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Cited by 182Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementMenstrual Health and Disorders

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

Open access
Donnez, Jacques, Dolmans, Marie-Madeleine·2021·Journal of Clinical Medicine
DOI 10.3390/jcm10051085PMC PMC7961981
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Abstract

Background: The first objective of this review was to present, based on recent literature, the most frequently applied medical options (oral contraceptive pills (OCPs) and progestogens) for the management of symptomatic endometriosis, and evaluate their effectiveness in treating premenopausal women with endometriosis-associated pelvic pain, dysmenorrhea, non-menstrual pelvic pain and dyspareunia. The second objective was to review the concept of progesterone resistance and newly available treatment options. Methods: We reviewed the most relevant papers (n = 73) on the efficacy of OCPs and progestogens as medical therapy for endometriosis, as well as those on progesterone resistance and new medical alternatives (oral gonadotropin-releasing hormone (GnRH) antagonist). Eleven papers, essentially reviews, were selected and scrutinized from among 94 papers discussing the concept of progesterone resistance. Results: Having reviewed the most significant papers, we can confirm that OCPs and progestogens are effective in two-thirds of women suffering from endometriosis, but that other options are required in case of failure (in one-third of women due to progesterone resistance) or intolerance to these compounds. 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. Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis, so lowering levels of circulating estrogens should be considered an effective medical approach. The efficacy of three oral GnRH antagonists is discussed on the basis of published studies. Conclusion: There is a place for GnRH antagonists in the management of symptomatic endometriosis and clinical trials should be conducted, taking into account the different phenotypes in order to propose novel algorithms.

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Written from the paper’s full text.

TL;DR

This narrative review concludes that oral contraceptives and progestogens relieve endometriosis-associated pain in about two-thirds of women, while progesterone resistance explains many non-responders, and it evaluates oral GnRH antagonists as newer options. It advocates phenotype-adapted, symptom-oriented medical management and further trials.

Key findings

  • First-line OCPs/progestogens are effective in two-thirds of women with symptomatic endometriosis, but one-third are non-responders, often explained by progesterone resistance; deep nodular endometriosis may be especially resistant. Progesterone resistance is linked to PR-B loss, ERβ upregulation, deficient 17β-HSD2, impaired retinoic acid signaling, inflammation/oxidative stress, genetics/epigenetics, and mesenchymal progenitors.
  • Elagolix phase III trials: dysmenorrhea improvement at 3 months was 46.4% with 150 mg once daily and 75.8% with 200 mg twice daily versus 19.6% with placebo in Elaris EM-I; in Elaris EM-II, 43.4% and 72.4% versus 22.7%. Non-menstrual pelvic pain improvement was 50.4%/54.5% versus 36.5% in EM-I and 49.8%/57.8% versus 36.5% in EM-II. Hot flushes were dose-dependent, and BMD decreased.
  • Linzagolix phase II (n = 328): ≥30% reduction in overall pelvic pain at week 12 was 61.5%, 56.4%, and 56.3% for 75, 100, and 200 mg versus 34.5% for placebo; at week 24, rates were 70.8%, 66.7%, and 77.3%. Amenorrhea at week 12 was 36.3%, 55.8%, and 80.9% versus 4.3%; 200 mg suppressed E2 to 11 pg/mL, and lumbar spine BMD changes were −0.80%, −1.37%, and −2.60%.
  • Relugolix phase III SPIRIT-1 (n = 635) and SPIRIT-2 (n = 616): at week 24, dysmenorrhea/non-menstrual pelvic pain responder rates with relugolix combination therapy were 75.5%/58.5% and 75.2%/66%; BMD changes were −0.70%/−1.99% and −0.78%/−1.92%; hot flushes were 10.4%/33.6% and 13.6%/35%. The authors conclude GnRH antagonists have a place in management, but phenotype-specific trials and cost-effectiveness considerations remain.

