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Cited by 381Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementMenstrual Health and Disorders

Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial

Strowitzki, T., Marr, J., Gerlinger, C., Faustmann, T., Seitz, C.·2010·Human Reproduction
DOI 10.1093/humrep/dep469
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Abstract

BACKGROUND: Dienogest is a selective progestin that has been investigated in a clinical trial programme for the treatment of endometriosis. The current non-inferiority trial compared the efficacy and safety of dienogest against leuprolide acetate (LA) for treating the pain associated with endometriosis. METHODS: Patients with confirmed endometriosis were randomized to treatment with dienogest (2 mg/day, orally) or LA (3.75 mg, depot i.m. injection, every 4 weeks) for 24 weeks. The primary efficacy variable was absolute change in pelvic pain from baseline to end of treatment, assessed by visual analogue scale (VAS). Safety variables included adverse event profile, laboratory parameters, bone mineral density (BMD), bone markers and bleeding patterns. RESULTS: A total of 252 women were randomized to treatment with dienogest (n = 124) or LA (n = 128); 87.9 and 93.8% of the respective groups completed the trial. Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA. Hypoestrogenic effects (e.g. hot flushes) were reported less frequently in the dienogest group. As expected, bleeding episodes were suppressed less with dienogest than with LA. Changes in mean lumbar BMD between screening and final visit were +0.25% with dienogest and -4.04% with LA subgroups (P = 0.0003). Markers of bone resorption increased with LA but not dienogest. CONCLUSIONS: Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.

Integrity signals

Registry

Crossref · 10.1093/humrep/dep469

Cites

41 of 42 references verified0 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

6 of 50 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    The primary analysis was based on the per protocol set, which included all randomized patients except those with major protocol deviations that affected the primary efficacy variable.

    “As is appropriate for noninferiority studies (Piaggio et al., 2006), the primary analysis was based on the per protocol set (PPS), which included all randomized patients except those with major protocol deviations that affected the primary efficacy variable.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Piaggio et al., 2006 source

      The Methodological Issues section (p. 2) says per-protocol or other non-ITT analyses might be desirable in noninferiority trials because ITT can increase the risk of falsely concluding noninferiority. It also warns that excluding nonadherent patients can bias results in either direction, so it does not unconditionally endorse a per-protocol primary analysis. The cited paper does not define the citing study’s specific PPS exclusions; those are the citing authors’ description of their own analysis. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    By Week 24, mean visual analogue scale scores had decreased to 12.7 mm in the dienogest group and 11.9 mm in the leuprolide acetate group in the per protocol set.

    “By Week 24, mean VAS scores had decreased to 12.7 (+20.3)mm in the dienogest group and to 11.9 (+16.9)mm in the LA group (PPS; Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Seven serious adverse events were reported in six women during the study.

    “Seven serious adverse events were reported in six women during the study.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Headache was the most common treatment-related adverse event in both groups (12.5% dienogest; 19.5% leuprolide acetate).

    “Headache was the most common treatment-related adverse event in both groups (12.5%, dienogest; 19.5%, LA; Table II).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The proportions of women who experienced an improvement in visual analogue scale score by study end were similar in the dienogest and leuprolide acetate groups.

    “The proportions of women who experienced an improvement in VAS score by study end were similar in the dienogest and LA groups.”
    Quote in the paperSubstantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation

    Depot medroxyprogesterone acetate has demonstrated efficacy equivalent to leuprolide acetate, but long-term use impacts adversely on bone mineral density, and the delay in resumption of ovulation that may follow discontinuation is a contraindication in women wishing to conceive in the near future.

    “Depot medroxyprogesterone acetate (MPA; 104 mg, subcutaneous injection, every 3 months) has demonstrated an efficacy equivalent to LA, but long-term use of depot MPA preparations is shown to impact adversely on bone mineral density (BMD), while the delay in resumption of ovulation that may follow discontinuation of this therapy is a contraindication to use in women wishing to conceive in the near”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Vercellini et al., 2003 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Crosignani et al., 2006 source
    • cites Schlaff et al., 2006 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Progestins offer long-term efficacy in endometriosis, but a number of these agents are associated with weight gain and androgenic effects when administered at the high doses required for efficacy.

