Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review

In the paper

“in one-third of women due to progesterone resistance”

• Also stated in: § 3. Why Do We Need New Options? · plain

  “one-third are non-responders due to progesterone resistance [5,6,61,62,68]”

What the sources say

• Not checked yetcites [5] Vercellini, 2016, Estrogen-progestins and progestins for the management of endometriosis, Fertil. Steril. source
• Not checked yetcites [6] Vercellini, 2018, Medical treatment of endometriosis-related pain, Best Pr. Res. Clin. Obstet. Gynaecol. source
• Partly supported

  Section 3, “Reducing low-value medical treatment” (page unavailable), acknowledges that some women do not respond to oral contraceptives or progestins and recommends other treatments for nonresponders. It does not say that one-third do not respond or attribute nonresponse to progesterone resistance. (LLM, conf=0.82)

  cites [61] Vercellini, 2017, Toward minimally disruptive management of symptomatic endometriosis: Reducing low-value care and the burden of treatment, Expert Rev. Pharmacoecon. Outcomes Res. sourceExperimental — accuracy not yet measured
• Partly supported

  In “Pathogenic and metabolic implications” (page unavailable), the paper says about two-thirds of patients appear satisfied with combined hormonal contraceptives, leaving roughly one-third needing alternatives. It does not say that one-third fail to respond to both OCPs and progestogens, or that progesterone resistance causes nonresponse; it instead lists nonresponse, intolerance, and contraindications to combined hormonal contraceptives as reasons to consider other treatments. (LLM, conf=0.90)

  cites [62] Vercellini, 2018, Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?, Fertil. Steril. sourceExperimental — accuracy not yet measured
• Not checked yetcites [68] Casper, 2017, Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills, Fertil. Steril. source

In the paper

“Progesterone resistance may of course explain this unexpected issue [18,19,20,21,22].”

What the sources say

• Not checked yetcites [18] Bulun, 2006, Progesterone resistance in endometriosis: Link to failure to metabolize estradiol, Mol. Cell. Endocrinol. source
• Partly supported

  The Results section on ERβ gain of function (page unavailable) reports reduced decidualization responses in ERβ-overexpressing human endometrial stromal cells after estradiol–medroxyprogesterone–cAMP treatment. This supports an impaired response to a progesterone-containing stimulus, but the paper does not link progesterone resistance to patients’ non-response to estroprogestin or progestin therapy. (LLM, conf=0.78)

  cites [19] Han, 2015, Estrogen receptor b modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis, Cell sourceExperimental — accuracy not yet measured
• Not checked yetcites [20] Pavone, 2010, Altered retinoid uptake and action contributes to cell survival in endometriosis, J. Clin. Endocrinol. Metab. source
• Not checked yetcites [21] Pavone, 2011, Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action, Hum. Reprod. source
• Not checked yetcites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source

In the paper

“Achieving a clinically meaningful response to endometriosis-related pain with elagolix was found to be associated with improvements in health-related quality of life and work productivity [111,112].”

What the sources say

• Supported

  The Study Design and Data Source section identifies the two trials as studies of elagolix in women with moderate to severe endometriosis-related pain. The Comment Principal findings and GYNECOLOGY Original Research sections report that clinical pain responders had improved health-related quality of life and workplace productivity. Page numbers are not supplied in our copy. (LLM, conf=0.94)

  cites [111] Pokrzywinski, 2020, Achieving clinically meaningful response in endometriosis pain symptoms is associated with improvements in health-related quality of life and work productivity: Analysis of 2 phase III clinical trials, Am. J. Obstet. Gynecol. source
• Partly supported

  The Discussion (page not provided) reports clinically meaningful improvements in health-related quality of life with elagolix and says those changes mirror improvements in pain scores. It also states that elagolix restored workplace productivity, citing another study. This paper does not establish that patients who achieved a clinically meaningful pain response were the ones who improved in both quality of life and work productivity. (LLM, conf=0.82)

  cites [112] Taylor, 2020, Health-related quality of life improvements in patients with endometriosis treated with elagolix, Obstet. Gynecol. sourceExperimental — accuracy not yet measured

In the paper

“Response rates for overall pelvic pain, dysmenorrhea and non-menstrual pelvic pain were maintained or increased after 24 weeks of treatment.”

