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

In the paper

“whereas low-dose oral NETA is probably the best choice for rectovaginal lesions”

What the sources say

• Partly supported

  The Abstract calls low-dose norethindrone acetate an effective, tolerable, inexpensive first-choice medical alternative to repeat surgery for symptomatic rectovaginal lesions in patients who do not seek conception. The claim's broader “best choice for rectovaginal lesions” omits those limits and suggests a preference over all treatments that the paper does not establish. (LLM, conf=0.88)

  cites Vercellini et al., 2005 sourceExperimental — accuracy not yet measured
• Not checked yetcites Vercellini et al., 2009d
• Not checked yetcites Remorgida et al., 2007a

In the paper

“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)”

What the sources say

• Not checked yetcites Missmer et al., 2004 source

In the paper

“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”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Takamura et al., 2009
• Not checked yetcites Seracchioli et al., 2010a

In the paper

“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).”

What the sources say

• Not checked yetcites Attia et al., 2000 source
• Not checked yetcites Igarashi et al., 2005 source
• Not checked yetcites Bukulmez et al., 2008

In the paper

“the induction of experimental disease in mice leads to a completely opposite hormonal receptor expression, as total endometrial PR and PR-B were shown to be increased, and PR-A decreased in animals with endometriosis”

What the sources say

• Not checked yetcites Lee et al., 2009

In the paper

“Numerous clinical studies and systematic reviews have consistently demonstrated that hormonal compounds with very dissimilar pharmacological profiles determine comparable pelvic pain reduction.”

What the sources say

• Not checked yetcites American College of Obstetricians and Gynecologysts, 2000
• Not checked yetcites Kennedy et al., 2005
• Not checked yetcites Royal College of Obstetricians and Gynaecologysts, 2006

In the paper

“and, most importantly, with potentially severe side effects”

In the paper

“several of the compounds included in Table I are associated with uncertain or no efficacy, such as pentoxifylline (Lv et al., 2009) or anti-TNF-a (Lv et al., 2010)”

What the sources say

• Not checked yetcites Lv et al., 2009
• Not checked yetcites Lv et al., 2010

In the paper

“Almost all of the completed clinical trials for which no information on their outcome is available in the public domain were sponsored by pharmaceutical companies.”

In the paper

“The downregulation of PR-B expression as a consequence of the hypermethylation of the gene promoter region has also been observed by Wu et al. (2006) in epithelial cells of some ectopic foci.”

What the sources say

• Not checked yetcites Wu et al., 2006

In the paper

“The extensive epidemiologic information available demonstrates that OCs and progestins are the safest medical alternative for long-term treatments of endometriosis”

What the sources say

• Not checked yetcites American College of Obstetricians and Gynecologysts, 2010
• Not checked yetcites Cibula et al., 2010
• Not checked yetcites Hannaford et al., 2010

In the paper

“In fact, histological examination of endometriotic lesions excised after treatment with letrozole shows preservation of endometrial glands and high stromal proliferative activity (Remorgida et al., 2007a).”

What the sources say

• Not checked yetcites Remorgida et al., 2007a

In the paper

“and not inferior to danazol, GnRH agonists and aromatase inhibitors”

What the sources say

• Not checked yetcites Vercellini et al., 1993 source
• Not checked yetcites Vercellini et al., 1996 source
• Not checked yetcites Prentice et al., 2000

In the paper

“When the efficacy of letrozole plus norethisterone acetate (NETA) was compared with that of NETA alone in women with rectovaginal endometriosis (Ferrero et al., 2009b), the reported intensity of pelvic pain was slightly lower in the combined regimen group”

What the sources say

• Not checked yetcites Ferrero et al., 2009b

In the paper

“Aromatase inhibitors seems effective in treating severe postmenopausal endometriosis through blockade of extraovarian estrogen production (American College of Obstetricians and Gynecologists, 2008)”

What the sources say

• Not checked yetcites American College of Obstetricians and Gynecologists, 2008

In the paper

“The results consistently confirmed that progestins and OCs are effective in relieving pain”

What the sources say

• Not checked yetcites Vercellini et al., 1993 source
• Not checked yetcites Vercellini et al., 1996 source
• Not checked yetcites Prentice et al., 2000

In the paper

“owing to the side effects of letrozole (mainly joint pain and myalgia), satisfaction with treatment was higher in subjects who used NETA alone”

What the sources say

• Not checked yetcites Ferrero et al., 2009b

In the paper

“Several lines of evidence support the role of OCs in the tertiary prevention of endometriomas.”

