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

In the paper

“Accordingly, significantly more women taking either dose of elagolix reported “much” or “very much” improvement on the patient global impression of change (PGIC) scale and a better quality of life on the EHP-30 questionnaire compared to women taking the placebo.”

In the paper

“The percentage of women who experienced a clinical improvement in dysmenorrhea was 46.4% with elagolix 150 mg once daily and 75.8% with elagolix 200 mg twice daily (compared with 19.6% 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

“A similar pattern was observed in responder rates for dysmenorrhea and non-menstrual pelvic pain, with significant differences observed compared to the placebo at 12 weeks with doses of 75 mg, 100 mg and 200 mg.”

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 Elaris EM-II, corresponding percentages were 49.8% and 57.8% (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

“Percentages of women experiencing a reduction of ≥30% in both dysmenorrhea and non-menstrual pelvic pain at 12 weeks were respectively 68.2% and 58.5% in the 75 mg group, 68.6% and 61.5% in the 100 mg group and 78.9% and 47.7% in the 200 mg 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

“Specifically, upon completion of treatment, respective responder rates for dysmenorrhea in Elaris EM-III and EM-IV were 52.1% and 50.8% with elagolix 150 mg once daily, and 78.1% and 75.9% with 200 mg twice daily (Table 2).”

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

“In Elaris EM-II, corresponding percentages were 43.4% and 72.4% (compared with 22.7% 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

“Responder rates for non-menstrual pelvic pain were 67.8% and 66.4% with elagolix 150 mg once daily, and 69.1% and 67.2% with 200 mg twice daily.”

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

“Concerning serum E2, there was rapid and full suppression to 11 pg/mL in the 200 mg dose group by week 4, which was maintained (range 11–16 pg/mL) up to week 24 (Figure 5).”

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

“Change was −10.4 in the relugolix 40 mg group, similar to observations in the leuprolin group [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

“Mean percentage (95% CI) BMD changes in the lumbar spine were −1.14 (−2.21 −0.07) at a dose of 75 mg, −1.40 (−3.35 +0.55) at a dose of 100 mg and −2.19 (−3.59 −0.78) at a dose of 200/100 mg.”

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

“Concerning the secondary endpoint, mean VAS scores for pelvic pain and dysmenorrhea started to fall within the first month of treatment, but results for dyspareunia showed no clear trend with relugolix.”

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

“Percentages of women experiencing a reduction of >30% in both dysmenorrhea and non-menstrual pelvic pain at week 24 were 58.3% and 72.9% in the 75 mg group, 82.1% and 64.1% in the 100 mg group and 84.1% and 72.7% in the 200 mg 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

“Hot flushes were more frequent at higher doses of linzagolix, namely, 19.3%, 26.9% and 42.1% with 75 mg, 100 mg and 200 mg, respectively, at week 12, with similar dose-related differences at week 24 (Table 1) [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

“Percentages of women experiencing a reduction of ≥30% in both dysmenorrhea and non-menstrual pelvic pain at week 52 were respectively 69.2% and 69.2% in the 75 mg group, 69.2% and 53.8% in the 100 mg group and 64.7 % and 76.5% in the 200/100 mg group.”

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

“Mean percentage changes in BMD from baseline were −2.1% in the relugolix 40 mg group and −2.2% in the leuprolin group [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

“A recent paper demonstrated the efficacy of linzagolix 200 mg in reducing lesion size and improving quality of life in case of severe adenomyosis, which is often associated with deep endometriosis [108,115].”

What the sources say

• Not checked yetcites [108] Donnez, 2020, Gonadotropin-releasing hormone antagonist (linzagolix): A new therapy for uterine adenomyosis, Fertil. Steril. source
• Not checked yetcites [115] Donnez, 2019, What if deep endometriotic nodules and uterine adenomyosis were actually two forms of the same disease?, Fertil. Steril. source

In the paper

“Concerning the different parts of the EHP-30 questionnaire, pain and powerlessness domains were significantly transformed with 75 mg, 100 mg and 200 mg doses, whereas for other domains linked to emotional well-being, social support and self-image, there was a consistent significant difference only in the 200 mg dose 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

“At week 12, estimated amenorrhea rates were 4.3% in the placebo group and 36.3%, 55.8% and 80.9% in the 75 mg, 100 mg and 200 mg dose groups, 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

“Compared to the placebo, there was a significant reduction in dyspareunia at 12 weeks with the 200 mg dose, but not with 75 mg or 100 mg.”