What the sources say

• Supported

  The Secondary Efficacy Endpoints section states that responder percentages for overall pelvic pain, dysmenorrhea, and non-menstrual pelvic pain at week 12 were maintained or increased at week 24. This directly supports the attributed claim about response rates after 24 weeks of linzagolix treatment. (LLM, conf=0.95)

  cites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“OCPs and progestogens are effective in two-thirds of women suffering from endometriosis”

• Also stated in: § An Unmet Need · boosted

  “first-line medical therapy (OCPs and progestogens) is effective in two-thirds of women suffering from endometriosis-related pain [5,6]”

• Also stated in: § 3. Why Do We Need New Options? · plain

  “Two-thirds of symptomatic women find pain relief and improvement in their general condition thanks to estroprogestins and progestin-only medication”

What the sources say

• Not checked yetcites [5] Vercellini, 2016, Estrogen-progestins and progestins for the management of endometriosis, Fertil. Steril. source
• Not checked yetcites [6] Vercellini, 2018, Medical treatment of endometriosis-related pain, Best Pr. Res. Clin. Obstet. Gynaecol. source

In the paper

“Percentages of women experiencing hot flushes at a dose of 150 mg (once daily) were respectively 23.7%, 22.6%, 44% and 36% in Elaris-I, -II, -III and -IV.”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source
• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“In Elaris EM-I, the percentage of women who noted an improvement in non-menstrual pelvic pain was 50.4% with elagolix 150 mg once daily and 54.5% with elagolix 200 mg twice daily (compared with 36.5% in the placebo group).”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“Regarding side effects, the most frequently reported were hot flushes, depending on the dose.”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source
• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“It should be noted that decreased BMD was the most common cause of treatment discontinuation in subsequent Elaris EM-III and -IV studies described below.”

What the sources say

• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“Overall, alleviation of both dysmenorrhea and non-menstrual pelvic pain were sustained for six months (Table 1).”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“Percentages of women with a ≥30% reduction in overall pelvic pain (primary efficacy endpoint) at week 12 were respectively 61.5%, 56.4% and 56.3% in the 75 mg, 100 mg and 200 mg groups compared to 34.5% in the placebo group [105].”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“The percentage of patients with a decrease of >5% from baseline in lumbar spine BMD was higher in the elagolix 200 mg twice daily group in all studies.”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“Elagolix causes a dose-dependent decrease in BMD.”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“Percentages of women with a ≥30% reduction in overall pelvic pain at week 24 were 70.8%, 66.7% and 77.3% in the 75 mg, 100 mg and 200 mg groups, respectively, in phase II trials (Table 1).”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“A significant reduction in overall pelvic pain was already evident four to eight weeks after starting treatment.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“In the EM-I and -II trials, Taylor et al. [102] reported that mean decreases in BMD in the lumbar spine, femoral neck and total hip after six months of treatment were significantly greater in patients receiving elagolix than in those given a placebo (excluding femoral neck BMD at a dose of 150 mg in Elaris EM-I (Figure 3).”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“At 200 mg (twice daily), percentages were respectively 42.3%, 47.6%, 72% and 77% [102,103].”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source
• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“In both studies, only women treated with elagolix at a dose of 200 mg twice daily showed a statistically significant greater reduction in dyspareunia after three months of treatment (compared with the placebo).”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

In the paper

“The majority of women reported much or very much improved endometriosis-associated pain after 12 months of treatment.”

What the sources say

• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“Elagolix did not completely suppress ovulation at either of the two doses.”

What the sources say

• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

In the paper

“With the 75 mg and 100 mg doses of linzagolix, there was dose-dependent partial suppression of serum E2 to between 20 and 60 pg/mL.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“For additional endpoints, findings similar to the VAS score were obtained with other indices for pain symptoms, such as the Biberoglu and Behrman (B&B) scale [118].”

What the sources say

• Not checked yetcites [118] Biberoglu, 1981, Dosage aspects of danazol therapy in endometriosis: Short-term and long-term effectiveness, Am. J. Obstet. Gynecol. source

In the paper

“There was a dose-dependent increase in the rate of amenorrhea from weeks 4 to 24.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“A phase II, open-label RCT including 487 women with endometriosis-associated pain found relugolix (10 mg, 20 mg or 40 mg orally once daily) and leuprolin for 24 weeks to be equally effective [104].”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source

In the paper

“Response rates for overall pelvic pain, dysmenorrhea and non-menstrual pelvic pain were maintained or increased after 52 weeks of treatment.”

