 will determine the therapeutic effects of Withaferin-A on endometriotic lesions
and endometrium. Specific Aim-2 will determine the therapeutic effects of Withaferin-A on central pain
mechanisms in endometriosis. The experimental approaches include the preclinical allograft mouse model of
endometriosis, RNA-Seq, electrophysiology of brain neurons, ascending and descending pain pathways, pain
behavior, in vivo bioimaging, fluorescence microscopy, and flow cytometry. Innovation and Impact: The new
information obtained should fill the gap in the knowledge on therapeutic effects of Withaferin-A in (i) central
mechanisms of pelvic pain, gene expression signatures in the pain-brain areas, and their association with chronic
pelvic pain in endometriosis; (ii) epithelial and stromal cell-specific gene expression signatures in the
endometriotic lesions and their association with growth and survival of endometriotic lesions; and (iii) epithelial
and stromal cell-specific gene expression signatures in the endometrium and their association with infertility. (iv)
The novel results will establish a molecular therapeutic and preclinical basis to use Withaferin-A as a non-
steroidal and non-opioid therapy to treat pelvic pain and infertility in women with endometriosis.

Grant Number: 5R01HD107406-04
NIH Institute/Center: NIH
Principal Investigator: Joe Arosh