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

“Indeed, dyspareunia was only significantly alleviated at the highest daily dose (200 mg twice daily), but not at a lower dose (150 mg once daily), while other types of endometriosis-associated pain were significantly reduced with both the lower and higher dose [96].”

What the sources say

• 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

In the paper

“Percentages of women showing a mean reduction in NRS scores of ≥2.8 points for dysmenorrhea and ≥2.1 points for non-menstrual pelvic pain at week 24 were respectively 75.5% and 58.5% in the relugolix CT arm in SPIRIT-1, and 75.2% and 66% in the relugolix CT arm in SPIRIT-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

“Mean percentage hot flushes in the relugolix CT and delayed relugolix CT groups at week 24 were 10.4% and 33.6% in SPIRIT-1 and 13.6% and 35% in SPIRIT-2 [118,119].”

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
• 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

In the paper

“Mean percentage BMD changes in the lumbar spine from baseline to week 24 in the relugolix CT and delayed relugolix CT arms were respectively −0.70 % and −1.99% in SPIRIT-1 and −0.78% and −1.92% in SPIRIT-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

“Based on the role of retrograde menstruation according to Sampson’s theory, blocking ovulation and menstruation by means of hormonal therapies may in theory be disease-modulating and control the symptoms of endometriosis.”

In the paper

“There are three distinct forms of the disease (peritoneal, ovarian and rectovaginal endometriosis)”

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

“although dysmenorrhea and chronic non-menstrual pelvic pain are the most prevalent [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

“There is therefore a need for effective long-term oral treatment capable of managing endometriosis symptoms, while alleviating the impact of side effects.”

• Also stated in: § Abstract · boosted

  “It is clear that there is a need for effective long-term oral treatment capable of managing endometriosis symptoms, while mitigating the impact of side effects.”

In the paper

“endometriosis, a common chronic inflammatory disease causing pain and infertility [1,2,3]”

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

In the paper

“However, hormonal treatment also impedes conception, excluding this approach in women wishing to conceive [1,4].”

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 [4] Ferrero, 2018, Current and emerging treatment options for endometriosis, Expert Opin. Pharmacother. source

In the paper

“Proinflammatory factors (like heme and iron) and cytokines (like tumor necrosis factor-alpha (TNFα) and interleukin 1 beta (IL1β)) may also disrupt PR function and play a role in progesterone resistance which finally leads to increased nuclear factor kappa B (NF-kB) activity, which is involved in endometriosis development [27,33,34].”

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 [33] Patel, 2014, Role of nuclear progesterone receptor isoforms in uterine pathophysiology, Hum. Reprod. Updat. source
• Not checked yetcites [34] Lousse, 2010, Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis, Fertil. Steril. source

In the paper

“Conversely, in endometriotic lesions, stromal cells showing progesterone resistance are unable to produce RA which results in loss of 17β-HSD2 expression and failure to inactivate local E2, ultimately leading to high E2 activity [14,15,16,20,21,22].”

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

“partial or complete progesterone resistance was identified in over 66% of cases in neonatal endometrium [24], while a full response to progesterone was observed in around 33% [24].”

What the sources say

• Not checked yetcites [24] Ober, 1955, Observations on the endometrium and ovary in the newborn, Pediatrics source

In the paper

“these endometrial cells also exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein [38,39,40] and finally resulting in a state of progesterone resistance.”

What the sources say

• Not checked yetcites [38] Neal, 2020, Expression of stromal progesterone receptor and differential methylation patterns in the endometrium may correlate with response to progesterone therapy in endometrial complex atypical hyperplasia, Reprod. Sci. source
• 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
• Not checked yetcites [40] Cakmak, 2010, Molecular mechanisms of treatment resistance in endometriosis: The role of progesterone–hox gene interactions, Semin. Reprod. Med. source

In the paper

“ERβ is the key mediator of estrogen action in endometriotic stromal cells and was found to transcriptionally repress ERα, possibly promoting disease progression by several pathways [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

“During the luteal phase, progesterone acts through PR-B and boosts transcription and secretion of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), responsible for converting E2 to the less active estrone [14,15,16].”

