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Cited by 181Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementGynecological conditions and treatments

“Waiting for Godot”: a commonsense approach to the medical treatment of endometriosis

Open access
Vercellini, P., Crosignani, P., Somigliana, E., Vigano, P., Frattaruolo, M. P., Fedele, L.·2011·Human Reproduction
DOI 10.1093/humrep/deq302
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Abstract

Conservative surgical treatment for symptomatic endometriosis is frequently associated with only partial relief of pelvic pain or its recurrence. Therefore, medical therapy constitutes an important alternative or complement to surgery. However, no available compound is cytoreductive, and suppression instead of elimination of implants is the only realistic objective of pharmacological intervention. Because this implies prolonged periods of treatments, only medications with a favourable safety/tolerability/efficacy/cost profile should be chosen. In the past few years, innumerable new drugs for endometriosis, which would interfere with several hypothesized pathogenic mechanisms, have been studied and their use foreseen. However, robust evidence of in vivo safety and efficacy is lacking and, at the moment, the principal modality to interfere with endometriosis metabolism is still hormonal manipulation. Regrettably, in spite of consistent demonstration of a major effect on pain even in patients with deeply infiltrating lesions, progestins are underestimated and dismissed in favour of more scientifically fashionable and up-to-the-minute alternatives. Moreover, oral contraceptives (OCs) dramatically reduce the rate of post-operative endometrioma recurrence and should now be considered an essential part of long-term therapeutic strategies in order to limit further damage to future fertility. Finally, women who have used OC for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer. To avoid the several subtle modalities for distorting facts and orientating opinions in favour of specific compounds, progestins and monophasic OC used continuously are here proposed as the reference comparator in all future randomized controlled trials on medical treatment for endometriosis.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that medical treatment for endometriosis should aim at long-term suppression rather than cure, and that progestins and continuous monophasic oral contraceptives (OCs) are effective, safe, inexpensive options that are underused. It proposes these as reference comparators in future randomized controlled trials and highlights postoperative OC use for preventing endometrioma and symptom recurrence.

Key findings

  • No available drug is cytoreductive; suppression is the only realistic objective, so prolonged therapy is needed. In nine controlled trials identified from 1990–2010, progestins and OCs relieved pain and were generally not inferior to danazol, GnRH agonists, and aromatase inhibitors.
  • Postoperative OC use dramatically reduced endometrioma recurrence in three controlled studies, with odds ratios from 0.04 (Takamura et al., 2009) to 0.32 (Seracchioli et al., 2010a). Two RCTs showed reduced dysmenorrhoea recurrence with postoperative progestin/OC versus expectant management (OR 0.14 and 0.32).
  • Recurrence after conservative surgery is common: 10% at 1 year, 25% at 3 years, and 45% at 5 years (Evers et al., 1991); >20% at 2 years and 40–50% at 5 years (Guo, 2009); endometrioma recurrence reportedly 30–50% after 2–5 years.
  • Costs are substantial: global endometriosis cost was $18.8–$22 billion per year based on 2002 US data; annual therapy costs ranged from €18 for low-dose norethisterone acetate to about €2100 for aromatase inhibitors or GnRH agonists, and about €4200 if combined.

Methods

  • Narrative review/opinion article; no primary data. A MEDLINE search from January 1990 to July 2010 in English (MeSH terms: endometriosis, progestins, OCs, medical therapy) identified nine controlled trials comparing a progestin or OC with an alternative hormonal compound.
  • A second MEDLINE search from January 2000 to July 2010 (MeSH terms: endometriosis, endometrioma, recurrence, OC, laparoscopy) identified three controlled studies on long-term postoperative OC use and endometrioma recurrence.
  • The paper also cites RCTs on postoperative progestin/OC use for symptom recurrence; study quality was not assessed, and no meta-analysis was performed.

Limitations

  • Stated: study quality was not assessed in the MEDLINE search; information on the cost of endometriosis to patients and society is limited.
  • Evident: this is a narrative/opinion review with explicit advocacy for progestins and OCs, without systematic quality appraisal, risk-of-bias assessment, or meta-analysis; conclusions may be influenced by selected citation and interpretation of the literature.

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

Integrity signals

Registry

Crossref · 10.1093/humrep/deq302

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Women who have used oral contraceptives for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer.

    “women who have used OC for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer”
    • Also stated in: § Life is now! · hedged
      “women who have used OC for prolonged periods might be reassured that they will be protected from an increase in risk of endometriosis-associated ovarian cancer (Missmer et al., 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Missmer et al., 2004 source

      Not checked in the free run.

