ESTROGEN THERAPY
Endometriosis: Bright future for a cloudy past? Warren B. Nothnick
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
New estrogen receptor ligands arrest endometriotic implant survival but spare reproductive cycles in a mouse model of endometriosis, thus forging a path to new treatment options (Zhao et al., this issue).
Characterized by pelvic pain and infertility, endometriosis is an “estrogen-dependent” disease that debilitates women of reproductive age. Current endometriosis treatment regimens elicit their benefcial efects on the disease symptoms by suppressing estrogen production or action. However, this approach of suppressing circulating estrogen concentrations has not proven to be a straightforward option for successful treatment. Te complexity of treating endometriosis stems from our poor understanding of the pathophysiological mechanisms and heterogeneity of the disease. Further, current endometriosis treatments are inefective in some women and, in those who achieve acceptable therapeutic efects, a balance must be achieved between suppression of disease symptoms and acceptability of side efects. Last, the current systemic approach for treating a local disease of the pelvic cavity by inducing an early menopausal state ofers no alternatives to those patients who wish to maintain menstrual cyclicity and fertility. Tus, although efective for many women, current treatments for endometriosis are far from ideal, necessitating the need for improved methods for managing the disease and its associated symptoms. Te bottleneck to treating endometriosis and preserving fertility stems from our poor understanding of the pathophysiological mechanisms and heterogeneity of the disease coupled with our inability to dissect the complexity of estrogen action within the endometriotic lesion. In this issue of Science Translational Medicine, Zhao and colleagues (1) demonstrate that new estrogen receptor ligands chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS) can arrest endometriotic implant survival in a preclinical mouse model of endometriosis while sparing reproductive cyclicity. Te auDepartment of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA. E-mail: [email protected]
thors also provide insight into the cell- and estrogen receptor type–specifc contributions through which estrogen mediates prosurvival efects on endometriotic lesions. AN AGE-OLD CONUNDRUM Endometriosis was frst described in the 1920s (2), and soon afer, clinicians implemented antiestrogen chemical suppression of the disease symptoms. Treatment options include danazol, progestins, and gonadotropin-releasing hormone (GnRH) agonists (3), all of which suppress the production of estrogen, thus reducing its systemic levels and subsequent cell signaling activity (pre-
sumably in epithelial and stromal cells in the endometriotic lesion). More recently, aromatase inhibitors (which block androgen conversion into estrogen) (4, 5) and GnRH antagonists (6) were introduced as treatment options for endometriosis. Tese drugs were proposed, respectively, to be more specifc (by reducing estrogen production locally in endometriotic implants) and more tolerable (by not causing the estrogen “fare-up” associated with GnRH agonists, which suppress estrogen levels through desensitization of the hypothalamic-pituitary axis only afer overstimulation of the pathway) relative to conventional therapies. Still, antiestrogen therapies remain the gold standard for endometriosis treatment. However, for the clinician, the conundrum of balancing systemic estrogen levels remains. Endometriosis treatment for those patients who are prescribed GnRH analogs ofen becomes a balancing act between suppressing estrogen to systemic concentrations that achieve endometriosis and arrest and maintaining the benefcial efects of the steroid (for example, on bone density). Considering the broad role of estrogen, not
Implant growth Estrogen Immune cells
𰁟
𰁠
Vasculature
Estrogen receptors Neurons
Implant arrest OHBS CLI Immune cells
𰁟
𰁠 Vasculature
Neurons
Endometriotic implant growth arrested Estrous cycle spared Reproductive capacity spared
Fig. 1. E-tale. Estrogen sites of action reside within endometriotic lesions. Estrogen that is derived either systemically or through local production within the endometriotic implant functions through ERα or ERβ that is expressed by endometrial stromal and epithelial cells as well as vasculature, neuronal, or immune cells to stimulate endometriotic implant establishment and survival (right). The estrogen receptor ligands OHBS and CLI block estrogen signaling, which stimulates prosurvival events within the implant to arrest survival (left). www.ScienceTranslationalMedicine.org 21 January 2015 Vol 7 Issue 271 271fs2