Methods

  • Narrative review with a PubMed/Embase search up to December 2020 using keywords including endometriosis, progesterone, progestogen, GnRH agonist, GnRH antagonist, medical therapy, and add-back therapy.
  • From 2010 to 2020, 4732 manuscripts were identified; after screening, 73 articles on OCPs/progestogens were selected, 94 papers on progesterone resistance were considered with 11 selected, and 20 original papers on oral GnRH antagonists were reviewed.
  • Synthesis is descriptive rather than a formal systematic review or meta-analysis, incorporating phase II/III trial data and conference presentations.

Limitations

  • No formal limitations section is provided. The authors state that further investigations are needed, including real-world populations, add-back therapy, comparisons with OCPs and progestins, and phenotype-specific trials; they also note that RCTs for SPRMs are lacking and that OCP evidence is limited and of low quality.
  • Evident from the text: article selection was subjective (“methodologically adequate, very well written, updated, informative and well balanced”), with no reported systematic quality assessment or risk-of-bias appraisal.
  • Evident from the text: some long-term GnRH antagonist data, including 52-week linzagolix and relugolix phase III results, are cited from conference presentations/abstracts rather than full peer-reviewed reports, and no meta-analysis is performed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/jcm10051085

Cites

130 of 130 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 308 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    OCPs and progestogens are effective in two-thirds of women with symptomatic endometriosis.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Vercellini, 2016, Estrogen-progestins and progestins for the management of endometriosis, Fertil. Steril. source

      Not checked in the free run.

    • cites [6] Vercellini, 2018, Medical treatment of endometriosis-related pain, Best Pr. Res. Clin. Obstet. Gynaecol. source

      Not checked in the free run.

  • Findingcitation

    Percentages of women experiencing hot flushes at elagolix 150 mg once daily were 23.7%, 22.6%, 44% and 36% in Elaris-I, -II, -III and -IV.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

      Not checked in the free run.

  • Findingcitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • 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

      Not checked in the free run.

    • cites [112] Taylor, 2020, Health-related quality of life improvements in patients with endometriosis treated with elagolix, Obstet. Gynecol. source

      Not checked in the free run.

  • Findingcitation

    In Elaris EM-I, the percentage of women with 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

  • Findingcitation

    The most frequently reported side effects of elagolix were hot flushes, depending on the dose.

    “Regarding side effects, the most frequently reported were hot flushes, depending on the dose.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

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  • May combine two claims. 75
  • Classified as probably not a substantial claim. 13

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    Findingcitation

    Significantly more women taking either dose of elagolix reported "much" or "very much" improvement on the PGIC scale and a better quality of life on the EHP-30 questionnaire compared to women taking placebo.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In Elaris EM-I, the percentage of women with 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In Elaris EM-II, the percentages of women with improvement in non-menstrual pelvic pain were 49.8% with elagolix 150 mg once daily and 57.8% with elagolix 200 mg twice daily, compared with 36.5% in the placebo group.

    “In Elaris EM-II, corresponding percentages were 49.8% and 57.8% (compared with 36.5% in the placebo group).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Upon completion of treatment, 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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In Elaris EM-II, the percentages of women with clinical improvement in dysmenorrhea were 43.4% with elagolix 150 mg once daily and 72.4% with elagolix 200 mg twice daily, compared with 22.7% in the placebo group.

    “In Elaris EM-II, corresponding percentages were 43.4% and 72.4% (compared with 22.7% in the placebo group).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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 in Elaris EM-III and EM-IV.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    With linzagolix 200 mg, serum E2 was rapidly and fully suppressed to 11 pg/mL by week 4, and this was maintained (range 11-16 pg/mL) up to week 24.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Change in mean VAS pelvic pain was −10.4 in the relugolix 40 mg group, similar to observations in the leuprolin group.