    “Progestins offer long-term efficacy in endometriosis, but a number of these agents are associated with weight gain and androgenic effects when administered at the high doses required for efficacy”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Mahutte and Arici, 2003 source
    • cites Vercellini et al., 2003 source

      The Introduction and Conclusions say progestogens can be used long term and effectively control endometriosis pain. The Results report weight gain with some treatments and describe medroxyprogesterone acetate as having moderate androgenic activity. They do not establish that high doses are required for efficacy or link those adverse effects specifically to such doses. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Irregular uterine bleeding is a known adverse effect of treatment with progestins, including depot preparations of MPA, which have been compared in trials against LA.

    “Irregular uterine bleeding is a known adverse effect of treatment with progestins, including depot preparations of MPA, which have been compared in trials against LA (Vercellini et al., 2003;Crosignani et al., 2006;Schlaff et al., 2006).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Vercellini et al., 2003 source

      The intramuscular-route section identifies DMPA as a depot formulation of MPA and says uterine breakthrough bleeding may be prolonged and repeated. The paper describes a DMPA trial against an oral contraceptive plus danazol, but the passages do not support the claim that depot MPA was compared against LA. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Crosignani et al., 2006 source
    • cites Schlaff et al., 2006 source

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

    Findingown data

    Mean body weight increased marginally and to a similar extent in the dienogest group (1.21 + 4.12 kg) and the LA group (1.15 + 3.46 kg; FAS).

    “Mean (+SD) body weight increased marginally and to a similar extent in the dienogest group (1.21 + 4.12 kg) and the LA group (1.15 + 3.46 kg; FAS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean levels of serum estradiol remained stable in the dienogest subgroup (n=32; from 256.3 to 249.9 pmol/l) and showed a pronounced decrease in the leuprolide acetate subgroup (n=38; from 299.0 to 68.5 pmol/l).

    “Mean levels of serum estradiol remained stable in the dienogest subgroup (n ¼ 32; from 256.3 to 249.9 pmol/l) and showed a pronounced decrease in the LA subgroup (n ¼ 38; from 299.0 to 68.5 pmol/l; Fig. 4a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Continued use of dienogest was associated with a shift in incidence toward amenorrhoea (from 1.8% in period 1 to 38.9% in period 2), with reductions in irregular and prolonged bleeding (16.7 and 7.4%, respectively, in period 2).

    “Continued use of dienogest was also associated with shift in incidence toward amenorrhoea (from 1.8% in period 1 to 38.9% in period 2), with reductions in irregular and prolonged bleeding (16.7 and 7.4%, respectively, in period 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean visual analogue scale score reductions in the full analysis set were 40.2 mm in the dienogest group and 41.8 mm in the leuprolide acetate group, representing a treatment difference of 1.6 mm (95% CI -6.42 to 9.58; P=0.0004).

    “Mean (+SD) VAS score reductions were 40.2 (+32.0)mm in the dienogest group and 41.8 (+28.6)mm in the LA group, representing a treatment difference of 1.6 mm (95% CI, -6.42 to 9.58; P for non-inferiority ¼ 0.0004).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The severity of the individual symptoms of pelvic pain, dysmenorrhoea and dyspareunia and the severity of the physical signs of pelvic tenderness and induration also decreased in both treatment groups between screening and final visit.

    “The severity of the individual symptoms of pelvic pain, dysmenorrhoea and dyspareunia and the severity of the physical signs of pelvic tenderness and induration also decreased in both treatment groups between screening and final visit (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The absolute reduction in visual analogue scale score was 47.5 mm with dienogest and 46.0 mm with leuprolide acetate, representing a treatment difference of 1.5 mm in favour of dienogest (95% CI -9.26 to 6.25).

    “The absolute reduction in VAS score was 47.5 (+28.8)mm with dienogest and 46.0 (+24.8)mm with LA, representing a treatment difference of 1.5 mm in favour of dienogest [95% confidence interval (CI), -9.26 to 6.25).”
    • Also stated in: § Abstract · boosted
      “Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean bone mineral density of the lumbar spine (L1-L4) was 1.062 g/cm2 in the dienogest subgroup and 1.070 g/cm2 in the leuprolide acetate subgroup at screening, and was 1.036 g/cm2 and 1.014 g/cm2, respectively, at final visit.