What the sources say

• Not checked yetcites [113] Taylor, 2019, Long term treatment of endometriosis associated pain (EAP) with linzagolix: Efficacy and safety after 12 months of treatment, Fertil. Steril. source
• Not checked yetcites [114] Bestel, 2020, Quality of life results after 52 weeks of treatment with linzagolix for endometriosis-associated pain, Obstet. Gynecol. source

In the paper

“Based on EHP-30 questionnaire results, treatment with linzagolix resulted in enhanced quality of life.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“Significantly more women reported “much” or “very much” improvement on the PGIC scale by week 12 in the 75 mg, 100 mg and 200 mg dose groups compared to the placebo group.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“In terms of quality of life, the EHP-30 score was better in relugolix-treated patients than in the placebo group.”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source

In the paper

“Regarding the primary endpoint of the phase II trial, changes from baseline in the mean visual analog scale (VAS) score for pelvic pain were −6.2 in the relugolix 10 mg group and −8.2 in the relugolix 20 mg group (Figure 6).”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source

In the paper

“Mean percentage (95% CI) BMD changes for the lumbar spine from baseline to week 24 in the 75 mg, 100 mg and 200 mg dose groups were −0.80% (−1.57, −0.03), −1.37% (−2.14, −0.59) and −2.60% (−3.56, −1.65), respectively.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“E2 and FSH levels decreased more rapidly after starting treatment with relugolix 40 mg than with leuprolin.”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source

In the paper

“At the 40 mg dose, hot flushes showed a similar frequency to the leuprolin group.”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source

In the paper

“A similar pattern was observed in responder rates for dysmenorrhea and non-menstrual pelvic pain, with significant differences compared to the placebo at 12 weeks in the relugolix CT arm in both SPIRIT-1 and -2.”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“Percentages of women with a ≥30% reduction in overall pelvic pain (OPP) (primary efficacy endpoint) at week 52 were 69.2%, 53.8% and 82.4% in the 75 mg, 100 mg and 200/100 mg groups, respectively.”

What the sources say

• Not checked yetcites [113] Taylor, 2019, Long term treatment of endometriosis associated pain (EAP) with linzagolix: Efficacy and safety after 12 months of treatment, Fertil. Steril. source
• Not checked yetcites [114] Bestel, 2020, Quality of life results after 52 weeks of treatment with linzagolix for endometriosis-associated pain, Obstet. Gynecol. source

In the paper

“Response rates for dysmenorrhea and non-menstrual pelvic pain were maintained or increased after 24 weeks of treatment.”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“Relugolix CT enhanced daily functioning, as demonstrated by the EHP-30 pain score domain at week 24 (p < 0.0001 in both studies)”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“Relugolix CT yielded significant improvements in dyspareunia, with 40% and 46% reductions from baseline in NRS scores (mean change).”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“Dysmenorrhea decreased rapidly from severe at baseline to mild by week 8 and was sustained through to week 24 in 73% and 75% of women in SPIRIT-1 and -2, respectively.”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“All results were statistically significant compared to the placebo (p < 0.0001).”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“These findings were also statistically significant in SPIRIT-1 and -2 (p = 0.0149 and p = 0.0371, respectively).”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“There is a place for GnRH antagonists in the management of symptomatic endometriosis”

In the paper

“Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis”

• Also stated in: § 1. Introduction · boosted

  “one common pathogenic mechanism shared by all forms of the condition is the impact of estradiol (E2)”

What the sources say

• Not checked yetcites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source
• Not checked yetcites [3] Giudice, 2010, Clinical practice. Endometriosis, N. Engl. J. Med. source

In the paper

“the impact of estradiol (E2), which is known to have proinflammatory and antiapoptotic effects on endometrial cells, especially in ectopic foci [2,3]”

What the sources say

• Not checked yetcites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source
• Not checked yetcites [3] Giudice, 2010, Clinical practice. Endometriosis, N. Engl. J. Med. source

In the paper

“so lowering levels of circulating estrogens should be considered an effective medical approach.”

In the paper

“second-line therapies (injectable depot formulations of gonadotropin-releasing hormone (GnRH) agonists), which are only proposed in case of OCP or progestogen failure, are associated with bothersome menopausal symptoms.”

What the sources say

• Not checked yetcites [11] Surrey, 2020, Real-World Characterization of Women with Diagnosed Endometriosis Initiating Therapy with Elagolix Using a US Claims Database, Clinicoecon Outcomes Res. source
• Not checked yetcites [12] Soliman, 2017, The burden of endometriosis symptoms on health-related quality of life in women in the United States: A cross-sectional study, J. Psychosom. Obstet. Gynecol. source
• Not checked yetcites [13] Soliman, 2016, The direct and indirect costs associated with endometriosis: A systematic literature review, Hum. Reprod. source

In the paper

“some miRNAs (miR-9m, miR-34 and miR-29c) are implicated in progesterone resistance.”

