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Differential expression of Kisspeptin and its receptor in eutopic and ectopic endometrium of women with and without endometriosis
O-106 Tuesday, October 31, 2017 11:45 AM EFFECT OF INFLAMMATORY ENVIRONMENT ON DEVELOPMENT OF ENDOMETRIOSIS IN MURINE MODEL. T. Toloubeydokhti,a L. Zhang,a K. Bruner-Tran,b K. G. Osteen,b A. Duleba.a aReproductive Medicine, University of California, San Diego, La Jolla, CA; bDepartment of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN. OBJECTIVE: Endometriosis is associated with intraperitoneal and systemic inflammatory environments. However, it is not clear whether inflammation is induced by endometriosis or whether inflammation predisposes the development of endometriosis. This study evaluated the effect of preexposure to an inflammatory stimulus on the risk of development of endometriosis in a murine model of this disease. DESIGN: In vivo study. MATERIALS AND METHODS: C57BL6 mice (n¼17) underwent oophorectomy and received slow-release estradiol via silastic implants 24 hour prior to random assignment to the phosphate buffered saline (PBS) group (n¼9; PBS intraperitoneal injections daily for 7 days) or to the lipopolysaccharide (LPS) group (n¼8, LPS 1.5 mg/kg intraperitoneal injections daily for 7 days). Subsequently, all animals received intraperitoneal injections of minced uterine tissues from Green Fluorescent Protein-positive (GFP+) donor mice euthanized 24 hour after oophorectomy and placement of estradiol implants. Recipient animals were euthanized 2 weeks after receiving the minced uterine tissue. Using ultraviolet light, endometriotic lesions were identified and excised. Number, size and location of endometriotic implants were compared between the LPS and PBS groups. Histologic assessment of lesions was performed following hematoxylin & eosin staining to verify the presence of endometrial glands and stroma. Wilcoxon rank sum test was used to compare the number and volume of lesions; P<0.05 was considered statistically significant. RESULTS: Endometriotic lesions were found in all eight mice preexposed to LPS but in only four of nine mice that received PBS (P¼0.03, Fisher’s exact test). Administration of LPS prior to induction of endometriosis also significantly increased the total number of endometriotic lesions per mouse in comparison to PBS (1.70.2 vs. 0.40.2; P¼0.004, respectively). Total volume of lesions per mouse ranged from 1.5 to 175 mm3 in the LPS group and from 0 to 87 mm3 in the PBS group; this difference was significant with the mean (SEM) in the LPS and PBS groups of 6116 mm3 vs. 14.715 mm3, P¼0.01, respectively. Histologic examination confirmed the uterine origin of the endometriotic lesions. CONCLUSIONS: Pre-exposure of mice to an inflammatory stimulus within the peritoneal cavity subsequently promoted the attachment and growth of endometriotic lesions. This finding suggests that biologic drivers of peritoneal inflammation may increase an individual’s risk for the development of endometriosis. In turn, therapeutic strategies focused on reducing peritoneal inflammation may be effective in limiting the development, progression or recurrence of endometriosis. Supported by: NIH:T32 Grant HD007203, NIEHS: RO1 Grant ES014942. O-107 Tuesday, October 31, 2017 12:00 PM DIFFERENTIAL EXPRESSION OF KISSPEPTIN AND ITS RECEPTOR IN EUTOPIC AND ECTOPIC ENDOMETRIUM OF WOMEN WITH AND WITHOUT ENDOMETRIOSIS. A. O. Abdelkareem,a,b A. Ait-Allah,a S. M. Rasheed,a Y. A. Helmy,a C. Allaire,b B. Peng,b P. Yong,b M. A. Bedaiwy.b aObstetrics and Gynecology, Faculty of Medicine, Sohag University, Sohag, Egypt; bDepartment of Obstetrics and Gynecology, University of British Columbia, BC Women’s Hospital, Vancouver, BC, Canada. OBJECTIVE: The neuropeptide Kisspeptin regulates gonadotrophinreleasing hormone release from the hypothalamus and is expressed peripherally in the endometrium. It also has anti-metastatic effects in many types of cancer. Like cancer, endometriosis exhibits migration and invasiveness. Our objective was to evaluate the expression of Kisspeptin and its receptor in different endometriotic lesions. DESIGN: This is a case control study. MATERIALS AND METHODS: We evaluated the expression of Kisspeptin and its receptor in women with (n¼35) and without (n¼14) endometriosis. Eutopic endometrium was obtained from patients with (EUO-E) and without (EUO-C) endometriosis. Additionally, tissues were collected from different endometriosis phenotypes including superficial implants (SUP), deep infiltrating endometriosis (DIE), and endometriomas (OMA). Immunohistochemistry staining was performed using antibodies against Kisspeptin and Kisspeptin receptor. These antibodies were validated using Immunocytochem-