    “Mean BMD of the lumbar spine (L1-L4) was 1.062 g/cm 2 in the dienogest subgroup (n ¼ 26) and 1.070 g/cm 2 in the LA subgroup (n ¼ 31) at screening, and was 1.036 g/cm 2 (n ¼ 23) and 1.014 g/cm 2 (n ¼ 30), respectively, at final visit (FAS).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In women whose measurements were available at both screening and final visit, mean lumbar bone mineral density increased by 0.0022 g/cm2 in the dienogest subgroup and decreased by 0.0415 g/cm2 in the leuprolide acetate subgroup, representing mean percentage changes of +0.25% and -4.04% (P=0.0003 for superiority of dienogest).

    “In women whose measurements were available at both screening and final visit, mean lumbar BMD increased by 0.0022 g/cm 2 in the dienogest subgroup (n ¼ 21) and decreased by 0.0415 g/cm 2 in the LA subgroup (n ¼ 29), representing mean (+SD) percentage changes of þ0.25 (+2.77) and -4.04 (+4.84) for dienogest and LA, respectively (P ¼ 0.0003 for superiority of dienogest; Fig. 4c).”
    • Also stated in: § Abstract · plain
      “Changes in mean lumbar BMD between screening and final visit were þ0.25% with dienogest and -4.04% with LA subgroups (P ¼ 0.0003).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The bone mineral density subgroup is representative of the overall study population.

  • May combine two claims.

    Findingown data

    Mean serum osteocalcin levels decreased by 0.4 nmol/l in the dienogest group and increased by 0.5 nmol/l in the leuprolide acetate group.

    “Mean (+SD) serum osteocalcin levels decreased by 0.4 (+1.5) nmol/l in the dienogest group and increased by 0.5 (+1.4) nmol/l in the LA group (FAS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Quality of life, assessed by the SF-36 Health Survey, improved in both treatment groups, with an indication of more pronounced benefit in the dienogest than leuprolide acetate group.

    “Quality of life, assessed by the SF-36 Health Survey, improved in both treatment groups, with an indication of more pronounced benefit in the dienogest than LA group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean urinary Cross-Laps levels increased by 7.6 mg/mmol creatinine in the dienogest group and by 189.4 mg/mmol creatinine in the leuprolide acetate group.

    “Mean (+SD) urinary Cross-Laps w levels increased by 7.6 (+261.8)mg/mmol creatinine in the dienogest group and by 189.4 (+231.0)mg/mmol creatinine in the LA group (FAS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean urine calcium levels decreased by 137.4 mmol/mol creatinine in the dienogest group and increased by 111.3 mmol/mol creatinine in the leuprolide acetate group during the study.

    “Mean (+SD) urine calcium levels decreased by 137.4 (+295.5)mmol/mol creatinine in the dienogest group and increased by 111.3 (+ 227.9) mmol/mol creatinine in the LA group during the study (FAS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In both groups, the number of bleeding/spotting episodes and the number of bleeding/spotting days over time decreased, with a stronger trend in the LA group than in the dienogest group.

    “In general, the number of bleeding/spotting episodes and the number of bleeding/spotting days over time decreased in both groups, with a stronger trend in the LA group than in the dienogest group (Table III).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Whereas 12.2% of women in the dienogest group and 6.3% of women in the leuprolide acetate group had very severe symptoms at screening, none had this symptom grade at final visit.

    “Whereas 12.2% of women in the dienogest group and 6.3% of women in the LA group had very severe symptoms at screening, none had this symptom grade at final visit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean lumbar BMD was unchanged over the study period in dienogest-treated women, but decreased by approximately 4% in the LA group, with statistically significant differences in mean BMD between the treatment groups.

    “Mean lumbar BMD was unchanged over the study period in dienogest-treated women, but decreased by approximately 4% in the LA group, with statistically significant differences in mean BMD between the treatment groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adverse events were of mild or moderate intensity in most women and overall rates of study discontinuation due to adverse events were low in both groups.

    “Adverse events were of mild or moderate intensity in most women and overall rates of study discontinuation due to adverse events were low in both groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Dienogest offers advantages compared with LA, including a substantially lower incidence of hot flushes and minimal change in BMD and bone metabolism.