In the paper

“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).”

What the sources say

• Not checked yetcites Takamura et al., 2009
• Not checked yetcites Seracchioli et al., 2010a

In the paper

“prolonged medical therapies may be needed for endometriosis, as for most chronic inflammatory disorders in general”

In the paper

“that can be effectively cured by definitive surgery (Shakiba et al., 2008)”

What the sources say

• Not checked yetcites Shakiba et al., 2008 source

In the paper

“Endometriosis is an estrogen-dependent chronic inflammatory disease (Giudice, 2010)”

What the sources say

• Not checked yetcites Giudice, 2010 source

In the paper

“Because this implies prolonged periods of treatments, only medications with a favourable safety/tolerability/efficacy/cost profile should be chosen.”

• Also stated in: § The unpalatable taste of medical therapies · hedged

  “Consequently, if medical treatment is indicated, it might be required for years, or until the patient seeks conception.”

In the paper

“the principal modality to interfere with endometriosis metabolism is still hormonal manipulation”

• Also stated in: § The unpalatable taste of medical therapies · hedged

  “At present, it appears that the principal modality to effectively achieve adequate lesion suppression and interfere with endometriosis progression is still hormonal manipulation.”

In the paper

“Therefore, medical therapy constitutes an important alternative or complement to surgery.”

In the paper

“suppression instead of elimination of implants is the only realistic objective of pharmacological intervention”

• Also stated in: § The unpalatable taste of medical therapies · plain

  “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)”

What the sources say

• Not checked yetcites Evers, 1987 source

In the paper

“Women with endometriosis tend to undergo a great deal of suffering”

What the sources say

• Not checked yetcites Vercellini et al., 2008a
• Not checked yetcites Vercellini et al., 2009c
• Not checked yetcites Allen et al., 2009

In the paper

“Conservative surgical treatment for symptomatic endometriosis is frequently associated with only partial relief of pelvic pain or its recurrence.”

• Also stated in: § Introduction · plain

  “Because conservative surgery is often associated with only partial relief or recurrence of symptoms (Vercellini et al., 2009a,b)”

What the sources say

• Not checked yetcites Vercellini et al., 2009a,b

In the paper

“This would explain why 9% of patients do not respond to progestin treatment (Guo, 2009).”

What the sources say

• Not checked yetcites Guo, 2009

In the paper

“Rising et al. (2008) demonstrated a major gap between information submitted to the Food and Drug Administration regarding new drug applications during the period 2001-2002, and information eventually reaching medical journals.”

What the sources say

• Not checked yetcites Rising et al., 2008

In the paper

“The majority of these discrepancies were in favour of the new drug.”

What the sources say

• Not checked yetcites Rising et al., 2008

In the paper

“Therefore, pain relief per se may not be the main factor for the choice of the drug to be used.”

In the paper

“Trials with favourable outcomes were nearly five times as likely to be published as those with unfavourable outcomes”

What the sources say

• Not checked yetcites Rising et al., 2008

In the paper

“Therefore, it cannot be excluded that secondary events, such as the increased inflammatory response observed in ectopic endometrium, may contribute to the differential receptor expression pattern demonstrated in some endometriotic lesions.”

In the paper

“Clearly, when these combined regimens are used for endometriosis, it is impossible to assess how much of the effect on pain is related to which of the two medications (Remorgida et al., 2007a).”

What the sources say

• Not checked yetcites Remorgida et al., 2007a

In the paper

“as it has been demonstrated that prostaglandins are among the most potent inducers of aromatase activity in endometriotic cells (Noble et al., 1997)”

What the sources say

• Not checked yetcites Noble et al., 1997 source

In the paper

“it has been inferred that evidently no optimal drug for endometriosis yet exists”

In the paper

“although several clinical trials evaluating the efficacy of various new compounds for endometriosis are listed as completed at ClinicalTrials.gov, the results of only a few have been published (Guo et al., 2009)”

What the sources say

• Not checked yetcites Guo et al., 2009

In the paper

“Therefore, pharmacological destruction of pelvic implants, if at all possible, would carry a high risk of damage to normally located mucosa, with potential consequences on menstrual pattern, fertility, and future pregnancies.”