    “Change was −10.4 in the relugolix 40 mg group, similar to observations in the leuprolin group [104].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [114] Bestel, 2020, Quality of life results after 52 weeks of treatment with linzagolix for endometriosis-associated pain, Obstet. Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    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 linzagolix 75 mg group, 82.1% and 64.1% in the 100 mg group, and 84.1% and 72.7% in the 200 mg group.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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 at week 12, with similar dose-related differences at week 24.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Percentages of women experiencing a reduction of ≥30% in both dysmenorrhea and non-menstrual pelvic pain at week 52 were 69.2% and 69.2% in the linzagolix 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.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [114] Bestel, 2020, Quality of life results after 52 weeks of treatment with linzagolix for endometriosis-associated pain, Obstet. Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “Mean percentage changes in BMD from baseline were −2.1% in the relugolix 40 mg group and −2.2% in the leuprolin group [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [108] Donnez, 2020, Gonadotropin-releasing hormone antagonist (linzagolix): A new therapy for uterine adenomyosis, Fertil. Steril. source

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    • cites [115] Donnez, 2019, What if deep endometriotic nodules and uterine adenomyosis were actually two forms of the same disease?, Fertil. Steril. source

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    Findingcitation

    Pain and powerlessness domains of the EHP-30 were significantly transformed with linzagolix 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

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    Findingcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    For elagolix, 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    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 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.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Biberoglu, 1981, Dosage aspects of danazol therapy in endometriosis: Short-term and long-term effectiveness, Am. J. Obstet. Gynecol. source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Findingcitation

    Mean percentage BMD changes in the lumbar spine from baseline to week 24 in the relugolix CT and delayed relugolix CT arms were −0.70% and −1.99% in SPIRIT-1 and −0.78% and −1.92% in SPIRIT-2.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Blocking ovulation and menstruation by hormonal therapies may be disease-modulating and control the symptoms of endometriosis.

    “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.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Retrograde menstruation according to Sampson's theory is a valid mechanism of endometriosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are three distinct forms of endometriosis: peritoneal, ovarian and rectovaginal.

    “There are three distinct forms of the disease (peritoneal, ovarian and rectovaginal endometriosis)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Dysmenorrhea and chronic non-menstrual pelvic pain are the most prevalent symptoms of endometriosis.

    “although dysmenorrhea and chronic non-menstrual pelvic pain are the most prevalent [2]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    There is a need for effective long-term oral treatment capable of managing endometriosis symptoms while alleviating side effects.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Surgery cannot cure endometriosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Endometriosis is a common chronic inflammatory disease causing pain and infertility.

    “endometriosis, a common chronic inflammatory disease causing pain and infertility [1,2,3]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [2] Nisolle, 1997, Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, Fertil. Steril. source

      Not checked in the free run.

    • cites [3] Giudice, 2010, Clinical practice. Endometriosis, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hormonal treatment impedes conception, excluding this approach in women wishing to conceive.

    “However, hormonal treatment also impedes conception, excluding this approach in women wishing to conceive [1,4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proinflammatory factors (heme, iron) and cytokines (TNFα, IL1β) may disrupt PR function and play a role in progesterone resistance, leading to increased NF-kB activity involved in endometriosis development.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Donnez, 2002, Iron overload in the peritoneal cavity of women with pelvic endome-triosis, Fertil. Steril. source

      Not checked in the free run.

    • cites [33] Patel, 2014, Role of nuclear progesterone receptor isoforms in uterine pathophysiology, Hum. Reprod. Updat. source

      Not checked in the free run.

    • cites [34] Lousse, 2010, Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In endometriotic lesions, stromal cells showing progesterone resistance are unable to produce retinoic acid, resulting in loss of 17β-HSD2 expression, failure to inactivate local E2, and high E2 activity.

    “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].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [14] Bulun, 2010, 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin. Reprod. Med. source

      Not checked in the free run.

    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

      Not checked in the free run.

    • cites [20] Pavone, 2010, Altered retinoid uptake and action contributes to cell survival in endometriosis, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [21] Pavone, 2011, Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action, Hum. Reprod. source

      Not checked in the free run.

    • cites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Partial or complete progesterone resistance is identified in over 66% of neonatal endometrial biopsies, while full response to progesterone is observed in around 33%.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Ober, 1955, Observations on the endometrium and ovary in the newborn, Pediatrics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These endometrial cells exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein and resulting in progesterone resistance.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [40] Cakmak, 2010, Molecular mechanisms of treatment resistance in endometriosis: The role of progesterone–hox gene interactions, Semin. Reprod. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERβ is the key mediator of estrogen action in endometriotic stromal cells and transcriptionally represses ERα, possibly promoting disease progression.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During the luteal phase, progesterone acts through PR-B and boosts transcription and secretion of 17β-HSD2, which converts E2 to less active estrone.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Bulun, 2010, 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis, Semin. Reprod. Med. source

      Not checked in the free run.