    “In addition, dienogest was associated with acceptable safety and tolerability, offering advantages when compared with LA including a substantially lower incidence of hot flushes and minimal change in BMD and bone metabolism.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study protocol was approved by local independent ethics committees and all participants provided written informed consent before study enrolment.

    “The study protocol was approved by the local independent ethics committees and all participants provided written, informed consent before study enrolment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Patients were randomized in a 1:1 distribution to receive dienogest 2 mg orally once daily or leuprolide acetate 3.75 mg depot intramuscularly every 4 weeks.

    “Patients were randomized in a 1:1 distribution to receive dienogest at a dose of 2 mg, given orally at the same time once daily, or LA at a standard dose of 3.75 mg as a depot i.m. injection every 4 weeks.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study was a 24-week, multicentre, randomized, open-label, parallel-group study of dienogest versus leuprolide acetate.

    “The study was a 24-week, multicentre, randomized, open-label, parallel-group study of dienogest versus LA.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Compliance with dienogest treatment was monitored by diary records completed by patients.

    “Compliance with dienogest treatment was monitored by diary records completed by patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The visual analogue scale is an appropriate and well-established tool for measuring pelvic pain associated with endometriosis.

    “The VAS score was selected as the primary efficacy variable in this study because the VAS is an appropriate and well-established tool for the measurement of pelvic pain associated with endometriosis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fauconnier et al., 2009 source

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

    Study design and conductnone given

    Randomization was done using randomization blocks, with a randomization list generated by Corporate Biometry, Schering AG.

    “Randomization was done using randomization blocks, with a randomization list generated by Corporate Biometry, Schering AG.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Assuming a withdrawal rate of 30%, a total of 252 patients was required for enrolment.

    “Assuming a withdrawal rate of 30%, a total of 252 patients was therefore required for enrolment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot leuprolide acetate at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.

    “Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The open-label design did not bias the assessment of pelvic pain by visual analogue scale.
    • Rests on an assumption: The bone mineral density subgroup is representative of the overall study population.
    • Rests on an assumption: The trial population is representative of women with endometriosis in general.

  • May combine two claims.

    Premisecitation

    Dienogest is a selective progestin that combines the pharmacological properties of 19-norprogestins and progesterone derivatives, offering a pronounced progestogenic effect at the endometrium with an absence of androgenicity and moderate suppression of ovarian activity.

    “Dienogest is a selective progestin that combines the pharmacological properties of 19-norprogestins and progesterone derivatives, offering a pronounced progestogenic effect at the endometrium with an absence of androgenicity and moderate suppression of ovarian activity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Oettel et al., 1999 source
    • cites Schindler et al., 2006 source
    • cites Sasagawa et al., 2008 source

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

    Study design and conductown data

    The full analysis set included 248 patients (n=120 dienogest; n=128 leuprolide acetate), while the per protocol set included 186 women (n=90 dienogest; n=96 leuprolide acetate).

    “The FAS analysis included 248 patients (n ¼ 120, dienogest; n ¼ 128, LA), while the PPS analysis included 186 women (n ¼ 90, dienogest; n ¼ 96, LA).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Danazol is characterized by adverse changes in lipid metabolism and androgenic adverse effects, including weight gain, oedema, acne, hirsutism and oily skin, which lead to low compliance with therapy.

    “Danazol is characterized by adverse changes in lipid metabolism and androgenic adverse effects, including weight gain, oedema, acne, hirsutism and oily skin, which lead to low compliance with therapy”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Winkel and Scialli, 2001 source
    • cites Selak et al., 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    The number of patients whose bone mineral density had to be measured was calculated under the assumption of a 4 percentage point difference in BMD change between treatments and a common standard deviation of 4 percentage points.

    “The number of patients whose BMD had to be measured was calculated under the assumption of a 4% point difference in BMD change between the treatments and a common SD of 4% points.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    A total of 88 evaluable patients were required in each treatment group to yield 90% power to demonstrate non-inferiority of dienogest relative to leuprolide acetate.

