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Cited by 64Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementGynecological conditions and treatments

A stepped-care approach to symptomatic endometriosis management: A participatory research initiative

Open access
Vercellini, Paolo, Donati, Agnese, Ottolini, Federica, Frassineti, Annalisa, Fiorini, Jessica, Nebuloni, Vanessa, Frattaruolo, Maria Pina, Roberto, Anna +2 more·2018·Fertility and Sterility
DOI 10.1016/j.fertnstert.2018.01.037
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Abstract

OBJECTIVE To assess the proportion of patients with symptomatic endometriosis satisfied with their medical treatment 12 months after enrollment in a stepped-care management protocol. DESIGN Prospective, single-arm, self-controlled study. SETTING Academic department. PATIENT(S) A cohort of 157 consecutive patients referred or self-referred to our center for symptomatic endometriosis. INTERVENTIONS(S) Systematic detailed information process on medical and surgical treatment followed by a shared decision to start a stepped-care protocol including three subsequent medical therapy steps (oral contraception [OC]; 2.5 mg/d norethindrone acetate [NETA]; 2 mg/d dienogest [DNG]) and a fourth surgical step. Stepping up was triggered by drug inefficacy/intolerance. MAIN OUTCOME MEASURE(S) Satisfaction with treatment was assessed according to a five-category scale (very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, very dissatisfied). Variations were measured in pain symptoms with the use of a 0-10-point numeric rating scale (NRS), in quality of life with the use of the Short Form 12 questionnaire (SF-12), and in sexual functioning with the use of the Female Sexual Function Index (FSFI). RESULT(S) At the end of the 12-month study period, 106 women were still using OC, 23 were using NETA, three were using DNG, and four had undergone surgery. Twenty-one participants (13%) dropped out from the study. In intention-to-treat analysis, excluding five drop-outs for pregnancy desire, the overall satisfaction rate with the stepped-care protocol was 62% (95/152; 95% CI 55%-70%). By 12-month follow-up, significant improvements were observed in all pain symptom scores and in SF-12 physical and mental component summary scores, whereas FSFI scores did not vary substantially. CONCLUSION(S) Most women with endometriosis-associated pelvic pain who chose a stepped-care approach were satisfied with OC and a low-cost progestin for the treatment of their symptoms. The need to step up to an expensive progestin or surgery was marginal.

AI snapshot

Written from the paper’s full text.

TL;DR

In a prospective, single-arm, self-controlled study of 157 women with symptomatic endometriosis, 62% (95/152; 95% CI 55%-70%) were satisfied with a stepped-care medical protocol at 12 months in intention-to-treat analysis. Pain and SF-12 scores improved significantly, while FSFI did not vary substantially.

Key findings

  • At 12 months, 106 women were still using OC, 23 were using NETA, three were using DNG, and four had undergone surgery; 21 participants (13%) dropped out. Intention-to-treat satisfaction excluding five dropouts for pregnancy desire was 62% (95/152; 95% CI 55%-70%); per-protocol satisfaction was 71% (95/133; 95% CI 63%-79%).
  • Prevalence of moderate or severe pain decreased from 94% to 12% for dysmenorrhea, from 59% to 30% for deep dyspareunia, from 43% to 12% for dyschezia, and from 44% to 23% for nonmenstrual pelvic pain. Median days with pain necessitating analgesics fell from 7 (4-10) to 0 (0-2) per month, and days with impairment of usual activities from 2 (0-4) to 0 (0-0).
  • SF-12 physical component summary improved from 41.4 ± 11.1 to 51.0 ± 8.7 and mental component summary from 41.9 ± 10.5 to 47.0 ± 10.0 (P<.001); FSFI total score changed from 26.4 ± 5.6 to 25.3 ± 6.1 (P=.07).
  • Side effects were experienced by about four out of five patients, but their severity determined drug discontinuation in only ten participants.