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

“human endometrial fibroblasts derived from mesenchymal progenitors (mesenchymal stem cells (MSCs)) inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis.”

What the sources say

• Not checked yetcites [44] Barragan, 2016, Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis, Biol. Reprod. source

In the paper

“Red lesions were found to be very active, with high proliferative activity and vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) content, explaining their frequent bleeding and remodeling during the menstrual period [46,47,48].”

What the sources say

• Not checked yetcites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source
• Not checked yetcites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. source
• Not checked yetcites [48] Donnez, 1998, Vascular endothelial growth factor (VEGF) in endometriosis, Hum. Reprod. source

In the paper

“These red lesions are resistant to progestin therapy, which may induce some decidualization, but not atrophy [46,47,48].”

What the sources say

• Not checked yetcites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source
• Not checked yetcites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. source
• Not checked yetcites [48] Donnez, 1998, Vascular endothelial growth factor (VEGF) in endometriosis, Hum. Reprod. source

In the paper

“in endometriotic implants, ERα is reduced but ERβ activity is upregulated, leading to complete loss of PR-B, which is then unable to induce 17β-HSD2.”

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

“Despite being 3 to 4 times more frequent, venous thrombotic events are much less severe than arterial thrombotic events, which are more associated with the EE dose than with the progestin type [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

“these authors concluded that OCPs can play an important role in the management of endometriosis, as two-thirds of women with symptomatic endometriosis respond to estroprogestins.”

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

“while OCPs are widely used to treat endometriosis-related pain, evidence of their efficacy is limited and there are insufficient data to make any judgment in terms of comparisons with other medical therapies.”

What the sources say

• Not checked yetcites [74] Brown, 2014, Endometriosis: An overview of cochrane reviews, Cochrane Database Syst. Rev.

In the paper

“a dose of 20 µg EE in low-dose OCPs is equivalent to 4–6 times the physiological dose of estrogen, which may promote attachment of endometrial cells deposited in the pelvis.”

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

In the paper

“PRs may be present, but biologically inactive. On the other hand, PRs may well be absent, leading to progesterone resistance and no decrease in lesion size with OCP or progestogen therapy [58].”

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

“a progestogen (lynestrenol) was unable to reduce vascularization (evaluated by the capillary–stroma relative surface area) in endometriotic lesions, but a significant decrease was observed after GnRH agonist therapy [55].”

What the sources say

• Not checked yetcites [55] Donnez, 1995, Surgery: Rectovaginal septum, endometriosis or adenomyosis: Laparoscopic management in a series of 231 patients, Hum. Reprod. source

In the paper

“the available literature considers combined hormone contraceptives to be effective for relief of endometriosis-related pain. However, corroborative data are of low quality and inadequate to draw conclusions on the superiority and relative benefits compared to other approaches [75].”

What the sources say

• Not checked yetcites [75] Jensen, 2018, Use of combined hormonal contraceptives for the treatment of endometriosis-related pain: A systematic review of the evidence, Fertil. Steril. source

In the paper

“they also concluded that oral norethisterone acetate (NETA) should be considered the first choice, given the extremely favorable cost-effectiveness profile.”

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

“A statistically significant, though modest, improvement in dysmenorrhea was found with OCPs given for four months compared to placebo. OCP administration resulted in about a 50% reduction in dysmenorrhea.”

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

“due to progesterone resistance, the progestin contained within the OCP and designed to antagonize the estrogen effect sometimes fails to produce the desired effect in endometriotic implants, resulting in relative estrogen dominance.”

In the paper

“Reis et al. [56] summarized the effect of progestins on endometriotic lesions as generating different levels of downregulation of ERs, a drop in local E2 production, a reduction in inflammation, and creation of a pseudo-pregnancy condition.”

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

“They concluded that all available progestins are effective in controlling pain symptoms in two-thirds of women with endometriosis.”

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

“These drugs cause competitive blockage of the GnRH receptor and hence dose-dependently suppress production of FSH and LH and inhibit secretion of ovarian steroid hormones without inducing a flare-up effect (Figure 1).”