    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human endometrial fibroblasts derived from mesenchymal progenitors (MSCs) inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Red endometriotic lesions are very active, with high proliferative activity and VEGF and MMP content, explaining their frequent bleeding and remodeling during the menstrual period.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source

      Not checked in the free run.

    • cites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. source

      Not checked in the free run.

    • cites [48] Donnez, 1998, Vascular endothelial growth factor (VEGF) in endometriosis, Hum. Reprod. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Red lesions are resistant to progestin therapy, which may induce some decidualization, but not atrophy.

    “These red lesions are resistant to progestin therapy, which may induce some decidualization, but not atrophy [46,47,48].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source

      Not checked in the free run.

    • cites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. source

      Not checked in the free run.

    • cites [48] Donnez, 1998, Vascular endothelial growth factor (VEGF) in endometriosis, Hum. Reprod. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Venous thrombotic events are 3 to 4 times more frequent but much less severe than arterial thrombotic events, which are more associated with EE dose than progestin type.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OCPs can play an important role in the management of endometriosis, as two-thirds of women with symptomatic endometriosis respond to estroprogestins.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [59] Vercellini, 2018, Management of endometriosis: Toward value-based, cost-effective, affordable care, J. Obstet. Gynaecol. Can. source

      Not checked in the free run.

    • cites [60] Vercellini, 2018, A stepped-care approach to symptomatic endometriosis management: A participatory research initiative, Fertil. Steril. source

      Not checked in the free run.

    • 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. source

      Not checked in the free run.

    • cites [62] Vercellini, 2018, Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence of OCP efficacy for endometriosis-related pain is limited and there are insufficient data to make any judgment in terms of comparisons with other medical therapies.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Brown, 2014, Endometriosis: An overview of cochrane reviews, Cochrane Database Syst. Rev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    PRs may be present but biologically inactive, or absent, leading to progesterone resistance and no decrease in lesion size with OCP or progestogen therapy.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A progestogen (lynestrenol) was unable to reduce vascularization in endometriotic lesions, but a significant decrease was observed after GnRH agonist therapy.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Donnez, 1995, Surgery: Rectovaginal septum, endometriosis or adenomyosis: Laparoscopic management in a series of 231 patients, Hum. Reprod. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Available literature considers combined hormone contraceptives to be effective for relief of endometriosis-related pain, but corroborative data are of low quality and inadequate to draw conclusions on superiority and relative benefits compared to other approaches.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Jensen, 2018, Use of combined hormonal contraceptives for the treatment of endometriosis-related pain: A systematic review of the evidence, Fertil. Steril. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Oral NETA should be considered the first choice among progestins given its favorable cost-effectiveness profile.

    “they also concluded that oral norethisterone acetate (NETA) should be considered the first choice, given the extremely favorable cost-effectiveness profile.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Buggio, 2017, Oral and depot progestin therapy for endometriosis: Towards a personalisez medicine, Expert Opin. Pharmacother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OCPs given for four months produce a statistically significant, though modest, improvement in dysmenorrhea compared to placebo, with about a 50% reduction in dysmenorrhea.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Harada, 2008, Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: A placebo-controlled, double-blind, randomized trial, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Due to progesterone resistance, the progestin contained within the OCP sometimes fails to produce the desired effect in endometriotic implants, resulting in relative estrogen dominance.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Progestins generate different levels of downregulation of ERs, a drop in local E2 production, a reduction in inflammation, and creation of a pseudo-pregnancy condition.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Reis, 2020, Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure, Hum. Reprod. Updat. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    All available progestins are effective in controlling pain symptoms in two-thirds of women with endometriosis.