What the sources say

• Not checked yetcites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source

In the paper

“with a number of polymorphisms in the PR gene implicated as a genetic cause of progesterone resistance.”

What the sources say

• Not checked yetcites [35] Simpson, 2003, Genetics of endometriosis, Obstet. Gynecol. Clin. North Am. source

In the paper

“In endometrial stromal cells, progesterone increases formation of RA, which triggers expression of 17β-HSD2 in epithelial cells.”

What the sources say

• Not checked yetcites [14] Bulun, 2010, 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin. Reprod. Med. source
• Not checked yetcites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source
• Not checked yetcites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source
• Not checked yetcites [20] Pavone, 2010, Altered retinoid uptake and action contributes to cell survival in endometriosis, J. Clin. Endocrinol. Metab. source
• Not checked yetcites [21] Pavone, 2011, Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action, Hum. Reprod. source
• Not checked yetcites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source

In the paper

“In eutopic endometrial cells of endometriosis patients, HOXA-10 does not show increased expression after ovulation due to hypermethylation and gene silencing of its promoter [39].”

What the sources say

• Not checked yetcites [39] Wu, 2005, Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis, Am. J. Obstet. Gynecol. source

In the paper

“impaired progesterone action is likely to be the cause of alterations in RA function in endometriotic tissue.”

What the sources say

• Not checked yetcites [20] Pavone, 2010, Altered retinoid uptake and action contributes to cell survival in endometriosis, J. Clin. Endocrinol. Metab. source
• Not checked yetcites [21] Pavone, 2011, Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action, Hum. Reprod. source

In the paper

“During the follicular phase, estrogen acts on eutopic endometrium through the estrogen receptor (ER) to increase transcription and protein levels of the progesterone receptor (PR), especially the PR-B isoform.”

What the sources say

• Not checked yetcites [14] Bulun, 2010, 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin. Reprod. Med. source
• Not checked yetcites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source
• Not checked yetcites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

In the paper

“A recent review by Reis et al. [56] also confirms that deep endometriosis appears to be more resistant to regression upon medical treatment.”

What the sources say

• Not checked yetcites [56] Reis, 2020, Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure, Hum. Reprod. Updat. source

In the paper

“Retrograde menstruation and bleeding of endometriotic lesions are responsible for the presence of erythrocytes in the pelvic cavity, which are likely to release pro-oxidant and proinflammatory factors like hemoglobin and its highly toxic byproducts heme and iron [27,28,29,30].”

What the sources say

• Not checked yetcites [27] Donnez, 2002, Iron overload in the peritoneal cavity of women with pelvic endome-triosis, Fertil. Steril. source
• Not checked yetcites [28] Dolmans, 2002, Potential involvement of hemoglobin and heme in the pathogenesis of peritoneal endometriosis, Fertil. Steril. source
• Not checked yetcites [29] Lousse, 2012, Peritoneal endometriosis is an inflam-matory disease, Front. Biosci. Elite Ed. source
• Not checked yetcites [30] Donnez, 2016, Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis, Fertil. Steril. source

In the paper

“post-operative recurrence is common, because persistent foci not detected at the time of surgery may progress under the influence of circulating estrogens [1,2,3,5,6].”

What the sources say

• Not checked yetcites [1] Donnez, 2002, The efficacy of medical and surgical treatment of endometriosis-associated infertility: Arguments in favour of a medico-surgical approach, Hum. Reprod. Update. source
• Not checked yetcites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source
• Not checked yetcites [3] Giudice, 2010, Clinical practice. Endometriosis, N. Engl. J. Med. source
• Not checked yetcites [5] Vercellini, 2016, Estrogen-progestins and progestins for the management of endometriosis, Fertil. Steril. source
• Not checked yetcites [6] Vercellini, 2018, Medical treatment of endometriosis-related pain, Best Pr. Res. Clin. Obstet. Gynaecol. source

In the paper

“endometriotic stromal cells show significantly lower ERα and higher ERβ levels than eutopic endometrial stromal cells [15].”