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istry staining of HepG2 cells transfected with siRNA for KISS-1 and KISS1R genes. Signal intensity and abundance were measured using Histo-score. Data were analyzed using Student’s t and one way ANOVA tests where appropriate. RESULTS: In eutopic endometrium, Kisspeptin expression was significantly lower in both glandular and stromal components of EUO-E compared to EUO-C regardless of the menstrual phase (P<0.001) with no difference in receptor expression. In endometriotic implants, Kisspeptin expression was significantly lower in both glandular and stromal components of DIE (P<0.001) and OMA (P<0.01) compared to SUP. On the other hand, Kisspeptin receptor expression was only lower in glandular component of OMA (P<0.05) compared to SUP. CONCLUSIONS: Kisspeptin and its receptor have a differential expression in patients with endometriosis with a tendency towards lower expression in the more invasive phenotypes of endometriosis. Given its anti-metastatic properties, lower Kisspeptin and Kisspeptin receptor expression may play a role in the pathogenesis of endometriosis invasiveness. O-108 Tuesday, October 31, 2017 12:15 PM LONG-TERM EFFECT OF ELAGOLIX ON THE ENDOMETRIUM: RESULTS FROM TWO PHASE 3 EXTENSION STUDIES IN WOMEN WITH ENDOMETRIOSIS-ASSOCIATED PAIN. B. A. Lessey,a M. P. Diamond,b S. Agarwal,c P. Dmowski,d W. R. Duan,e J. W. Thomas,e K. Chwalisz.e aObstetrics & Gynecology, Reproductive Endocrinology & Infertility, Greenville Health System, Greenville, SC; bAugusta Univ., Augusta, GA; cCenter for Endometriosis Research & Treatment, UCSD, La Jolla, CA; dInstitute for the Study & Treatment of Endometriosis, Oak Brook, IL; eAbbVie, North Chicago, IL. OBJECTIVE: To evaluate the long-term effect of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, on endometrial morphology and thickness in women with endometriosis-associated pain. DESIGN: Elaris EM-III and Elaris EM-IV were two, extension studies of the 6-month (M) pivotal, phase 3 studies. The extension studies evaluated two elagolix doses (150 mg once daily [QD] and 200 mg twice daily [BID]) for an additional 6M (overall treatment period of 12M). The data presented are from women who received elagolix in both the pivotal and extension studies (elagolix/elagolix participants). MATERIALS AND METHODS: Elagolix/elagolix participants (randomized and treated: Elaris EM-III, n¼287; Elaris EM-IV, n¼282) were premenopausal, 18-49 year-old women with surgically diagnosed endometriosis. Some women received more than 12M of treatment due to the timing of their enrollment in the extension studies. Endometrial thickness was measured via trans-vaginal ultrasound (TVU, day 4-8 menstrual cycle) at baseline and M6 in both studies and endometrial biopsies were performed at M6 (Elaris EMIII only). Baseline biopsies (in Elaris EM-III only) and TVU endometrial thickness measurements were assessed prior to dosing in the pivotal studies. Data from Elaris EM-IV are preliminary; final data will be included in the presentation. RESULTS: The reductions in proliferative and secretory patterns and increase in quiescent/minimally stimulated endometrial biopsy patterns observed in the pivotal study were maintained over 12M of treatment (Elaris EM-III only). There were no adverse endometrial findings. Following 12M of treatment, the mean (SD) change in endometrial thickness, as measured by TVU, was 0.6 (3.8) mm at 150 mg QD and -0.8 (3.4) mm at 200 mg BID for Elaris EM-III and 1.3 (3.5) mm at 150 mg QD and -0.5 (4.0) mm at 200 mg BID for Elaris EM-IV. CONCLUSIONS: Consistent with the mechanism of action and data from the pivotal studies, long-term elagolix treatment led to a dose-dependent suppression of endometrial proliferation as evidenced by endometrial biopsy results and TVU endometrial thickness measurements. Supported by: AbbVie Inc. funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication.
MALE REPRODUCTION AND UROLOGY O-109 Tuesday, October 31, 2017 11:00 AM TRENDS IN DIAGNOSIS AND MANAGEMENT OF VARICOCELES AMONG U.S. MEN. C. Guercio,a D. Patil,b A. Mehta.c aEmory University School of Medicine, Atlanta, GA; bEmory Urology, Sr. Biostatistician, Atlanta, GA; cEmory University, Atlanta, GA.