1
Downloaded from stm.sciencemag.org on March 10, 2015
FOCUS
only in the reproductive tract but also on the cardiovascular system, bones, and brain (7), it is perplexing that more endometriotic lesion–specifc treatments have not been developed. Much of this failure results from our poor understanding of the disease pathophysiology and the heterogeneity of the endometriotic lesions among as well as within patients. Te current report by Zhao and colleagues (1) sheds new light on the mechanisms of endometriotic lesion survival, ofers new insight into the multifaceted cellular and estrogenic interactions within the disease tissue, and, in turn, provides muchneeded clues toward the development of endometriotic implant–specifc antiestrogenic therapy. Estrogen’s actions are mediated primarily through two nuclear receptors, estrogen receptor α (ERα) and ERβ, both of which are aberrantly expressed in endometriotic lesions compared to normal, eutopic endometrium (8). Te authors demonstrated that estrogen acts via interplay between both receptor types expressed on endometriotic cells as well as on cells of the vasculature, neuronal system, and immune system that infiltrate the lesions (Fig. 1). Systemic administration of OHBS—which primarily inhibits ERα signaling—and CLI—which inhibits primarily ERβ signaling—both resulted in the reduction of cell proliferation, microvessel density, innervation, cytokine (IL6, Ccl2, Ccl5 TNFα, NFκB, and COX2) expression, and T cell and macrophage infltration in endometriotic implants in mice. Associated with suppression of these parameters was an increase in apoptosis of endometriotic implant tissue but, remarkably, no detrimental efect on cells of the eutopic endometrium. Further, the depletion of systemic macrophages showed that the prosurvival efects of estrogen are mediated at least in part through these immune cells, which infltrate or reside within endometriotic implants. Tis later observation emphasized that both OHBS and CLI exhibit anti-infammatory activity, which may play a role in the arrest of endometriotic implant survival. LIGHT AT THE END OF THE THERAPEUTIC TUNNEL Te new work (1) suggests that CLI and OHBS represent a new line of endometriosis therapy that ofers benefts over current therapies primarily through more direct
efects on the disease tissue—which in turn spares the menstrual cycle. Tis latter feature is advantageous to women with endometriosis who wish to maintain their monthly menstrual cycles in the hopes of achieving pregnancy. Tat being said, an immediate point of consideration going forward is whether compounds such as CLI or OHBS impact pregnancy establishment, pregnancy maintenance, or ofspring well-being. Furthermore, although beyond the scope of the Zhao et al. report, the authors acknowledge the necessity to determine whether CLI or OHBS alleviates the pain associated with endometriosis, which will require the incorporation of new experimental pain models. Because rodents with experimentally induced endometriosis exhibit pelvic pain (9), this assessment seems feasible and should be on the agenda for future studies with these and any forthcoming compounds examined as treatments for endometriosis. A second major consideration for evaluation of CLI and OHBS as endometriosis treatments is the potential impact on other estrogen target tissues such as bone, heart, and brain (7). A major drawback with current endometriosis treatments is the induction of an early menopause-like state and the hypoestrogen environment they create. Assessment of bone density during concurrent treatment with CLI and OHBS for endometriosis can easily be conducted in experimental mouse models similar to that used by Zhao and colleagues and should be performed to test whether these new compounds lack the detrimental of-target effects that now necessitate concurrent estrogen add-back therapy. Additional of-target efects of these receptor ligands will need to be evaluated once optimal time courses for treatment are established. In the current study, treatment with either compound was limited to a 6-week period. Although this treatment protocol was efective in preventing further growth of the implants, a complete regression of disease did not occur. It is unclear whether a longer duration of treatment would result in a more complete regression of the ectopic tissue or whether of-target efects of continued exposure to these compounds would ensue. Last, the preclinical mouse model used by Zhao et al. (1) is a valid experimental model for the evaluation of new endometriosis