What the sources say

• Not checked yetcites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

In the paper

“these first-line medical therapies demonstrate limited long-term efficacy”

What the sources say

• Not checked yetcites [11] Surrey, 2020, Real-World Characterization of Women with Diagnosed Endometriosis Initiating Therapy with Elagolix Using a US Claims Database, Clinicoecon Outcomes Res. source
• Not checked yetcites [12] Soliman, 2017, The burden of endometriosis symptoms on health-related quality of life in women in the United States: A cross-sectional study, J. Psychosom. Obstet. Gynecol. source
• Not checked yetcites [13] Soliman, 2016, The direct and indirect costs associated with endometriosis: A systematic literature review, Hum. Reprod. source

In the paper

“PR resistance in endometriotic cells results in CRABP2 deficiency, thereby favoring survival, development and persistence of endometriotic implants [15,16].”

What the sources say

• Not checked yetcites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source
• Not checked yetcites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

In the paper

“As there are not enough robust data demonstrating the superiority of one progestin over the others”

What the sources say

• Not checked yetcites [76] Buggio, 2017, Oral and depot progestin therapy for endometriosis: Towards a personalisez medicine, Expert Opin. Pharmacother. source

In the paper

“Some studies have revealed the absence of proliferation index changes under progestogen therapy [77,78,79,80,81].”

What the sources say

• Not checked yetcites [77] Donnez, 1987, Combined (hormonal and microsurgical) therapy in infertile women with endometriosis, Fertil. Steril. source
• Not checked yetcites [78] Donnez, 1996, Large ovarian endometriomas, Hum. Reprod. source
• Not checked yetcites [79] Donnez, 1988, Histologic study of ovarian endometriosis after hormonal therapy, Fertil. Steril. source
• Not checked yetcites [80] Donnez, 1990, Evaluation of preoperative use of danazol, gestrinone, lynestrenol, buserelin spray and buserelin implant, in the treatment of endometriosis associated infertility, Prog. Clin. Boil. Res.
• Not checked yetcites [81] Donnez, 1990, Endometriosis-associated infertility: Evaluation of preoperative use of danazol, gestrinone, and buserelin, Int. J. Fertil.

In the paper

“There was, however, a lack of any beneficial effect of OCPs on non-menstrual pelvic pain and dyspareunia”

What the sources say

• Not checked yetcites [59] Vercellini, 2018, Management of endometriosis: Toward value-based, cost-effective, affordable care, J. Obstet. Gynaecol. Can. source
• Not checked yetcites [60] Vercellini, 2018, A stepped-care approach to symptomatic endometriosis management: A participatory research initiative, Fertil. Steril. source
• Not checked yetcites [61] Vercellini, 2017, Toward minimally disruptive management of symptomatic endometriosis: Reducing low-value care and the burden of treatment, Expert Rev. Pharmacoecon. Outcomes Res. source
• Not checked yetcites [62] Vercellini, 2018, Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?, Fertil. Steril. source

In the paper

“33% of patients given estroprogestins and/or progestins do not respond to therapy.”

What the sources say

• Not checked yetcites [5] Vercellini, 2016, Estrogen-progestins and progestins for the management of endometriosis, Fertil. Steril. source
• Not checked yetcites [6] Vercellini, 2018, Medical treatment of endometriosis-related pain, Best Pr. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [59] Vercellini, 2018, Management of endometriosis: Toward value-based, cost-effective, affordable care, J. Obstet. Gynaecol. Can. source
• Not checked yetcites [60] Vercellini, 2018, A stepped-care approach to symptomatic endometriosis management: A participatory research initiative, Fertil. Steril. source
• Not checked yetcites [61] Vercellini, 2017, Toward minimally disruptive management of symptomatic endometriosis: Reducing low-value care and the burden of treatment, Expert Rev. Pharmacoecon. Outcomes Res. source
• Not checked yetcites [62] Vercellini, 2018, Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?, Fertil. Steril. source

In the paper

“an increased risk of the disease was observed in past users of OCPs [72,73]”

What the sources say

• Not checked yetcites [72] Chapron, 2011, Oral contraceptives and endometriosis: The past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis, Hum. Reprod. source
• Not checked yetcites [73] Vercellini, 2011, Oral contraceptives and risk of endo-metriosis: A systematic review and meta-analysis, Hum. Reprod. Update source

In the paper

“reinforcing the hypothesis that high doses of estrogen in OCPs could lead to progression to a more invasive type of endometriosis [68,72].”