  • Findingnone given

    Progestins have a major effect on pain even in patients with deeply infiltrating lesions.

    “in spite of consistent demonstration of a major effect on pain even in patients with deeply infiltrating lesions, progestins are underestimated and dismissed in favour of more scientifically fashionable and up-to-the-minute alternatives”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Robust evidence of in vivo safety and efficacy is lacking for new drugs for endometriosis.

    “However, robust evidence of in vivo safety and efficacy is lacking and, at the moment, the principal modality to interfere with endometriosis metabolism is still hormonal manipulation.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Oral contraceptives dramatically reduce the rate of post-operative endometrioma recurrence.

    “oral contraceptives (OCs) dramatically reduce the rate of post-operative endometrioma recurrence”
    • Also stated in: § Prevention of recurrence? Yes we can! · boosted
      “A dramatic reduction in the risk of reappearance of endometriotic cysts in OC users was consistently observed independent of cyclic or continuous use, with odds ratios varying from 0.04 (Takamura et al., 2009) to 0.32 (Seracchioli et al., 2010a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Takamura et al., 2009

      Not checked in the free run.

    • cites Seracchioli et al., 2010a

      Not checked in the free run.

  • Findingcitation

    A decreased PR-B/PR-A ratio has been demonstrated in ectopic tissue and in eutopic endometrium of women with endometriosis, albeit not consistently.

    “A decreased PR-B/PR-A ratio has been demonstrated not only in ectopic tissue (Attia et al., 2000), but also in eutopic endometrium of women with endometriosis (Igarashi et al., 2005), albeit not consistently (Bukulmez et al., 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Attia et al., 2000 source

      Not checked in the free run.

    • cites Igarashi et al., 2005 source

      Not checked in the free run.

    • cites Bukulmez et al., 2008

      Not checked in the free run.

  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1
  • May combine two claims. 14

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

    Findingnone given

    No available compound for endometriosis is cytoreductive.

    “However, no available compound is cytoreductive, and suppression instead of elimination of implants is the only realistic objective of pharmacological intervention.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingcitation

    Progestins and oral contraceptives are generally well-tolerated.

    “generally well-tolerated”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Vercellini et al., 1993 source

      Not checked in the free run.

    • cites Vercellini et al., 1996 source

      Not checked in the free run.

    • cites Prentice et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    After treatment discontinuation, symptoms recurred without significant between-group differences, demonstrating that aromatase inhibitors are neither cytoreductive nor curative.

    “After treatment discontinuation, symptoms recurred without significant between-group differences, demonstrating that also aromatase inhibitors are neither cytoreductive nor curative.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ferrero et al., 2009b

      Not checked in the free run.

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

    Interpretationreasoning

    Disease control may result in an acceptable improvement of quality of life only if safety, tolerability and costs of medications are taken into adequate account.

    “Disease control may result in an acceptable improvement of quality of life, only if also safety, tolerability and costs of medications are taken into adequate account.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The risk of major untoward effects may be acceptable in oncology context, but not in otherwise healthy women affected by a benign condition.

    “The risk of major untoward effects may be acceptable in the above clinical context, but not in otherwise healthy women affected by a benign condition.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    There are substantial economic implications if efficacy is overestimated and the medication over-utilized, given that usually new molecules are among the most costly drugs on the market.

    “there are also substantial economic implications if efficacy is overestimated and the medication over-utilized, given that usually new molecules are among the most costly drugs on the market”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: New molecules are usually among the most costly drugs on the market.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    It is unclear if increased expression of aromatase constitutes the reason for survival and proliferation of regurgitated endometrial cells, or if it is the consequence of local inflammation.

    “However, again it is unclear if the increased expression of this cytochrome P-450 complex constitutes the very reason for survival and proliferation of regurgitated endometrial cells, or if it is the consequence of local inflammation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    During the reproductive period, aromatase inhibitors stimulate ovarian function, reducing hypothalamic-pituitary estrogen feedback, with consequent rise in GnRH secretion, elevations in FSH and LH, and augmented follicular development.

    “Moreover, during the reproductive period, aromatase inhibitors stimulate ovarian function, as they reduce the hypothalamic-pituitary estrogen feedback, with consequent rise in GnRH secretion, elevations in FSH and LH, and augmented follicular development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    For the present, the therapeutic target is not endometriosis cytoreduction, but suppression, which implies the survival of ectopic implants independently of the drug type, dosage, and duration of use.

    “for the present the therapeutic target is not endometriosis cytoreduction, but suppression, which implies the survival of ectopic implants independently of the drug type, dosage, and duration of use (Evers, 1987)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Evers, 1987 source

      Not checked in the free run.