treatments. However, care should be taken when extrapolating these fndings to treatment of the human disease. Tis assertion holds true for the use of anti-infammatory or immunomodulatory drugs to treat endometriosis, which has been tested in animals in the context of defning endometriosis as an autoimmune (10) or infammatory disease (5); but, for as-yet-unknown reasons, such mediators have yet to show promise as treatment options for endometriosis in humans.Te anti-infammatory action of CLI and OHBS manifested in the experimental mouse models used by Zhao et al. must be duplicated using in vivo models that at minimum harbor human endometriotic lesions or ideally using nonhuman primate models to provide further proof of concept. REFERENCES 1. Y. Zhao, P. Gong, Y. Chen, J. C. Nwachukwu, S. Srinivasan, C. Ko, M. K. Bagchi, R. N. Taylor, K. S. Korach, K. W. Nettles, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci. Transl. Med. 7, 271ra9 (2015). 2. J. A. Sampson, Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110, 43 (1927). 3. V. M. Rice, Conventional medical therapies for endometriosis. Ann. N. Y. Acad. Sci. 955, 343–352 (2002). 4. M. P. Diamond, B. Carr, W. P. Dmowski, W. Koltun, C. O’Brien, P. Jiang, J. Burke, R. Jimenez, E. Garner, K. Chwalisz, Elagolix treatment for endometriosis-associated pain: Results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod. Sci. 21, 363–371 (2014). 5. T. M. D’Hooghe, Immunomodulators and aromatase inhibitors: Are they the next generation of treatment for endometriosis? Curr. Opin. Obstet. Gynecol. 15, 243–249 (2003). 6. M. E. Pavone, S. E. Bulun, Aromatase inhibitors for the treatment of endometriosis. Fertil. Steril. 98, 1370–1379 (2012). 7. J. Cui, Y. Shen, R. Li, Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol. Med. 19, 197–209 (2013). 8. J. Kitawaki, N. Kado, H. Ishihara, H. Koshiba, Y. Kitaoka, H. Honjo, Endometriosis: The pathophysiology as an estrogen-dependent disease. J. Steroid Biochem. Mol. Biol. 83, 149–155 (2002). 9. P. Stratton, K. J. Berkley, Chronic pelvic pain and endometriosis: Translational evidence of the relationship and implications. Hum. Reprod. Update 17, 327–346 (2011). 10. W. B. Nothnick, Treating endometriosis as an autoimmune disease. Fertil. Steril. 76, 223–231 (2001).
10.1126/scitranslmed.aaa5075 Citation: W. B. Nothnick, Endometriosis: Bright future for a cloudy past? Sci. Transl. Med. 7, 271fs2 (2015).
www.ScienceTranslationalMedicine.org 21 January 2015 Vol 7 Issue 271 271fs2
2
Downloaded from stm.sciencemag.org on March 10, 2015
FOCUS
Endometriosis: Bright future for a cloudy past? Warren B. Nothnick
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
New estrogen receptor ligands arrest endometriotic implant survival but spare reproductive cycles in a mouse model of endometriosis, thus forging a path to new treatment options (Zhao et al., this issue).
Characterized by pelvic pain and infertility, endometriosis is an “estrogen-dependent” disease that debilitates women of reproductive age. Current endometriosis treatment regimens elicit their benefcial efects on the disease symptoms by suppressing estrogen production or action. However, this approach of suppressing circulating estrogen concentrations has not proven to be a straightforward option for successful treatment. Te complexity of treating endometriosis stems from our poor understanding of the pathophysiological mechanisms and heterogeneity of the disease. Further, current endometriosis treatments are inefective in some women and, in those who achieve acceptable therapeutic efects, a balance must be achieved between suppression of disease symptoms and acceptability of side efects. Last, the current systemic approach for treating a local disease of the pelvic cavity by inducing an early menopausal state ofers no alternatives to those patients who wish to maintain menstrual cyclicity and fertility. Tus, although efective for many women, current treatments for endometriosis are far from ideal, necessitating the need for improved methods for managing the disease and its associated symptoms. Te bottleneck to treating endometriosis and preserving fertility stems from our poor understanding of the pathophysiological mechanisms and heterogeneity of the disease coupled with our inability to dissect the complexity of estrogen action within the endometriotic lesion. In this issue of Science Translational Medicine, Zhao and colleagues (1) demonstrate that new estrogen receptor ligands chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS) can arrest endometriotic implant survival in a preclinical mouse model of endometriosis while sparing reproductive cyclicity. Te auDepartment of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA. E-mail: [email protected]