What the sources say

• Not checked yetcites [68] Casper, 2017, Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills, Fertil. Steril. source
• Not checked yetcites [72] Chapron, 2011, Oral contraceptives and endometriosis: The past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis, Hum. Reprod. source

In the paper

“the risk of venous or arterial thrombosis is not negligible [54,55,56,57,58,59,60,61,62,63,64,65,66,67].”

What the sources say

• Not checked yetcites [54] Donnez, O., and Donnez, J. (2020). Deep endometriosis: The place of laparoscopic shaving. Best Pr. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [55] Donnez, 1995, Surgery: Rectovaginal septum, endometriosis or adenomyosis: Laparoscopic management in a series of 231 patients, Hum. Reprod. source
• Not checked yetcites [56] Reis, 2020, Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure, Hum. Reprod. Updat. source
• Not checked yetcites [57] Barra, 2019, A comprehensive review of hormonal and biological therapies for endometriosis: Latest developments, Expert Opin. Biol. Ther. source
• Not checked yetcites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source
• Not checked yetcites [59] Vercellini, 2018, Management of endometriosis: Toward value-based, cost-effective, affordable care, J. Obstet. Gynaecol. Can. source
• Not checked yetcites [60] Vercellini, 2018, A stepped-care approach to symptomatic endometriosis management: A participatory research initiative, Fertil. Steril. source
• Not checked yetcites [61] Vercellini, 2017, Toward minimally disruptive management of symptomatic endometriosis: Reducing low-value care and the burden of treatment, Expert Rev. Pharmacoecon. Outcomes Res. source
• Not checked yetcites [62] Vercellini, 2018, Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?, Fertil. Steril. source
• Not checked yetcites [63] Harada, 2008, Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: A placebo-controlled, double-blind, randomized trial, Fertil. Steril. source

In the paper

“the impact of progestogens on the morphology and vascularization of ectopic endometrial tissue and atrophy is much more questionable [77,78,79,80,81].”

What the sources say

• Not checked yetcites [77] Donnez, 1987, Combined (hormonal and microsurgical) therapy in infertile women with endometriosis, Fertil. Steril. source
• Not checked yetcites [78] Donnez, 1996, Large ovarian endometriomas, Hum. Reprod. source
• Not checked yetcites [79] Donnez, 1988, Histologic study of ovarian endometriosis after hormonal therapy, Fertil. Steril. source
• Not checked yetcites [80] Donnez, 1990, Evaluation of preoperative use of danazol, gestrinone, lynestrenol, buserelin spray and buserelin implant, in the treatment of endometriosis associated infertility, Prog. Clin. Boil. Res.
• Not checked yetcites [81] Donnez, 1990, Endometriosis-associated infertility: Evaluation of preoperative use of danazol, gestrinone, and buserelin, Int. J. Fertil.

In the paper

“Surprisingly, only one randomized placebo-controlled clinical trial of OCPs in endometriosis has ever been published [63].”

What the sources say

• Not checked yetcites [63] Harada, 2008, Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: A placebo-controlled, double-blind, randomized trial, Fertil. Steril. source

In the paper

“progestin-only preparations (NETA and desogestrel pills) were not shown to increase the risk of venous thromboembolism [67].”

What the sources say

• Not checked yetcites [67] Lidegaard, 2011, Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–2009, BMJ source

In the paper

“Effects in terms of atrophy are much less pronounced than with GnRh agonist [81].”

What the sources say

• Not checked yetcites [81] Donnez, 1990, Endometriosis-associated infertility: Evaluation of preoperative use of danazol, gestrinone, and buserelin, Int. J. Fertil.

In the paper

“It was noted that menstrual pain (dysmenorrhea) was almost eradicated in both groups as a result of amenorrhea induced by the two progestins [83].”

What the sources say

• Not checked yetcites [83] Vercellini, 2016, Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: A before and after study, Fertil. Steril. source

In the paper

“GnRH agonists are effective at treating endometriosis symptoms, but they have numerous limitations, including a delayed therapeutic impact because of the flare-up effect, excessive suppression of E2 to less than 20 pg/mL (with related unfavorable side effects), inability to titrate E2 levels, and unpredictable reversibility of treatment when injectable depot forms of GnRH agonists are used [95,96,”

What the sources say

• Not checked yetcites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.
• Not checked yetcites [96] Dragoman, 2016, Research gaps identified during the 2014 update of the WHO medical eligibility criteria for contraceptive use and selected practice recommendations for contraceptive use, Contracept source
• Not checked yetcites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [98] Donnez, 1994, Advanced endoscopic techniques used in dysfunctional bleeding, fibroids and endometriosis, and the role of gonadotrophin-releasing hormone agonist treatment, Br. J. Obstet. Gynaecol. source

In the paper

“There is an increased risk of venous or arterial embolism [65,66,67].”