In the paper

“The reduction in lesion volume is not predictable and not significant in the vast majority of cases. Conflicting results have been observed [77,78,79,80,81,82,86,87,88].”

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.
• Not checked yetcites [82] Mabrouk, 2017, Short-term histopathological effects of dienogest therapy on ovarian endometriomas: In vivo, nonrandomized, controlled trial, Gynecol. Endocrinol. source
• Not checked yetcites [86] Ferrero, 2012, Changes in the size of rectovaginal endometriotic nodules infiltrating the rectum during hormonal therapies, Arch. Gynecol. Obstet. source
• Not checked yetcites [87] Razzi, 2007, Use of a progestogen only preparation containing desogestrel in the treatment of recurrent pelvic pain after conservative surgery for endometriosis, Eur. J. Obstet. Gynecol. Reprod. Biol. source
• Not checked yetcites [88] Cursino, 2017, Dienogest and deep infiltrating endometriosis: The remission of symptoms is not related to endometriosis nodule remission, Eur. J. Obstet. Gynecol. Reprod. Biol. source

In the paper

“PR deficiency is evident in endometriotic lesions, leading to progesterone resistance and defective progesterone action, with obvious consequences on the survival and development of endometriotic tissues [15,22,84].”

What the sources say

• Not checked yetcites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source
• Not checked yetcites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source
• Not checked yetcites [84] Kim, 2013, Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer, Endocr. Rev. source

In the paper

“A study comparing NETA and dienogest [83] reported that 70% and 72% of patients, respectively, were very satisfied or satisfied, meaning that a substantial proportion, around 30% of women, were left dissatisfied, 10% of whom were very dissatisfied.”

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

“Of course, suppressing ovulation and reducing the amount of menstrual bleeding greatly reduces the number of erythrocytes regurgitated into the pelvis, resulting in a decrease in oxidative stress and the inflammatory environment [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

“among new drugs, selective progesterone receptor modulators (SPRMs) are not an option as they induce progesterone modulator-associated endometrial changes (PAECs) in ectopic foci and their efficacy is limited [89,90,91].”

What the sources say

• Not checked yetcites [89] Donnez, 2016, Uterine fibroid management: From the present to the future, Hum. Reprod. Update source
• Not checked yetcites [90] Donnez, 2020, Hormone therapy for intramural myoma-related infertility from ulipristal acetate to GnRH an-tagonist: A review, Reprod. Biomed. Online source
• Not checked yetcites [91] Donnez, 2020, Fibroids and medical therapy: Bridging the gap from selective progesterone receptor modulators to gonadotropin-releasing hormone antagonist, Fertil. Steril. source

In the paper

“The mechanism is different from that of the GnRH agonist which, after a first phase of stimulation, desensitizes GnRH receptors, leading to full suppression of LH and FSH production and subsequently to complete suppression of E2 to levels similar to those observed after bilateral oophorectomy [95,96,97,98].”

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

“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

“endometriotic stromal cells are poorly differentiated with deficient PRs and fail to send physiological paracrine signals to adjacent epithelial cells, explaining the absence of response in more than 30% of women treated with progestins [58,84].”

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
• Not checked yetcites [84] Kim, 2013, Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer, Endocr. Rev. source

In the paper

“It is mainly metabolized by the liver (mostly cytochrome P450 3A (CYP3A)-mediated), and 90% of excretion of elagolix and its metabolites occurs in the feces [99].”

What the sources say

• Not checked yetcites [99] Ng, 2017, Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women, J. Clin. Endocrinol. Metab. source

In the paper

“In conclusion, use of elagolix 200 mg twice daily causes strong suppression of E2 and marked improvements in dysmenorrhea, non-menstrual pelvic pain and dyspareunia, albeit at the cost of more hot flushes and a more pronounced decrease in BMD (Figure 4).”

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

“Linzagolix has a half-life of 15–18 h, high oral bioavailability, low volume of distribution, no food effects and an absence of interactions with transporters and CYP3A4 enzymes [98,100].”

What the sources say

• 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
• Not checked yetcites [100] Carr, 2014, Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: Effects on bone mineral density, Reprod. Sci. source

In the paper

“As reported by Taylor et al. [107], the recommended treatment duration in women with normal liver function or mild hepatic impairment is up to 24 months with elagolix 150 mg once daily, and up to 6 months with 200 mg twice daily.”