Methods

  • Prospective, single-arm, self-controlled observational study in an academic endometriosis department; 157 consecutive women aged 18-40 with surgical or nonsurgical diagnosis of ovarian and/or deep endometriosis and moderate or severe pelvic pain of >6 months’ duration, not seeking conception.
  • Stepped-care protocol: step 1 continuous low-dose monophasic OC; step 2 NETA 2.5 mg/day; step 3 DNG 2 mg/day; step 4 surgery. Stepping up was triggered by drug inefficacy or intolerance; assessments occurred at 3, 6, and 12 months.
  • Satisfaction was measured on a five-category scale; pain by 0-10 NRS; quality of life by SF-12; sexual functioning by FSFI. Satisfaction was analyzed by intention-to-treat, considering all dropouts except pregnancy desire as dissatisfied; secondary outcomes were per-protocol using paired tests, Wilcoxon, McNemar, Fisher exact, and logistic regression.

Limitations

  • Stated in the paper: the self-controlled design may appear to be a limitation, but was chosen to limit confounding; selection bias/self-selection favoring hormonal therapy limits generalizability to women who prefer medical rather than surgical treatment; self-referred patients may not represent the general endometriosis population.
  • Stated in the paper: regression toward the mean and carry-over effects could not be excluded; side-effect incidence may be high because side effects were actively investigated; the psychologic effect of shared decision-making was not measured.
  • Evident from the text: the single-arm design without a concurrent control or blinding means improvements cannot be attributed solely to the stepped-care protocol; satisfaction was dichotomized, and the study excluded women with endometriomas >4 cm and those already satisfied with pharmacologic therapy.

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

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2018.01.037

Cites

91 of 91 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 68 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The median number of days with pain necessitating analgesics decreased from 7 (IQR 4-10) to 0 (IQR 0-2) per month.

    “The median (IQR) number of days with pain necessitating analgesics decreased from 7 (4-10) to 0 (0-2) per month, and the number of days with impairment of usual activities decreased from 2 (0-4) to 0 (0-0).”
    Quote in the paperSubstantial claim
  • Findingown data

    The median number of days with impairment of usual activities decreased from 2 (IQR 0-4) to 0 (IQR 0-0).

    “The median (IQR) number of days with pain necessitating analgesics decreased from 7 (4-10) to 0 (0-2) per month, and the number of days with impairment of usual activities decreased from 2 (0-4) to 0 (0-0).”
    Quote in the paperSubstantial claim
  • Findingown data

    The prevalence of moderate or severe deep dyspareunia decreased from 59% to 30% at the end of the study period.

    “At the end of study period, the prevalence of moderate or severe pain decreased from 94% to 12% for dysmenorrhea, from 59% to 30% for deep dyspareunia, from 43% to 12% for dyschezia, and from 44% to 23% for nonmenstrual pelvic pain.”
    Quote in the paperSubstantial claim
  • Findingown data

    In intention-to-treat analysis, excluding five drop-outs for pregnancy desire, the overall satisfaction rate with the stepped-care protocol was 62% (95/152; 95% CI 55%-70%).

    “In intention-to-treat analysis, excluding five drop-outs for pregnancy desire, the overall satisfaction rate with the stepped-care protocol was 62% (95/152; 95% CI 55%-70%).”
    Quote in the paperSubstantial claim
  • Findingown data

    Baseline demographic and clinical characteristics of the 95 satisfied and 57 dissatisfied patients in the intention-to-treat analysis were substantially similar.

    “Baseline demographic and clinical characteristics of the 95 satisfied and 57 dissatisfied patients in the intention-totreat analysis were substantially similar.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 26
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In univariate analysis, BMI and SF-12 mental component summary score were significantly different between satisfied and dissatisfied women, with BMI slightly higher and SF-12 mental component lower in dissatisfied women.

    “In univariate analysis, statistically significant differences were observed only for BMI and the SF-12 mental component summary score, which were slightly higher and lower, respectively, in the group of dissatisfied women (Supplemental Table 2, available at www.fertstert.org).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the logistic regression model, both BMI and the SF-12 mental component summary score remained significantly associated with satisfaction with treatment (P=.033 and P=.043, respectively).

    “In the logistic regression model, both BMI and the SF-12 mental component summary score remained significantly associated with satisfaction with treatment (P¼ .033and P¼ .043,respectively).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    FSFI scores did not vary substantially by 12-month follow-up.

    “A trend toward a marginal worsening of the FSFI score was observed (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the end of the 12-month study period, 106 women were still using OC, 23 were using NETA, three were using DNG, and four had undergone surgery.