    “A total of 88 evaluable patients were required in each treatment group to yield a power (1 -b) of 90% to demonstrate the non-inferiority of dienogest relative to LA.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Twenty-two evaluable patients per group were needed to achieve 90% power for the bone mineral density comparison.

    “By this approach, 22 evaluable patients per group were needed to achieve the power (1-b) ¼ 90%.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In a phase II dose-finding study, dienogest 2 mg daily offered improvements in patient-reported symptoms and in second-look laparoscopic assessments of pathology after 24 weeks.

    “In a phase II dose-finding study, dienogest 2 mg daily offered improvements in patient-reported symptoms and in second-look laparoscopic assessments of pathology after 24 weeks.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ko ¨hler et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Of 269 women screened, 252 were randomized to dienogest (n=124) or leuprolide acetate (n=128).

    “Of 269 women screened, 252 were randomized to treatment with either dienogest (n ¼ 124) or LA (n ¼ 128; Fig. 1).”
    • Also stated in: § Abstract · plain
      “A total of 252 women were randomized to treatment with dienogest (n ¼ 124) or LA (n ¼ 128); 87.9 and 93.8% of the respective groups completed the trial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In clinical trials, dienogest was shown to be an effective and well-tolerated treatment for endometriosis.

    “In clinical trials, including a dose-response study (Ko ¨hler et al., 2010), a placebo-controlled study (Seitz et al., 2008), an activecontrolled study versus triptorelin after laparoscopic surgery (Cosson et al., 2002) and a long-term safety study (Seitz et al., 2009), dienogest was shown to be an effective and well-tolerated treatment for endometriosis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Köhler et al., 2010 source
    • cites Seitz et al., 2008 source
    • cites Cosson et al., 2002 source

  • May combine two claims.

    Premisecitation

    Combined oral contraceptives are not approved for endometriosis in most countries and lack a solid body of supportive clinical trial evidence.

    “Combined oral contraceptives, whereas widely used to manage symptoms of endometriosis, are not approved for this indication in most countries and lack a solid body of supportive clinical trial evidence”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Davis et al., 2007 source

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

    Study design and conductown data

    Bone mineral density was assessed in a subgroup of 57 women (n=26 dienogest; n=31 leuprolide acetate), and estradiol levels were measured in 70 women (n=32 dienogest; n=38 leuprolide acetate).

    “BMD was assessed in a subgroup of 57 women (n ¼ 26, dienogest; n ¼ 31, LA), and estradiol levels were measured in 70 women (n ¼ 32, dienogest; n ¼ 38, LA).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The sample size was calculated on the assumption of equal efficacy for dienogest and leuprolide acetate and a common standard deviation of 30 mm for the primary efficacy variable.

    “The sample size was calculated on the assumption of equal efficacy for dienogest and LA and a common standard deviation (SD) of 30 mm for the primary efficacy variable.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The efficacy and safety profile of dienogest characterized in this study suggests that dienogest may offer an effective and well-tolerated treatment in endometriosis.

    “The efficacy and safety profile of dienogest characterized in this study suggests that dienogest may offer an effective and well-tolerated treatment in endometriosis.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    As VAS scoring for pain is a subjective measure, the process of obtaining patients' scores by investigators could have introduced bias.

    “As VAS scoring for pain is a subjective measure, the process of obtaining patients' scores by investigators could have introduced bias.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GnRH agonists such as LA are associated with hypoestrogenic effects and related adverse effects on BMD, which limits treatment to 6 months in the absence of add-back therapy.

    “GnRH agonists such as LA are associated with hypoestrogenic effects and related adverse effects on BMD (Winkel and Scialli, 2001), which limits treatment to 6 months in the absence of add-back therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Winkel and Scialli, 2001 source

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

    Premisecitation

    Although add-back therapy can reduce the hypoestrogenic effects of GnRH agonists, the optimal add-back regimen has not yet been established and this approach adds to the cost of therapy.

    “Although add-back therapy can reduce the hypoestrogenic effects of GnRH agonists, the optimal add-back regimen has not yet been established and this approach adds to the cost of therapy (Mounsey et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mounsey et al., 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Dienogest appears to have no relevant effect on lipids and lacks androgenic side effects.