    “They concluded that all available progestins are effective in controlling pain symptoms in two-thirds of women with endometriosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Buggio, 2017, Oral and depot progestin therapy for endometriosis: Towards a personalisez medicine, Expert Opin. Pharmacother. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    GnRH antagonists cause competitive blockage of the GnRH receptor and dose-dependently suppress production of FSH and LH and inhibit secretion of ovarian steroid hormones without inducing a flare-up effect.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The reduction in lesion volume with estroprogestins or progestins is not predictable and not significant in the vast majority of cases.

    “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].”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [77] Donnez, 1987, Combined (hormonal and microsurgical) therapy in infertile women with endometriosis, Fertil. Steril. source

      Not checked in the free run.

    • cites [78] Donnez, 1996, Large ovarian endometriomas, Hum. Reprod. source

      Not checked in the free run.

    • cites [79] Donnez, 1988, Histologic study of ovarian endometriosis after hormonal therapy, Fertil. Steril. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [81] Donnez, 1990, Endometriosis-associated infertility: Evaluation of preoperative use of danazol, gestrinone, and buserelin, Int. J. Fertil.

      Not checked in the free run.

    • cites [82] Mabrouk, 2017, Short-term histopathological effects of dienogest therapy on ovarian endometriomas: In vivo, nonrandomized, controlled trial, Gynecol. Endocrinol. source

      Not checked in the free run.

    • cites [86] Ferrero, 2012, Changes in the size of rectovaginal endometriotic nodules infiltrating the rectum during hormonal therapies, Arch. Gynecol. Obstet. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PR deficiency is evident in endometriotic lesions, leading to progesterone resistance and defective progesterone action, with consequences on survival and development of endometriotic tissues.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [22] Patel, 2017, Progesterone resistance in endometriosis: Origins, consequences and interventions, Acta Obstet. Gynecol. Scand. source

      Not checked in the free run.

    • cites [84] Kim, 2013, Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer, Endocr. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study comparing NETA and dienogest, 70% and 72% of patients respectively were very satisfied or satisfied, meaning around 30% were dissatisfied, 10% very dissatisfied.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Vercellini, 2016, Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: A before and after study, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Suppressing ovulation and reducing menstrual bleeding greatly reduces the number of erythrocytes regurgitated into the pelvis, resulting in a decrease in oxidative stress and the inflammatory environment.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Donnez, 2016, Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SPRMs are not an option for endometriosis because they induce progesterone modulator-associated endometrial changes (PAECs) in ectopic foci and their efficacy is limited.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [89] Donnez, 2016, Uterine fibroid management: From the present to the future, Hum. Reprod. Update source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [91] Donnez, 2020, Fibroids and medical therapy: Bridging the gap from selective progesterone receptor modulators to gonadotropin-releasing hormone antagonist, Fertil. Steril. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanism of GnRH antagonists differs from that of GnRH agonists, which after a first phase of stimulation desensitize GnRH receptors, leading to full suppression of LH and FSH production and complete suppression of E2 to levels similar to those after bilateral oophorectomy.

    “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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    GnRH agonists excessively suppress E2 to less than 20 pg/mL, with related unfavorable side effects.

    “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,”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [95] Brown, 2010, Gonadotrophin-releasing hormone analogues for pain associated with endometriosis, Cochrane Database Syst. Rev.

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [97] Donnez, 2004, Surgical management of endometriosis, Best Pract. Res. Clin. Obstet. Gynaecol. source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Interpretationcitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [84] Kim, 2013, Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer, Endocr. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elagolix is mainly metabolized by the liver, mostly by CYP3A, and 90% of excretion of elagolix and its metabolites occurs in the feces.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ng, 2017, Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] Taylor, 2017, Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [103] Surrey, 2018, Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies, Obstet. Gynecol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Estrogens play a crucial role not only in survival of endometriotic implants, but also in coordinated vasculogenesis and neurogenesis by different pathways involving ER signaling.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] Barra, 2019, Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain, Drugs Today source

      Not checked in the free run.

    • cites [15] Bulun, 2019, Endometriosis, Endocr. Rev. source

      Not checked in the free run.