    “At the end of the 12-month study period, 106 women were still using OC, 23 were using NETA, three were using DNG, and four women had undergone surgery (including one who requested surgery at the 12-month evaluation, after completion of the pre-planned 1-year medical treatment period).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both the physical and the mental components of health-related quality of life, as measured by the SF-12, were substantially improved with the use of medical treatment.

    “Both the physical and the mental components of health-related quality of life, as measured by this instrument, were substantially improved with the use of medical treatment.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    The incidence of side-effects of OC and progestins was surprisingly high.

    “The incidence of side-effects of OC and progestins was surprisingly high.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Laparoscopic surgery is associated with a 70%-80% probability of partial or complete pain relief.

    “Finally, patients were also informed that laparoscopic surgery was a reasonable alternative associated with a 70%-80% probability of partial or complete pain relief in case they declined medical therapy or switching from OC to a progestin, but that the risk of pain and lesion recurrence was $10% per year without long-term postoperative medical treatment (2, 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Guo, 2009, Recurrence of endometriosis and its control, Hum Reprod Update source

      Not checked in the free run.

    • cites [3] Vercellini, 2009, The effect of surgery for symptomatic endometriosis: the other side of the story, Hum Reprod Update source

      Not checked in the free run.

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

    Premisecitation

    The risk of pain and lesion recurrence after laparoscopic surgery is ≥10% per year without long-term postoperative medical treatment.

    “Finally, patients were also informed that laparoscopic surgery was a reasonable alternative associated with a 70%-80% probability of partial or complete pain relief in case they declined medical therapy or switching from OC to a progestin, but that the risk of pain and lesion recurrence was $10% per year without long-term postoperative medical treatment (2, 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Guo, 2009, Recurrence of endometriosis and its control, Hum Reprod Update source

      Not checked in the free run.

    • cites [3] Vercellini, 2009, The effect of surgery for symptomatic endometriosis: the other side of the story, Hum Reprod Update source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dienogest's effect on pain is significantly superior to placebo and equivalent to a GnRH analogue.

    “Dienogest, a semisynthetic 19-nortestosterone-derivative progestin, has been investigated and registered also for the treatment of endometriosis.Its effect on pain was demonstrated to be significantly superior to placebo and equivalent to a GnRH analogue (43,44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Strowitzki, 2010, Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial, Hum Reprod source

      Not checked in the free run.

    • cites [44] Strowitzki, 2010, Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study, Eur J Obstet Gynecol Reprod Biol source

      Not checked in the free run.

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

    Premisecitation

    The continuous use of OC is suggested to achieve amenorrhea and relieve pain at withdrawal bleeding that may still afflict endometriosis patients using OC cyclically.

    “In particular, the continuous use of OC is suggested to achieve amenorrhea and relieve pain at withdrawal bleeding that may still afflict endometriosis patients using OC cyclically (32,33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Vercellini, 2003, Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen, Fertil Steril source

      Not checked in the free run.

    • cites [33] Laux-Biehlmann, 2015, Menstruation pulls the trigger for inflammation and pain in endometriosis, Trends Pharmacol Sci source

      Not checked in the free run.

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

    Premisecitation

    Norethindrone acetate has been repeatedly evaluated in women with endometriosis.

    “Norethindrone acetate, a 19-nortestosterone-derivative progestin, has been repeatedly evaluated in women with endometriosis (35)(36)(37)(38)(39)(40)(41), and has been successfully used in our referral center for several years (20,21,42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (35)(36)(37)(38)(39)(40)(41)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hormonal compounds to treat endometriosis have different metabolic and subjective side-effects and costs.

    “Based on secondary research findings (10) and according to guidelines issued by several international gynecologic societies, hormonal compounds to treat endometriosis have similar effects on pain, but different metabolic and subjective side-effects and costs (1,(11)(12)(13)(14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 1,(11)(12)(13)(14)

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Patient satisfaction rate was estimated according to the intention-to-treat principle, considering as dissatisfied all patients who dropped out for any reason except conception seeking.

    “Estimate of patient satisfaction rate was performed according to the intention-to-treat principle, considering as dissatisfied all patients who dropped out of the study for any reason except conception seeking, thus including a request for not using pre-planned medical therapies or need for surgery, as well as loss to follow-up.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Dienogest may have an adverse impact on bone mineral density.