thors also provide insight into the cell- and estrogen receptor type–specifc contributions through which estrogen mediates prosurvival efects on endometriotic lesions. AN AGE-OLD CONUNDRUM Endometriosis was frst described in the 1920s (2), and soon afer, clinicians implemented antiestrogen chemical suppression of the disease symptoms. Treatment options include danazol, progestins, and gonadotropin-releasing hormone (GnRH) agonists (3), all of which suppress the production of estrogen, thus reducing its systemic levels and subsequent cell signaling activity (pre-
sumably in epithelial and stromal cells in the endometriotic lesion). More recently, aromatase inhibitors (which block androgen conversion into estrogen) (4, 5) and GnRH antagonists (6) were introduced as treatment options for endometriosis. Tese drugs were proposed, respectively, to be more specifc (by reducing estrogen production locally in endometriotic implants) and more tolerable (by not causing the estrogen “fare-up” associated with GnRH agonists, which suppress estrogen levels through desensitization of the hypothalamic-pituitary axis only afer overstimulation of the pathway) relative to conventional therapies. Still, antiestrogen therapies remain the gold standard for endometriosis treatment. However, for the clinician, the conundrum of balancing systemic estrogen levels remains. Endometriosis treatment for those patients who are prescribed GnRH analogs ofen becomes a balancing act between suppressing estrogen to systemic concentrations that achieve endometriosis and arrest and maintaining the benefcial efects of the steroid (for example, on bone density). Considering the broad role of estrogen, not
Implant growth Estrogen Immune cells
𰁟
𰁠
Vasculature
Estrogen receptors Neurons
Implant arrest OHBS CLI Immune cells
𰁟
𰁠 Vasculature
Neurons
Endometriotic implant growth arrested Estrous cycle spared Reproductive capacity spared
Fig. 1. E-tale. Estrogen sites of action reside within endometriotic lesions. Estrogen that is derived either systemically or through local production within the endometriotic implant functions through ERα or ERβ that is expressed by endometrial stromal and epithelial cells as well as vasculature, neuronal, or immune cells to stimulate endometriotic implant establishment and survival (right). The estrogen receptor ligands OHBS and CLI block estrogen signaling, which stimulates prosurvival events within the implant to arrest survival (left). www.ScienceTranslationalMedicine.org 21 January 2015 Vol 7 Issue 271 271fs2
1
Downloaded from stm.sciencemag.org on March 10, 2015
FOCUS
only in the reproductive tract but also on the cardiovascular system, bones, and brain (7), it is perplexing that more endometriotic lesion–specifc treatments have not been developed. Much of this failure results from our poor understanding of the disease pathophysiology and the heterogeneity of the endometriotic lesions among as well as within patients. Te current report by Zhao and colleagues (1) sheds new light on the mechanisms of endometriotic lesion survival, ofers new insight into the multifaceted cellular and estrogenic interactions within the disease tissue, and, in turn, provides muchneeded clues toward the development of endometriotic implant–specifc antiestrogenic therapy. Estrogen’s actions are mediated primarily through two nuclear receptors, estrogen receptor α (ERα) and ERβ, both of which are aberrantly expressed in endometriotic lesions compared to normal, eutopic endometrium (8). Te authors demonstrated that estrogen acts via interplay between both receptor types expressed on endometriotic cells as well as on cells of the vasculature, neuronal system, and immune system that infiltrate the lesions (Fig. 1). Systemic administration of OHBS—which primarily inhibits ERα signaling—and CLI—which inhibits primarily ERβ signaling—both resulted in the reduction of cell proliferation, microvessel density, innervation, cytokine (IL6, Ccl2, Ccl5 TNFα, NFκB, and COX2) expression, and T cell and macrophage infltration in endometriotic implants in mice. Associated with suppression of these parameters was an increase in apoptosis of endometriotic implant tissue but, remarkably, no detrimental efect on cells of the eutopic endometrium. Further, the depletion of systemic macrophages showed that the prosurvival efects of estrogen are mediated at least in part through these immune cells, which infltrate or reside within endometriotic implants. Tis later observation emphasized that both OHBS and CLI exhibit anti-infammatory activity, which may play a role in the arrest of endometriotic implant survival. LIGHT AT THE END OF THE THERAPEUTIC TUNNEL Te new work (1) suggests that CLI and OHBS represent a new line of endometriosis therapy that ofers benefts over current therapies primarily through more direct