    • cites [16] Yilmaz, 2019, Endometriosis and nuclear receptors, Hum. Reprod. Update source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    GnRH antagonists have rapid reversibility and recovery of hormone secretion after stopping treatment.

    “There is rapid reversibility and recovery of hormone secretion after stopping treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Striking a balance between efficacy and safety/tolerability may unlock the potential of GnRH antagonists, suggesting the possibility of individual tailoring according to symptoms and the wishes of the patient.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elagolix is rapidly absorbed after oral administration and its mean plasma half-life ranges from 2.4 to 6.3 h.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [99] Ng, 2017, Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [110] Barra, 2019, Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain, Drugs Today source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

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

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Relugolix has a half-life of 37-42 h and is mainly metabolized by the liver.

    “Relugolix has a half-life of 37–42 h and is mainly metabolized by the liver [104,117].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

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

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Higher rates of hypoestrogenic symptoms were observed with linzagolix 200 mg, 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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    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, may provide relief from endometriosis-associated pain while reducing side effects caused by extreme hypoestrogenism.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Ferrero, 2012, Changes in the size of rectovaginal endometriotic nodules infiltrating the rectum during hormonal therapies, Arch. Gynecol. Obstet. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

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

    “Relugolix CT is well tolerated, the incidence of vasomotor symptoms is similar to the placebo, and BMD is maintained over 24 weeks.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progesterone resistance is 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.

    “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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [46] Donnez, 1996, Stereometric evaluation of peritoneal endometriosis and endometriotic nodules of the rectovaginal septum, Hum. Reprod. source

      Not checked in the free run.

    • cites [47] Donnez, 1996, Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities, Fertil. Steril. source

      Not checked in the free run.

    • cites [56] Reis, 2020, Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure, Hum. Reprod. Updat. source

      Not checked in the free run.

    • cites [58] Flores, 2018, Progesterone receptor status predicts response to progestin therapy in endome-triosis, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Robust clinical evidence shows oral GnRH antagonists to be effective and well tolerated in patients with moderate-to-severe endometriosis-associated pain.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to Wang et al., the two recent FDA-approved doses of elagolix for 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

79 of 79

  • The authors state this as an assumption.

    Retrograde menstruation according to Sampson's theory is a valid mechanism of endometriosis.

    “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.”

  • The paper relies on this without support.

    Surgery cannot cure endometriosis.

    “surgery is of course able to eliminate visible endometriotic lesions, but cannot cure the disease.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Linzagolix response rates did not all remain stable or increase at 52 weeks

    Minor

    The paper says response rates were maintained or increased after 52 weeks, but the overall pelvic pain response rate for the 100 mg group fell from 66.7% at week 24 to 53.8% at week 52. The 75 mg group's rate also fell, from 70.8% to 69.2%.

  • Relugolix trial is described as both open-label and double-blind

    Minor

    The text calls the phase II relugolix trial open-label, but the title of the cited study describes it as double-blind.

2 of 2

Cites

Flagged first, then by citations

3 of the 133 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Donnez, J., & Dolmans, M.-M.
Affiliations
  • UCLouvain (BE)
  • Cliniques Universitaires Saint-Luc (BE)
Corresponding author
Donnez, Jacques
ORCID
Venue
Journal of Clinical Medicine
Publisher
MDPI AG
Published
2021-03-05
Volume
10
Issue
5
Pages
1085
ISSN
2077-0383 (ISSN-L)
DOI
10.3390/jcm10051085
PMC
PMC7961981
OpenAlex
W3133947928
Semantic Scholar
082ade52a8643600f6d43ad727bd91902f892058
Cited by
182
References
133
Citations by year
2026: 22 · 2025: 24 · 2024: 36 · 2023: 35 · 2022: 45 · 2021: 19
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fonds De La Recherche Scientifique - FNRS (5/4/150/5, grant 5/4/150/5)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
Keywords
endometriosis, medical therapy, progestogens, oral contraceptives, progesterone resistance, GnRH antagonist, dysmenorrhea, dyspareunia, non-menstrual pelvic pain, estrogen, premenopausal women, treatment efficacy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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