What the sources say

• 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

“As estrogens play a crucial role not only in survival of endometriotic implants, but also in coordinated vasculogenesis and neurogenesis [110] by different pathways involving ER signaling [15,16], it is logical to consider lowering estrogen levels as a therapeutic approach.”

What the sources say

• Not checked yetcites [110] Barra, 2019, Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain, Drugs Today 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

“There is rapid reversibility and recovery of hormone secretion after stopping treatment.”

In the paper

“Striking a balance between efficacy and safety/tolerability may unlock the potential of this new class of drug, suggesting the possibility of individual tailoring according to symptoms and the wishes of the patient.”

In the paper

“Elagolix is rapidly absorbed after oral administration and its mean plasma half-life (t1/2) ranges from 2.4 to 6.3 h [99,107,110].”

What the sources say

• Not checked yetcites [99] Ng, 2017, Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women, J. Clin. Endocrinol. Metab. 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
• Not checked yetcites [110] Barra, 2019, Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain, Drugs Today source

In the paper

“These results suggest that although partial suppression of E2 has a significant impact on important aspects of general well-being, full suppression with 200 mg has a more constant effect across more aspects of quality of life affected by endometriosis [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

“Relugolix has a half-life of 37–42 h and is mainly metabolized by the liver [104,117].”

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 [117] Markham, 2019, Relugolix: First global approval, Drugs source

In the paper

“Most subjects taking the 200 mg dose showed a BMD decrease of >3% at 24 weeks, which would necessitate hormone add-back therapy for longer-term use.”

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

“However, higher rates of hypoestrogenic symptoms were observed, including BMD loss of ≥3% after 24 weeks, indicating that this once-daily dose will require hormone add-back therapy if used for longer than six months [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

“These two studies clearly confirmed that GnRH antagonist suppresses ovarian function in a dose-dependent manner, allowing modulation of E2 levels which, according to the threshold hypothesis [86], may provide relief from endometriosis-associated pain while reducing side effects caused by extreme hypoestrogenism.”

What the sources say

• Not checked yetcites [86] Ferrero, 2012, Changes in the size of rectovaginal endometriotic nodules infiltrating the rectum during hormonal therapies, Arch. Gynecol. Obstet. source

In the paper

“Relugolix CT is well tolerated, the incidence of vasomotor symptoms is similar to the placebo, and BMD is maintained over 24 weeks.”

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

“According to the ASRM Practice Committee [121], endometriosis requires a life-long management plan, with the goal of maximizing use of medical therapy and avoiding repeated surgical procedures.”

What the sources say

• Not checked yetcites [121] Practice Committee of the American Society for Reproductive Medicine (2018). American Society for Reproductive Medicine position statement on uterus transplantation: A committee opinion. Fertil. Steril., 110, 605–610.

In the paper

“In the present paper, we thoroughly scrutinized the concept of progesterone resistance as an explanation for why 33% of patients do not respond to OCPs and progestins, with this percentage climbing even higher in women with deep nodular endometriosis [46,47,56,58].”

What the sources say

• Not checked yetcites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source
• Not checked yetcites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. 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 [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

In the paper

“Although further investigations, including assessment of efficacy and safety in real-world populations, potential for use of add-back therapy, and comparisons with OCPs and progestins are needed, we agree with Leyland et al. [126] that robust clinical evidence shows oral GnRH antagonists to be effective and well tolerated in patients with moderate-to-severe endometriosis-associated pain.”

What the sources say

• Not checked yetcites [126] Leyland, N., Estes, S.J., Lessey, B.A., Advincula, A.P., and Taylor, H.S. (2020). A clinician’s guide to the treatment of endometriosis with elagolix. J. Womens Heal.

In the paper

“Moreover, according to Wang et al. [125], the two recent FDA-approved doses of elagolix for the management of moderate-to-severe pain associated with endometriosis, namely, 24 months of 150 mg once daily or six months of 200 mg twice daily, both proved cost-effective versus leuprolide acetate over 1–2 years.”

What the sources say

• Not checked yetcites [125] Wang, 2019, Cost–effectiveness of elagolix versus leuprolide acetate for treating moderate-to-severe endometriosis pain in the USA, J. Comp. Eff. Res. source