What the sources say

• Not checked yetcites [65] Manzoli, 2012, Oral contraceptives and venous thromboembolism: A systematic review and meta-analysis, Drug Saf.
• Not checked yetcites [66] Lidegaard, 2012, Venous thrombosis in users of non-oral hormonal contraception: Follow-up study, Denmark 2001–2010, BMJ source
• Not checked yetcites [67] Lidegaard, 2011, Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–2009, BMJ source

In the paper

“randomized controlled trials (RCTs) to evaluate the effect of SPRMs on endometriosis are lacking.”

In the paper

“The side effects of estroprogestins are essentially related to the type of progestin used [67].”

What the sources say

• Not checked yetcites [67] Lidegaard, 2011, Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–2009, BMJ source

In the paper

“To date, the only option to restore sufficient E2 levels to avoid menopausal symptoms and BMD loss has been combined administration of a GnRH agonist (depot injection) and estrogens/progestins (add-back therapy).”

In the paper

“PR status is strongly associated with a response to progestin-based therapies (including combined OCPs).”

What the sources say

• Not checked yetcites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

In the paper

“GnRH agonists are effective at treating endometriosis symptoms, but they have numerous limitations, including a delayed therapeutic impact because of the flare-up effect, excessive suppression of E2 to less than 20 pg/mL (with related unfavorable side effects), inability to titrate E2 levels, and unpredictable reversibility of treatment when injectable depot forms of GnRH agonists are used [95,96,”

What the sources say

• Not checked yetcites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.
• Not checked yetcites [96] Dragoman, 2016, Research gaps identified during the 2014 update of the WHO medical eligibility criteria for contraceptive use and selected practice recommendations for contraceptive use, Contracept source
• Not checked yetcites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [98] Donnez, 1994, Advanced endoscopic techniques used in dysfunctional bleeding, fibroids and endometriosis, and the role of gonadotrophin-releasing hormone agonist treatment, Br. J. Obstet. Gynaecol. source

In the paper

“A recent study demonstrated no differences in ovarian endometriomas in terms of necrosis or glandular atrophy between women receiving dienogest and those not [82].”

What the sources say

• Not checked yetcites [82] Mabrouk, 2017, Short-term histopathological effects of dienogest therapy on ovarian endometriomas: In vivo, nonrandomized, controlled trial, Gynecol. Endocrinol. source

In the paper

“in this study, low PR levels were observed in subjects who failed to respond.”

What the sources say

• Not checked yetcites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

In the paper

“On the other hand, according to ESHRE guidelines, progestogen-only add-back therapy does not prevent BMD loss [94].”

What the sources say

• Not checked yetcites [94] (2020, October 01). European Society of Human Reproduction and Embryology ESHRE Guideline for the Diagnosis and Treatment of Endome-Triosis. Available online: http://guidelines.endometriosis.org/index.html.

In the paper

“GnRH agonists are effective at treating endometriosis symptoms, but they have numerous limitations, including a delayed therapeutic impact because of the flare-up effect, excessive suppression of E2 to less than 20 pg/mL (with related unfavorable side effects), inability to titrate E2 levels, and unpredictable reversibility of treatment when injectable depot forms of GnRH agonists are used [95,96,”

What the sources say

• Not checked yetcites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.
• Not checked yetcites [96] Dragoman, 2016, Research gaps identified during the 2014 update of the WHO medical eligibility criteria for contraceptive use and selected practice recommendations for contraceptive use, Contracept source
• Not checked yetcites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [98] Donnez, 1994, Advanced endoscopic techniques used in dysfunctional bleeding, fibroids and endometriosis, and the role of gonadotrophin-releasing hormone agonist treatment, Br. J. Obstet. Gynaecol. source

In the paper

“Efficacy was similar in terms of pain reduction (dysmenorrhea, dyspareunia, non-menstrual pelvic pain).”

What the sources say

• Not checked yetcites [83] Vercellini, 2016, Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: A before and after study, Fertil. Steril. source

In the paper

“Partial suppression of E2 within the 30–60 pg/mL range could be the optimal compromise between efficacy, tolerance and safety [85].”