    “Women were informed that DNG was indicated as step 3 instead of step 2 because DNG is much more expensive that NETA and may have an adverse impact on bone mineral density (43,45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Strowitzki, 2010, Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial, Hum Reprod source

      Not checked in the free run.

    • cites [45] Momoeda, 2009, Long-term use of dienogest for the treatment of endometriosis, J Obstet Gynaecol Res source

      Not checked in the free run.

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

    Interpretationreasoning

    In such a case (carry-over effect), the effect would have been negative and led to a decrease in the patient satisfaction rate.

    “However, in such a case the effect would have been negative and led to a decrease in the patient satisfaction rate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The adoption of an intention-to-treat analysis to assess patient satisfaction and including as dissatisfied all participants who underwent surgery and all drop-outs except women who discontinued treatment to seek a conception should have avoided overoptimistic results generally associated with observational study designs.

    “Moreover, the adoption of an intention-to-treat analysis to assess patient satisfaction and including as dissatisfied all participants who underwent surgery and all drop-outs except women who discontinued treatment to seek a conception should have avoided overoptimistic results which are generally associated with observational study designs.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The regression toward the mean phenomenon could have affected the observed data.

    “Theoretically, the ''regression toward the mean'' phenomenon could have affected the observed data, because extreme values are frequently influenced by random variation and when remeasured they tend to be closer to the mean of the original population from which the study subjects were drawn (32,63).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Vercellini, 2003, Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen, Fertil Steril source

      Not checked in the free run.

    • cites [63] Louis, 1986, Crossover and self-controlled designs in clinical research

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The authors recruited a series of consecutive women with endometriosis seeking care for their pain symptoms, and what they observed might provide an overall representation of what unselected women can expect from medical treatment in the real world.

    “We recruited a series of consecutive women with endometriosis seeking care for their pain symptoms, and what we have observed might provide an overall representation of what unselected women can expect from medical treatment in the real world.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Satisfaction with treatment was dichotomized into satisfied and dissatisfied to limit potential confounding.

    “To limit the potential effect of confounding, satisfaction with treatment was dichotomized into ''satisfied'' (very satisfied plus satisfied) and ''dissatisfied'' (neither satisfied nor dissatisfied plus dissatisfied plus very dissatisfied).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    When patients' conditions are worse than average and standard therapies seem to have lost efficacy, some general amelioration may occur that has nothing to do with improved treatment.

    “Therefore, when the patients' conditions are worse than average and standard therapies seem to have lost efficacy, some general amelioration may occur that has nothing to do with improved treatment (32,63).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Vercellini, 2003, Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen, Fertil Steril source

      Not checked in the free run.

    • cites [63] Louis, 1986, Crossover and self-controlled designs in clinical research

      Not checked in the free run.

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

    Study design and conductcitation

    The FSFI is a validated instrument for evaluating female sexual dysfunction and sexual satisfaction.

    “The Female Sexual Function Index (FSFI) questionnaire is a 19-item multidimensional self-report instrument for evaluating the main categories of female sexual dysfunction and sexual satisfaction (54,55).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Rosen, 2000, The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function, J Sex Marital Ther source

      Not checked in the free run.

    • cites [55] Meston, 2003, Validation of the Female Sexual Function Index (FSFI) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder, J Sex Marital Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Outcomes may vary in centers applying different approaches regarding patient information and decision making.

    “In theory, outcomes may vary in centers applying different approaches regarding patient information and decision making.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    This problem (non-representativeness) also affects studies conducted in centers adopting mainly a surgical approach.

    “However, this is a problem also for studies conducted in centers adopting mainly a surgical approach.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    It may not be excluded that patients self-referring to the center are not representative of the general population of women with endometriosis, because they may be more prone to start medical therapies rather than request surgery.

    “More in general, it may not be excluded that patients selfreferring to our center are not representative of the general population of women with endometriosis, because they may be more prone to start medical therapies rather than request surgery.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Many patients may now easily identify through the internet and patient association websites those referral centers that are in favor of medical treatment.

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

    Study design and conductcitation

    The SF-12 is a well-known and validated self-administered 12-item instrument.

    “Quality of life was assessed with the use of the Short Form 12 (SF-12) health survey, a well known and validated selfadministered 12-item instrument developed from the original SF-36 questionnaire (50, 51).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Ware, 1992, The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection, Med Care source

      Not checked in the free run.