    “Dienogest, in contrast, appears to have no relevant effect on lipids (Ko ¨hler et al., 1989;Schindler et al., 2006;Seitz et al., 2008) and lacks androgenic side effects (Oettel et al., 1999;Schindler et al., 2003).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ko ¨hler et al., 1989 source
    • cites Schindler et al., 2006 source
    • cites Seitz et al., 2008 source
    • Rests on an assumption: Danazol is associated with adverse effects on lipid metabolism and androgenic adverse effects.

  • May combine two claims.

    Interpretationown data

    These outcomes are robust and clinically relevant in the treatment of endometriosis.

    “Despite these potential limitations, dienogest provided consistent improvements in a range of patient-and physician-assessed symptoms at 24 weeks similar to LA, indicating that these outcomes are robust and clinically relevant in the treatment of endometriosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This may also indicate an advantage of dienogest compared with depot MPA, which has been associated with a significant loss of BMD resulting in a 'black box warning' by the US Food and Drug Administration.

    “This may also indicate an advantage of dienogest compared with depot MPA, which has been associated with a significant loss of BMD resulting in a 'black box warning' by the US Food and Drug Administration (Physician Information, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Physician Information, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductreasoning

    Treatment duration was restricted to 24 weeks, which was necessary because GnRH agonists are approved in the treatment of endometriosis for up to 6 months only, due to their deleterious effects on BMD.

    “A further potential limitation of the study relates to a treatment duration that was restricted to 24 weeks, which was necessary because GnRH agonists are approved in the treatment of endometriosis for up to 6 months only, due to their deleterious effects on BMD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Other studies that examined bleeding patterns during dienogest treatment, including the 1-year extension study, also reported progressive reductions in bleeding irregularity over time.

    “Other studies that examined bleeding patterns during dienogest treatment, including the 1-year extension study, also reported progressive reductions in bleeding irregularity over time (Cosson et al., 2002;Seitz et al., 2008Seitz et al., , 2009;;Ko ¨hler et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cosson et al., 2002 source
    • cites Seitz et al., 2008 source
    • cites Ko ¨hler et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

49 of 49

  • The paper relies on this without support.

    The open-label design did not bias the assessment of pelvic pain by visual analogue scale.

    “The study was a 24-week, multicentre, randomized, open-label, parallel-group study of dienogest versus LA.”
    “The primary efficacy variable was the absolute change in endometriosis-associated pelvic pain from baseline to the end of treatment, assessed by a visual analogue scale (VAS; 0 mm ¼ absence of pain, 100 mm ¼ unbearable pain).”

  • The paper relies on this without support.

    The bone mineral density subgroup is representative of the overall study population.

    “BMD was assessed in a subgroup of 57 women (n ¼ 26, dienogest; n ¼ 31, LA)”
    “In women whose measurements were available at both screening and final visit, mean lumbar BMD increased by 0.0022 g/cm 2 in the dienogest subgroup (n ¼ 21) and decreased by 0.0415 g/cm 2 in the LA subgroup (n ¼ 29)”

  • The paper relies on this without support.

    The trial population is representative of women with endometriosis in general.

    “Women aged 18 -45 years were eligible for study enrolment if they experienced pain associated with histologically proven endometriosis in revised-American Fertility Society (r-AFS, 1985) stages I -IV.”
    “Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis”

  • The paper relies on this without support.

    Pelvic pain is one of the most important symptoms of endometriosis.

    “as pelvic pain is one of the most important symptoms of endometriosis”

  • The paper relies on this without support.

    Weight gain is a characteristic of a number of other progestins used in endometriosis.

    “Weight gain, which is a characteristic of a number of other progestins used in endometriosis, was minimal in dienogesttreated women.”

  • The paper relies on this without support.

    Danazol is associated with adverse effects on lipid metabolism and androgenic adverse effects.

    “Danazol, although remaining a standard therapy for endometriosis in some countries, is associated with adverse effects on lipid metabolism and androgenic adverse effects.”
6 of 6

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?

  • Progestins limit the risk of post-operative dysmenorrhea recurrence when released locally via an intrauterine system.

    “Progestins can be used in women with metabolic or cardiovascular contraindications to estrogen–progestins and limit the risk of post-operative dysmenorrhea recurrence also when released locally via an intrauterine system (Strowitzki et al., 2010; Brown et al., 2012; Petraglia et al., 2012; Abou-Setta et al., 2013).”