    • Rests on an assumption: A compound with selective properties only against the ectopic endometrial cell has not yet been synthesized.

  • May combine two claims.

    Premisecitation

    According to Evers et al. (1991), 10% of patients redeveloped signs and symptoms of endometriosis after a 1-year follow-up period, 25% after 3 years and 45% after 5 years.

    “According to Evers et al. (1991), 10% of patients redeveloped signs and symptoms of endometriosis after a 1-year follow-up period, 25% after 3 years and 45% after 5 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Evers et al., 1991

      Not checked in the free run.

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

    Interpretationreasoning

    Excessive hypo-estrogenism as well as hyper-androgenism would considerably undermine safety and tolerability through subjective and metabolic untoward effects.

    “In both cases, subjective and metabolic untoward effects would considerably undermine safety and tolerability.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Study quality was not assessed in the review of controlled trials on progestins and oral contraceptives.

    “Study quality was not assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Prescribing medications for a few months has no clear rationale and exposes women to recurrences of symptoms and lesions and to the risk of repetitive surgery.

    “In fact, prescribing medications for a few months has no clear rationale and exposes women to extenuating recurrences of symptoms and lesions and to the risk of repetitive surgery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Maintaining that progestins and OCs may be of little value in the prevention of endometrioma recurrence and that post-operative medications may cause unnecessary side effects and cost increase seems questionable in light of recent research findings.

    “Maintaining that progestins and OCs may be of a little value in the prevention of endometrioma recurrence and that the use of post-operative medications may cause unnecessary side effects and cost increase seems questionable in light of recent research findings.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The global cost of endometriosis is substantially higher than the estimated costs of Crohn's disease ($865 million) and migraine ($13-17 billion).

    “which is substantially higher than the estimated costs of other chronic disorders, such as Crohn's disease ($865 million) and migraine ($13-17 billion; Rogers et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rogers et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Progestins and OCs are still addressed with scepticism and sometimes not even mentioned among effective therapeutic alternatives.

    “these medications are still addressed with scepticism and sometimes not even mentioned among effective therapeutic alternatives.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    DeCherney (1992) maintains that the endometriosis annual recurrence rate may be as high as 15% and that cumulative rates are 40% after 3-5 years.

    “Also DeCherney (1992) maintains that the endometriosis annual recurrence rate may be as high as 15% and that cumulative rates 40% after 3-5 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DeCherney, 1992

      Not checked in the free run.

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

    Premisecitation

    According to studies based on 2002 US data, the global annual cost of endometriosis, including analgesics, hormonal therapies, gynaecological consultations, hospital admissions, surgical procedures, days off-work and reduced productivity, varies between $18.8 and $22 billion.

    “According to studies based on 2002 US data, the global cost of the disease (including analgesics, hormonal therapies, gynaecological consultations, hospital admissions, surgical procedures, days off-work and reduced productivity) varies between $18.8 and $22 billion per year (Gao et al., 2006;Simoens et al., 2007)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gao et al., 2006 source

      Not checked in the free run.

    • cites Simoens et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Pain symptoms relapse exposes patients to repetitive suffering, frustration, multiple courses of medical therapy and risk of serial surgery.

    “Moreover, pain symptoms relapse exposes patients to repetitive suffering, frustration, multiple courses of medical therapy and risk of serial surgery.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Guo (2009) calculated that the disease relapse rate is higher than 20% at 2 years and 40-50% at 5 years.

    “Recently, Guo (2009) calculated that the disease relapse rate is higher than 20% at 2 years and 40 -50% at 5 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guo, 2009

      Not checked in the free run.

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

    Interpretationreasoning

    The latest pills are generally the most expensive, but not necessarily the most cost-effective.

    “The latest pills are generally the most expensive, but not necessarily the most cost-effective.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Not all women using progestins will be relieved from pain, satisfied with treatment, continue it, or avoid surgery.

    “Not all women using progestins will be relieved from pain, not all will be satisfied with their treatment, not all will continue it and not all will avoid surgery.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The mechanism of action of OCs in preventing endometrioma recurrence seems to be ovulation inhibition.

    “as the mechanism of action seems to be ovulation inhibition.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Misinformation may expose many women with endometriosis to repeated surgery and a decrease in the probability of conception.

    “should be informed in an unbiased manner, as any misinformation may expose many of them to repeated surgery and a decrease in the probability of conception.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    At least two-thirds of women using progestins could substantially ameliorate their health-related quality of life, controlling the disease with marginal associated morbidity.