    • cites [51] McHorney, 1999, The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs, Med Care source

      Not checked in the free run.

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

    Study design and conductnone given

    A carry-over effect could not be excluded when stepping up because of drug inefficacy or intolerance.

    “Also, a carry-over effect could not be excluded when stepping up because of drug inefficacy or intolerance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductreasoning

    The attitude of the personnel toward discussing benefits and harms of all available treatment options, and the systematic application of a shared decision-making process, may have had per se a psychologic effect, because women likely felt understood and supported.

    “In addition, the attitude of the personnel of our center toward discussing benefits and harms of all available treatment options, and the systematic application of a shared decision-making process, may have had per se a psychologic effect, because women likely felt understood and supported, although we did not measure such aspects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Of the 38 women who declared themselves dissatisfied with medical treatment, only two requested surgery, and the other 36 preferred to tolerate reduced but persistent pain or some side-effects rather than undergo surgery.

    “Unexpectedly, of the 38 women who declared themselves to be dissatisfied with medical treatment, only two requested surgery, and the other 36 preferred to tolerate reduced but persistent pain or some side-effects rather than undergo surgery.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The FSFI has been validated and demonstrated acceptable internal consistency and test-retest reliability.

    “The FSFI also has been validated and demonstrated acceptable internal consistency and test-retest reliability (55,56).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Meston, 2003, Validation of the Female Sexual Function Index (FSFI) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder, J Sex Marital Ther source

      Not checked in the free run.

    • cites [56] Wiegel, 2005, The Female Sexual Function Index (FSFI): cross-validation and development of clinical cutoff scores, J Sex Marital Ther source

      Not checked in the free run.

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

    Interpretationreasoning

    If a new drug has a demonstrated large effect on pain, this does not mean that all patients with endometriosis should use that drug if its safety and tolerability are no better than those of existing alternatives but its cost is much higher.

    “In other words, if a new drug has a demonstrated large effect on pain, this does not mean that all patients with endometriosis should use that drug if its safety and tolerability are no better than those of existing alternatives but its cost is much higher.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    The results of explanatory randomized controlled trials aimed at defining the effect of experimental treatments may not be directly transferable to all patients, because when treating a chronic disorder for years, the effect on pain is one among several factors to be considered.

    “The results of explanatory randomized controlled trials (RCTs) aimed at defining the effect of experimental treatments may not be directly transferable to all patients, because when treating a chronic disorder for years, the effect on pain is one among several factors to be considered.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Occurrence of side-effects associated with medical treatments was actively investigated by research fellows, and this may have led to listing even mild disturbances that otherwise would not have been reported.

    “However, occurrence of side-effects associated with medical treatments was actively investigated by research fellows, and this may have led to listing even mild disturbances that otherwise would not have been reported.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Engaging patients for research on endometriosis management may help in defining those priorities that are most important to them, at the same time advancing truly shared decision making.

    “Engaging patients for research on endometriosis management may help in defining those priorities that are most important to them, at the same time advancing truly shared decision making (69)(70)(71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (69)(70)(71)

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The observed results may be valid only for patients who prefer medical rather than surgical treatment, and may not be generalizable to all patients with endometriosis.

    “Replication of our findings by other investigators is advisable, because the observed results may be valid only for patients who prefer medical rather than surgical treatment, and may not be generalizable to all patients with endometriosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many patients may now easily identify through the internet and patient association websites those referral centers that are in favor of medical treatment.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Patients encountered in everyday practice may have different characteristics from those enrolled in explanatory RCTs.

    “Moreover, patients encountered in everyday practice may have different characteristics from those enrolled in explanatory RCTs.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    The ultimate prognosis and likelihood of success with prolonged first-line medical treatment without stepping up to second-line compounds or surgery is currently unknown or undefined.

    “Despite decades of intensive clinical research, the ultimate prognosis of a woman with symptomatic endometriosis who chooses prolonged medical treatment with first-line drugs instead of surgery is currently unknown.”
    “In other words, the likelihood that a woman will succeed in successfully controlling her complaints and be satisfied with her treatment without having to step up to second-line compounds and eventually to surgery is currently undefined.”

  • The paper relies on this without support.

    Surgery is expensive.

    “Finally, surgery is expensive.”

  • The paper relies on this without support.