efects on the disease tissue—which in turn spares the menstrual cycle. Tis latter feature is advantageous to women with endometriosis who wish to maintain their monthly menstrual cycles in the hopes of achieving pregnancy. Tat being said, an immediate point of consideration going forward is whether compounds such as CLI or OHBS impact pregnancy establishment, pregnancy maintenance, or ofspring well-being. Furthermore, although beyond the scope of the Zhao et al. report, the authors acknowledge the necessity to determine whether CLI or OHBS alleviates the pain associated with endometriosis, which will require the incorporation of new experimental pain models. Because rodents with experimentally induced endometriosis exhibit pelvic pain (9), this assessment seems feasible and should be on the agenda for future studies with these and any forthcoming compounds examined as treatments for endometriosis. A second major consideration for evaluation of CLI and OHBS as endometriosis treatments is the potential impact on other estrogen target tissues such as bone, heart, and brain (7). A major drawback with current endometriosis treatments is the induction of an early menopause-like state and the hypoestrogen environment they create. Assessment of bone density during concurrent treatment with CLI and OHBS for endometriosis can easily be conducted in experimental mouse models similar to that used by Zhao and colleagues and should be performed to test whether these new compounds lack the detrimental of-target effects that now necessitate concurrent estrogen add-back therapy. Additional of-target efects of these receptor ligands will need to be evaluated once optimal time courses for treatment are established. In the current study, treatment with either compound was limited to a 6-week period. Although this treatment protocol was efective in preventing further growth of the implants, a complete regression of disease did not occur. It is unclear whether a longer duration of treatment would result in a more complete regression of the ectopic tissue or whether of-target efects of continued exposure to these compounds would ensue. Last, the preclinical mouse model used by Zhao et al. (1) is a valid experimental model for the evaluation of new endometriosis
treatments. However, care should be taken when extrapolating these fndings to treatment of the human disease. Tis assertion holds true for the use of anti-infammatory or immunomodulatory drugs to treat endometriosis, which has been tested in animals in the context of defning endometriosis as an autoimmune (10) or infammatory disease (5); but, for as-yet-unknown reasons, such mediators have yet to show promise as treatment options for endometriosis in humans.Te anti-infammatory action of CLI and OHBS manifested in the experimental mouse models used by Zhao et al. must be duplicated using in vivo models that at minimum harbor human endometriotic lesions or ideally using nonhuman primate models to provide further proof of concept. REFERENCES 1. Y. Zhao, P. Gong, Y. Chen, J. C. Nwachukwu, S. Srinivasan, C. Ko, M. K. Bagchi, R. N. Taylor, K. S. Korach, K. W. Nettles, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci. Transl. Med. 7, 271ra9 (2015). 2. J. A. Sampson, Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110, 43 (1927). 3. V. M. Rice, Conventional medical therapies for endometriosis. Ann. N. Y. Acad. Sci. 955, 343–352 (2002). 4. M. P. Diamond, B. Carr, W. P. Dmowski, W. Koltun, C. O’Brien, P. Jiang, J. Burke, R. Jimenez, E. Garner, K. Chwalisz, Elagolix treatment for endometriosis-associated pain: Results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod. Sci. 21, 363–371 (2014). 5. T. M. D’Hooghe, Immunomodulators and aromatase inhibitors: Are they the next generation of treatment for endometriosis? Curr. Opin. Obstet. Gynecol. 15, 243–249 (2003). 6. M. E. Pavone, S. E. Bulun, Aromatase inhibitors for the treatment of endometriosis. Fertil. Steril. 98, 1370–1379 (2012). 7. J. Cui, Y. Shen, R. Li, Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol. Med. 19, 197–209 (2013). 8. J. Kitawaki, N. Kado, H. Ishihara, H. Koshiba, Y. Kitaoka, H. Honjo, Endometriosis: The pathophysiology as an estrogen-dependent disease. J. Steroid Biochem. Mol. Biol. 83, 149–155 (2002). 9. P. Stratton, K. J. Berkley, Chronic pelvic pain and endometriosis: Translational evidence of the relationship and implications. Hum. Reprod. Update 17, 327–346 (2011). 10. W. B. Nothnick, Treating endometriosis as an autoimmune disease. Fertil. Steril. 76, 223–231 (2001).
10.1126/scitranslmed.aaa5075 Citation: W. B. Nothnick, Endometriosis: Bright future for a cloudy past? Sci. Transl. Med. 7, 271fs2 (2015).
www.ScienceTranslationalMedicine.org 21 January 2015 Vol 7 Issue 271 271fs2
2
Downloaded from stm.sciencemag.org on March 10, 2015
FOCUS