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istry staining of HepG2 cells transfected with siRNA for KISS-1 and KISS1R genes. Signal intensity and abundance were measured using Histo-score. Data were analyzed using Student’s t and one way ANOVA tests where appropriate. RESULTS: In eutopic endometrium, Kisspeptin expression was significantly lower in both glandular and stromal components of EUO-E compared to EUO-C regardless of the menstrual phase (P<0.001) with no difference in receptor expression. In endometriotic implants, Kisspeptin expression was significantly lower in both glandular and stromal components of DIE (P<0.001) and OMA (P<0.01) compared to SUP. On the other hand, Kisspeptin receptor expression was only lower in glandular component of OMA (P<0.05) compared to SUP. CONCLUSIONS: Kisspeptin and its receptor have a differential expression in patients with endometriosis with a tendency towards lower expression in the more invasive phenotypes of endometriosis. Given its anti-metastatic properties, lower Kisspeptin and Kisspeptin receptor expression may play a role in the pathogenesis of endometriosis invasiveness. O-108 Tuesday, October 31, 2017 12:15 PM LONG-TERM EFFECT OF ELAGOLIX ON THE ENDOMETRIUM: RESULTS FROM TWO PHASE 3 EXTENSION STUDIES IN WOMEN WITH ENDOMETRIOSIS-ASSOCIATED PAIN. B. A. Lessey,a M. P. Diamond,b S. Agarwal,c P. Dmowski,d W. R. Duan,e J. W. Thomas,e K. Chwalisz.e aObstetrics & Gynecology, Reproductive Endocrinology & Infertility, Greenville Health System, Greenville, SC; bAugusta Univ., Augusta, GA; cCenter for Endometriosis Research & Treatment, UCSD, La Jolla, CA; dInstitute for the Study & Treatment of Endometriosis, Oak Brook, IL; eAbbVie, North Chicago, IL. OBJECTIVE: To evaluate the long-term effect of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, on endometrial morphology and thickness in women with endometriosis-associated pain. DESIGN: Elaris EM-III and Elaris EM-IV were two, extension studies of the 6-month (M) pivotal, phase 3 studies. The extension studies evaluated two elagolix doses (150 mg once daily [QD] and 200 mg twice daily [BID]) for an additional 6M (overall treatment period of 12M). The data presented are from women who received elagolix in both the pivotal and extension studies (elagolix/elagolix participants). MATERIALS AND METHODS: Elagolix/elagolix participants (randomized and treated: Elaris EM-III, n¼287; Elaris EM-IV, n¼282) were premenopausal, 18-49 year-old women with surgically diagnosed endometriosis. Some women received more than 12M of treatment due to the timing of their enrollment in the extension studies. Endometrial thickness was measured via trans-vaginal ultrasound (TVU, day 4-8 menstrual cycle) at baseline and M6 in both studies and endometrial biopsies were performed at M6 (Elaris EMIII only). Baseline biopsies (in Elaris EM-III only) and TVU endometrial thickness measurements were assessed prior to dosing in the pivotal studies. Data from Elaris EM-IV are preliminary; final data will be included in the presentation. RESULTS: The reductions in proliferative and secretory patterns and increase in quiescent/minimally stimulated endometrial biopsy patterns observed in the pivotal study were maintained over 12M of treatment (Elaris EM-III only). There were no adverse endometrial findings. Following 12M of treatment, the mean (SD) change in endometrial thickness, as measured by TVU, was 0.6 (3.8) mm at 150 mg QD and -0.8 (3.4) mm at 200 mg BID for Elaris EM-III and 1.3 (3.5) mm at 150 mg QD and -0.5 (4.0) mm at 200 mg BID for Elaris EM-IV. CONCLUSIONS: Consistent with the mechanism of action and data from the pivotal studies, long-term elagolix treatment led to a dose-dependent suppression of endometrial proliferation as evidenced by endometrial biopsy results and TVU endometrial thickness measurements. Supported by: AbbVie Inc. funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication.
MALE REPRODUCTION AND UROLOGY O-109 Tuesday, October 31, 2017 11:00 AM TRENDS IN DIAGNOSIS AND MANAGEMENT OF VARICOCELES AMONG U.S. MEN. C. Guercio,a D. Patil,b A. Mehta.c aEmory University School of Medicine, Atlanta, GA; bEmory Urology, Sr. Biostatistician, Atlanta, GA; cEmory University, Atlanta, GA.
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