What the sources say

• Not checked yetcites [85] Donnez, 2017, Partial suppression of estradiol: A new strategy in endometriosis management?, Fertil. Steril. source

In the paper

“GnRH agonists are effective at treating endometriosis symptoms, but they have numerous limitations, including a delayed therapeutic impact because of the flare-up effect, excessive suppression of E2 to less than 20 pg/mL (with related unfavorable side effects), inability to titrate E2 levels, and unpredictable reversibility of treatment when injectable depot forms of GnRH agonists are used [95,96,”

What the sources say

• Not checked yetcites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.
• Not checked yetcites [96] Dragoman, 2016, Research gaps identified during the 2014 update of the WHO medical eligibility criteria for contraceptive use and selected practice recommendations for contraceptive use, Contracept source
• Not checked yetcites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source
• Not checked yetcites [98] Donnez, 1994, Advanced endoscopic techniques used in dysfunctional bleeding, fibroids and endometriosis, and the role of gonadotrophin-releasing hormone agonist treatment, Br. J. Obstet. Gynaecol. source

In the paper

“Based on results from RCTs in women with endometriosis, NETA (5 mg/d) was approved by the Food and Drug Administration (FDA) as add-back therapy when combined with a GnRH agonist [93].”

What the sources say

• Not checked yetcites [93] Chwalisz, 2012, The hormonal profile of norethindrone acetate: Rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis, Reprod. Sci. source

In the paper

“By inducing amenorrhea and halting menstrual bleeding and reflux, or even simply lessening its severity, pelvic oxidative stress, the main source of inflammation, can be significantly reduced [30].”

What the sources say

• Not checked yetcites [30] Donnez, 2016, Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis, Fertil. Steril. source

In the paper

“Two more oral GnRH antagonists, namely, relugolix (TAK385) [104] and linzagolix (OBE-2109) [105], have recently yielded very robust results in randomized, placebo-controlled clinical trials for the treatment of pain associated with endometriosis, and will be discussed in detail further.”

What the sources say

• Not checked yetcites [104] Osuga, 2021, Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: A randomized, double-blind, place-bo-controlled study, Fertil. Steril. source
• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“Overall, the pharmacokinetic properties of elagolix at 150 mg once daily and 200 mg twice daily do not appear to be affected, to a clinically meaningful extent, by body weight, body mass index, race/ethnicity or the presence of endometriosis [102,103,107].”

What the sources say

• Not checked yetcites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source
• Not checked yetcites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source
• Not checked yetcites [107] Taylor, 2019, Clinical evaluation of the oral gonadotropin-releasing hormone-antagonist elagolix for the management of endometriosis-associated pain, Pain Manag. source

In the paper

“They produce dose-dependent estrogen suppression, from partial suppression at lower doses to almost full suppression at higher doses (Figure 2).”

In the paper

“One GnRH antagonist (elagolix) was approved by the US FDA in July 2018 [109].”

What the sources say

• Not checked yetcites [109] Lamb, 2018, Elagolix: First global approval, Drugs source

In the paper

“it is logical to consider lowering estrogen levels as a therapeutic approach.”

In the paper

“In conclusion, consistent with full suppression of serum E2 to postmenopausal levels, once-daily linzagolix 200 mg provided an additional significant impact on dyspareunia and some aspects of quality of life.”

What the sources say

• Not checked yetcites [105] Donnez, 2020, Treatment of endome-triosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: A randomized clinical trial, Fertil. Steril. source

In the paper

“In conclusion, oral relugolix CT taken once daily significantly reduced dysmenorrhea and non-menstrual pelvic pain in women with endometriosis compared to a placebo.”

What the sources say

• Not checked yetcites [119] Becker, 2020, Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: Phase 3 randomized, double-blind, placebo-controlled study (spirit 2), Fertil. Steril. source
• Not checked yetcites [120] Zandvliet, 2020, Simulated long-term effects of relugolix combination therapy on bone mineral density at the lumbar spine as predicted by a validated semi-mechanistic exposure-response model, Fertil. Steril. source

In the paper

“We would advocate a strategy based on the different phenotypes of endometriosis, clearly recognized as three separate entities since the original publication by Nisolle and Donnez in 1997 [2].”

What the sources say

• Not checked yetcites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source

In the paper

“Avoiding repeat surgery in case of recurrence of pain is even more important, as it is well known that this is often the source of severe complications [123].”

What the sources say

• Not checked yetcites [123] Donnez, 2017, Choosing the right surgical technique for deep endometriosis: Shaving, disc excision, or bowel resection?, Fertil. Steril. source