Female reproductive tract pain: targets, challenges, and outcomes

Jobling, Phillip; O’Hara, Kate; Hua, Susan

doi:10.3389/fphar.2014.00017

Cited by 14 publications

(10 citation statements)

References 119 publications

(149 reference statements)

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“…Inhibition of NFκB successfully diminishes cytokine production, but the effects of inhibition are broad, considering the relative importance of NFκB signaling in essential innate immune responses and the initiation of inflammation 62-64 . However, topical applications of NFκB in the context of LPV may pose fewer systemic effects 77 , although this remains to be evaluated. Nonetheless, further examination of the mechanisms contributing to the generation of pro-pain mediators would increase our overall knowledge of a poorly understood disorder and offer a wider selection of therapeutic targets for the design of treatments that will begin to address the underlying causes of disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel mechanisms involved in generating localized vulvodynia pain

Falsetta

Foster

Woeller

et al. 2015

American Journal of Obstetrics and Gynecology

102

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Objective Our goal was to gain a better understanding of the inflammatory pathways affected during localized vulvodynia, a poorly understood, common, and debilitating condition characterized by chronic pain of the vulvar vestibule. Methods In a control matched study, primary human fibroblast strains were generated from biopsies collected from localized provoked vulvodynia (LPV) cases and age and race-matched controls. We then examined intracellular mechanisms by which these fibroblasts recognize pathogenic Candida albicans; >70% of vulvodynia patients report the occurrence of prior chronic Candida infections, which is accompanied by localized inflammation and elevated production of pro-inflammatory/pain-associated interleukin 6 (IL-6) and prostaglandin E2 (PGE2). We focused on examining the signaling pathways involved in recognition of yeast components that are present and abundant during chronic infection. Results Dectin-1, a surface receptor that binds C. albicans cell wall glucan, was significantly elevated in vestibular versus external vulvar cells (from areas without pain) in both cases and controls, while its abundance was highest in LPV cases. Blocking Dectin-1 signaling significantly reduced pain-associated IL-6 and PGE2 production during the response to C. albicans. Furthermore, LPV patient vestibular cells produced inflammatory mediators in response to low numbers of C. albicans cells, while external vulvar fibroblasts were nonresponsive. Inhibition of NFκB (pro-inflammatory transcription factor) nearly abrogated IL-6 and PGE2 production induced by C. albicans, in keeping with observations that Dectin-1 signals through the NFκB pathway. Conclusion These findings implicate that a fibroblast-mediated pro-inflammatory response to C. albicans contributes to the induction of pain in LPV cases. Targeting this response may be an ideal strategy for the development of new vulvodynia therapies.

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Section: Discussionmentioning

confidence: 99%

Identification of novel mechanisms involved in generating localized vulvodynia pain

Falsetta

Foster

Woeller

et al. 2015

American Journal of Obstetrics and Gynecology

102

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“…Thus, NFκB would likely be an effective therapeutic target. Furthermore, topical application would reduce the risk of any undesirable systemic effects that may accompany LPV treatment with agents targeting NFκB 34 .…”

Section: Discussionmentioning

confidence: 99%

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Falsetta

Foster

Woeller

et al. 2016

The Journal of Pain

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Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates NFκB signaling (a major inflammatory pathway), while inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy. Perspective: There is an unmet need for the development of more effective vulvodynia therapies. As we explore the mechanisms by which human vulvar fibroblasts respond to proinflammatory/pro-pain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge which could significantly improve patient care.

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“…These disorders can cause severe symptoms, including pain, frequent urination, altered menstruation, and are linked to negative reproductive outcomes, such as miscarriage and infertility. In this section, we briefly review five of the most common disorders that lead to infertility in women: premature ovarian failure (POF), polycystic ovary syndrome (PCOS), endometriosis, Asherman syndrome, and preeclampsia [ 3 , 4 , 5 ] ( Figure 1 ).…”

Section: Female Reproductive System Disordersmentioning

confidence: 99%

“…Ovarian function is dependent on an array of coordinated autocrine, endocrine, and paracrine signaling pathways. Ovarian dysfunction can result from a number of reproductive system disorders, which lead to not only infertility, but also systemic health complications [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells as a Bio Organ for Treatment of Female Infertility

Esfandyari

Chugh

Park

et al. 2020

Cells

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Female infertility is a global medical condition that can be caused by various disorders of the reproductive system, including premature ovarian failure (POF), polycystic ovary syndrome (PCOS), endometriosis, Asherman syndrome, and preeclampsia. It affects the quality of life of both patients and couples. Mesenchymal stem cells (MSCs) have received increasing attention as a potential cell-based therapy, with several advantages over other cell sources, including greater abundance, fewer ethical considerations, and high capacity for self-renewal and differentiation. Clinical researchers have examined the therapeutic use of MSCs in female infertility. In this review, we discuss recent studies on the use of MSCs in various reproductive disorders that lead to infertility. We also describe the role of microRNAs (miRNAs) and exosomal miRNAs in controlling MSC gene expression and driving MSC therapeutic outcomes. The clinical application of MSCs holds great promise for the treatment of infertility or ovarian insufficiency, and to improve reproductive health for a significant number of women worldwide.

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Female reproductive tract pain: targets, challenges, and outcomes

Cited by 14 publications

References 119 publications

Identification of novel mechanisms involved in generating localized vulvodynia pain

Identification of novel mechanisms involved in generating localized vulvodynia pain

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Mesenchymal Stem Cells as a Bio Organ for Treatment of Female Infertility

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