    Outcomes of complex surgical procedures are strictly operator dependent and therefore scarcely reproducible.

    “Outcomes of complex surgical procedures are strictly operator dependent and therefore scarcely reproducible.”

  • The paper relies on this without support.

    NETA is very cheap, whereas DNG is costly.

    “Moreover, NETA is very cheap, whereas DNG is costly.”

  • The paper relies on this without support.

    The estrogen component of OC may limit therapeutic efficacy on endometriotic implants, and a shift to progestin monotherapy may improve pain in case of symptom persistence.

    “It was explained that the estrogen included in OC on one hand may prevent potentially detrimental effects of hypoestrogenizing treatments (e.g., vaginal dryness, decrease in bone mineral density, and unfavorable modifications in serum lipid pattern), but on the other hand may limit the therapeutic efficacy on endometriotic implants that, being estrogen sensitive, may retain part of their metabolic”
    “Thus, in case of symptom persistence, a shift to a progestin monotherapy may improve pain.”

  • The paper relies on this without support.

    Changing from NETA to DNG may relieve symptoms to a greater extent, or untoward effects may subside.

    “Therefore, changing from NETA to DNG may relieve symptoms to a greater extent, or untoward effects may subside.”

  • The paper relies on this without support.

    Repeated surgery may become less effective against pain and riskier.

    “Finally, it was explained that repeated surgery, owing to the presence of adhesions distorting abdominal-pelvic anatomy, may become less effective against pain as well as riskier, although precise estimates can not be provided because of paucity of published data.”

  • The paper relies on this without support.

    The maximum cyst diameter for which surgery may be safely avoided in patients aged ≤40 years is currently undefined.

    “However, the maximum cyst diameter for which surgery may be safely avoided in patients aged %40 years is currently undefined.”

  • The paper relies on this without support.

    Many patients may now easily identify through the internet and patient association websites those referral centers that are in favor of medical treatment.

    “In fact, many patients may now easily identify through the internet and patient association websites those referral centers that are in favor of medical treatment.”

  • The paper relies on this without support.

    In Italy, the yearly cost of treatment with the OC combinations used in the study is $188-197/V159-167/£146-154, with NETA $20/V17/£16, and with DNG $861/V730/£672.

    “In Italy, the yearly cost of treatment with the OC combinations used in our study is $188-197/V159-167/£146-154, with NETA $20/V17/£16, and with DNG $861/V730/£672.”
10 of 10

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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.

  • Baseline dysmenorrhea standard deviation exceeds what the scale permits

    Minor

    A score restricted to 0-10 cannot have a standard deviation of 4.8 when its mean is 8.6; even the maximum possible standard deviation for 133 observations is about 3.5. The reported baseline pain-score summary is therefore internally inconsistent.

1 of 1

Cites

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4 of the 95 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Vercellini, P., Donati, A., Ottolini, F., Frassineti, A., Fiorini, J., Nebuloni, V., Frattaruolo, M. P., Roberto, A., Mosconi, P., & Somigliana, E.
Affiliations
  • University of Milan (IT)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
  • Mario Negri Institute for Pharmacological Research (IT)
Corresponding author
Vercellini, Paolo
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2018-06
Volume
109
Issue
6
Pages
1086-1096
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2018.01.037
OpenAlex
W2806866870
Semantic Scholar
339e71bf2cdd60359dbb75e37ae3b12fb70a24e1
Cited by
64
References
95
Citations by year
2026: 3 · 2025: 4 · 2024: 5 · 2023: 35 · 2022: 2 · 2021: 9 · 2020: 3 · 2019: 2 · 2018: 1
FWCI
4.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • Ministero dell’Istruzione, dell’Università e della Ricerca
  • Ferring Pharmaceuticals
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 › Obstetrics and Gynecology › Gynecological conditions and treatments
Keywords
treatment satisfaction, oral contraception, norethindrone acetate, dienogest, progestins, shared decision-making, pelvic pain, quality of life, sexual function, surgical treatment
MeSH terms
Adolescent, Adult, Contraceptives, Oral, Endometriosis, Female, Humans, Patient Participation, Quality of Life, Surveys and Questionnaires, Sexual Dysfunction, Physiological, Patient Satisfaction, Pelvic Pain, Patient-Centered Care, Young Adult, Self Report

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.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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