    From When more is not better: 10 ‘don’ts’ in endometriosis management. An ETIC* position statement (2019) · cites this paper as Strowitzki et al., 2010

  • Progestins can be used in women with metabolic or cardiovascular contraindications to estrogen-progestins.

    “Progestins can be used in women with metabolic or cardiovascular contraindications to estrogen–progestins and limit the risk of post-operative dysmenorrhea recurrence also when released locally via an intrauterine system (Strowitzki et al., 2010; Brown et al., 2012; Petraglia et al., 2012; Abou-Setta et al., 2013).”

    From When more is not better: 10 ‘don’ts’ in endometriosis management. An ETIC* position statement (2019) · cites this paper as Strowitzki et al., 2010

  • The lack of changes in laboratory parameters supports previous trials that investigated the metabolic effects of dienogest.

    “The lack of changes in laboratory parameters supports previous trials that investigated the metabolic effects of dienogest [13, 14, 16, 23].”

    From Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment (2012) · cites this paper as [14]

  • There were minimal changes in mean body weight, consistent with the previous dienogest experience.

    “In addition, there were minimal changes in mean body weight, consistent with the previous dienogest experience [13, 14, 16].”

    From Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment (2012) · cites this paper as [14]

  • Clinical trials of 12-24 weeks' duration have shown that dienogest at a dose of 2 mg/day provides effective pain relief equivalent to GnRH agonists, a reduction of endometriotic lesions and a favorable safety and tolerability profile in endometriosis.

    “Clinical trials of 12–24 weeks’ duration have shown that dienogest (at a dose of 2 mg/day) provides effective pain relief equivalent to GnRH agonists, a reduction of endometriotic lesions and a favorable safety and tolerability profile in endometriosis [12–14].”

    From Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment (2012) · cites this paper as [14]

Self-check

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

  • Dienogest acne percentage is misrounded

    Minor

    Table II reports five cases among 120 women as 4.1%. That fraction is approximately 4.17%, which rounds to 4.2% at the table's precision.

    Reported 4.1 · recomputed 4.166667

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1002/14651858.cd000346

    Major

    The cited work was retracted on 1999-04-26 (notice 10.1002/14651858.cd000346.pub2), before this paper was published (2010-01-19). Its authors could have known.

    Cited work 10.1002/14651858.cd000346 · retracted 1999-04-26 · notice 10.1002/14651858.cd000346.pub2 · this paper published 2010-01-19

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 11

  1. 1986, 34, 253
  2. 2007, Cochrane database of systematic reviews (Online), 3, CD001019
  3. 2009, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 107, S190
  4. 2007, JPN PHARMACOL THER, 35, 769
  5. Mounsey, 2006, American family physician, 74, 594
  6. 2000, Cochrane database of systematic reviews (Online), 2, CD000346
  7. 2008, 73, 222
  8. 2003, 46, S7
  9. 2008, Fertility and sterility, 90, S140
  10. 2009, Fertility and sterility, 92, S107
  11. Wells, 1993, The Journal of Rheumatology, 20, 557

Cited by

Sorted by citations

Related

Authors
Strowitzki, T., Marr, J., Gerlinger, C., Faustmann, T., & Seitz, C.
Affiliations
  • Heidelberg University (DE)
  • Bayer (Germany) (DE)
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2010-01-19
Volume
25
Issue
3
Pages
633-641
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dep469
OpenAlex
W2101417341
Cited by
381
References
38
Citations by year
2026: 15 · 2025: 17 · 2024: 23 · 2023: 26 · 2022: 13 · 2021: 27 · 2020: 19 · 2019: 16 · 2018: 29 · 2017: 31 · 2016: 17 · 2015: 42 · 2014: 26 · 2013: 24 · 2012: 22
FWCI
30.34
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
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
dienogest, leuprolide, endometriosis, pelvic pain, GnRH agonist, non-inferiority, bone mineral density, bone resorption markers, bleeding patterns, safety and tolerability
MeSH terms
Adult, Endometriosis, Female, Humans, Nandrolone, Progestins, Quality of Life, Bone Density, Leuprolide, Pelvic Pain

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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