    “But at least two-thirds of them could substantially ameliorate their health-related quality of life, controlling the disease with marginal associated morbidity.”
    Quote in the paperNot a substantial claim
25 of 25

  • The paper relies on this without support.

    Definitive surgery for endometriosis is generally not accepted by patients wishing to preserve fertility.

    “an option generally not accepted by patients wishing to preserve fertility”

  • The paper relies on this without support.

    Publication of reports in peer-reviewed journals is the most important source of information on novel drugs for physicians who generally have limited clinical experience with the latest treatments.

    “publication of reports in 'peer-reviewed' journals constitutes the most important source of information on novel drugs for physicians who generally have limited clinical experience with the latest treatments”

  • The paper relies on this without support.

    New molecules are usually among the most costly drugs on the market.

    “usually new molecules are among the most costly drugs on the market”

  • The paper relies on this without support.

    A compound with selective properties only against the ectopic endometrial cell has not yet been synthesized.

    “As a compound with selective properties only against the ectopic endometrial cell has not yet been synthesized”

  • The paper relies on this without support.

    Medical therapies for endometriosis are not curative.

    “given that medical therapies for endometriosis are not curative”

  • The paper relies on this without support.

    Medical treatment for endometriosis does not influence reproductive performance of infertile women.

    “Medical treatment for endometriosis does not influence reproductive performance of infertile women.”

  • The paper relies on this without support.

    Dropouts are usually largely dissatisfied because of persisting pain or development of major side effects.

    “In fact, dropouts are usually largely dissatisfied because of persisting pain or development of major side effects.”
7 of 7

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?

  • Estrogen-progestins and progestins appear to be among the compounds that most favorably balance benefits, harms, and costs when hormonal treatments are continued for long periods.

    “Finally, when hormonal treatments are to be continued for long periods, estrogen-progestins and progestins appear to be among the compounds that most favorably balance benefits, harms, and costs (30,31).”

    From A stepped-care approach to symptomatic endometriosis management: A participatory research initiative (2018) · cites this paper as [31]

Cites

1 retracted

Flagged first, then by citations

2 of the 112 references couldn’t be matched to a known paper.

Research works printed but not linked: 18

  1. 2006, Cochrane database of systematic reviews (Online), 18, CD005072
  2. 2005, Fertility and sterility, 81, 290
  3. 2008, MIDDLE EAST FERTIL SOC J, 13, 304
  4. 2009, Cochrane database of systematic reviews (Online), 15, CD004753
  5. 2008, 11, 1533
  6. 2007, Cochrane database of systematic reviews (Online), 18, CD001019
  7. 1991, The British journal of clinical practice, 45, 45
  8. 2009, Cochrane database of systematic reviews (Online), 8, CD007677
  9. 2010, Cochrane database of systematic reviews (Online), 17, CD008088
  10. 2003, Journal of Molecular Endocrinology, 2, 241
  11. 2008, Fertility and sterility, 90, S260
  12. 2000, Cochrane database of systematic reviews (Online), 2, CD002122
  13. 2004, Cochrane database of systematic reviews (Online), 2, CD000346
  14. 2008, 11, 1561
  15. 2007, Cochrane database of systematic reviews (Online), 17, CD000068
  16. 2010, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obst  trique et gyn  cologie du Canada : JOGC, 32, S1
  17. 2008, American journal of obstetrics and gynecology, 198, 504
  18. 2004, Cochrane database of systematic reviews (Online), 3, CD003678

Cited by

Sorted by citations

Related

Authors
Vercellini, P., Crosignani, P., Somigliana, E., Vigano, P., Frattaruolo, M. P., & Fedele, L.
Affiliations
  • University of Milan (IT)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
Corresponding author
Vercellini, P.
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2010-11-11
Volume
26
Issue
1
Pages
3-13
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/deq302
OpenAlex
W2117571760
Semantic Scholar
63311710c2bb2995a9c0e275757690da0a84e5e1
Cited by
180
References
112
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 15 · 2017: 16 · 2016: 13 · 2015: 18 · 2014: 9 · 2013: 25 · 2012: 18
FWCI
23.24
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Human Reproduction (publishedVersion, public-domain)
  • 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 › Obstetrics and Gynecology › Gynecological conditions and treatments
Keywords
endometriosis, progestins, oral contraceptives, hormonal manipulation, endometrioma recurrence, postoperative recurrence, endometriosis-associated ovarian cancer, deep infiltrating endometriosis, pelvic pain, drug safety and tolerability
MeSH terms
Contraceptives, Oral, Endometriosis, Female, Humans, Drugs, Investigational, Randomized Controlled Trials as Topic, Secondary Prevention, Drug-Related Side Effects and Adverse Reactions

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