In the paper

“discrepancies have been observed between type of outcomes, statistical analyses and conclusions presented in new drug applications and those appearing in journal articles”

What the sources say

• Not checked yetcites Rising et al., 2008

In the paper

“and a relevant amount of data on primary outcomes has not been reported”

What the sources say

• Not checked yetcites Rising et al., 2008

In the paper

“the receptor pattern and the biologic behaviour of the two mucosae are substantially similar (Noel et al., 2010)”

What the sources say

• Not checked yetcites Noel et al., 2010 source

In the paper

“endometriosis appears to originate from intrauterine endometrium”

What the sources say

• Not checked yetcites Noel et al., 2010 source

In the paper

“The only current, meaningful modality to substantially alleviate pain is suppression of ovarian function and induction of a steady hormonal condition, anovulation and, eventually, amenorrhoea.”

In the paper

“Other pharmacological compounds do not seem to guarantee better long-term results and are much more expensive.”

In the paper

“and its suppression should substantially decrease the likelihood of cyst reappearance after laparoscopic treatment”

In the paper

“Thus, the solution to avoid repetitive short-term medical treatments and multiple laparoscopies appears already at hand (Seracchioli et al., 2009)”

What the sources say

• Not checked yetcites Seracchioli et al., 2009

In the paper

“Taking into account only efficacy analyses, and excluding dropouts with the justification that complete pain diaries are not available, usually determines an overestimate of treatment efficacy and tolerability.”

In the paper

“Unfortunately, it is taken for granted that an effective pharmacological therapy with such characteristics is lacking, when the available scientific information shows a different scenario.”

In the paper

“Alternatively, if the antalgic properties of a drug are to be shown, what better than a placebo-controlled study, given that the placebo-effect is short-lived in this clinical condition (Fedele et al., 1989).”

What the sources say

• Not checked yetcites Fedele et al., 1989 source

In the paper

“Other pharmacological compounds do not seem to guarantee better long-term results and are much more expensive.”

In the paper

“One of the methods to sway the evidence could be selecting the outcome in relation to the 'experimental' compound being investigated (Lee et al., 2008).”

What the sources say

• Not checked yetcites Lee et al., 2008 source

In the paper

“However, six RCTs have already demonstrated that various treatments used for the relief of pain in women with symptomatic endometriosis are far superior to placebo (Telimaa et al., 1987;Dlugi et al., 1990;Fedele et al., 1993;Bergqvist et al., 1998;Harada et al., 2008;Strowitzki et al., 2010b).”

What the sources say

• Not checked yetcites Telimaa et al., 1987 source
• Not checked yetcites Dlugi et al., 1990 source
• Not checked yetcites Fedele et al., 1993 source

In the paper

“If the number of dropouts is substantially different between two treatment arms, their exclusion may easily result in a spurious demonstration of equivalence of effect size or 'non-inferiority'.”

In the paper

“progestins and OCs may benefit the majority of patients with symptomatic or recurring endometriosis”

In the paper

“The consequences of endometriosis relapse on reproductive performance may be particularly detrimental, owing to peritoneal as well as gonadal damage caused by both recurrent disease and repeated surgical trauma (Vercellini et al., 2009e).”

What the sources say

• Not checked yetcites Vercellini et al., 2009e

In the paper

“Therefore, the possibility of preventing recurrences after conservative surgery is essential to achieve an acceptable quality of life and to preserve the already reduced reproductive potential (Rogers et al., 2009).”

What the sources say

• Not checked yetcites Rogers et al., 2009

In the paper

“implementation of a tertiary prevention strategy with OCs or progestins after surgery is associated with a decrease in symptoms and lesions recurrence”

What the sources say

• Not checked yetcites Vercellini et al., 2008b
• Not checked yetcites Seracchioli et al., 2009
• Not checked yetcites Takamura et al., 2009

In the paper

“There are huge differences in the annual cost of therapy depending on the type of medication chosen, ranging from E18 for low-dose NETA to around E2100 for aromatase inhibitors or GnRH agonists (Vercellini et al., 2009d).”

What the sources say

• Not checked yetcites Vercellini et al., 2009d

In the paper

“Concerning prevention of endometrioma recurrence, OCs are extremely effective whether used continuously or cyclically”

In the paper

“whereas NETA appears to be the preferable compound in patients with rectovaginal disease.”

In the paper

“The available evidence supports the notion that, with regard to pain relief, OCs used continuously is a worthy option in women with peritoneal and ovarian lesions”