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Potentized estrogen in homeopathic treatment of endometriosis-associated pelvic pain: A 24-week, randomized, double-blind, placebo-controlled study

  • Marcus Zulian Teixeira
    Correspondence
    Corresponding author. Hospital das Clínicas da FMUSP, Departamento de Ginecologia e Obstetrícia, Av. Dr. Enéas de Carvalho Aguiar, 255, 10° andar, sala 10.166, 05403-000 São Paulo/SP, Brazil.
    Affiliations
    Department of Obstetrics and Gynecology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
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  • Sérgio Podgaec
    Affiliations
    Department of Obstetrics and Gynecology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil

    Jewish Teaching and Research Institute, Albert Einstein Hospital, Sao Paulo, Brazil
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  • Edmund Chada Baracat
    Affiliations
    Department of Obstetrics and Gynecology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
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Published:January 24, 2017DOI:https://doi.org/10.1016/j.ejogrb.2017.01.052

      Abstract

      Objective

      To evaluate the efficacy and safety of potentized estrogen compared to placebo in homeopathic treatment of endometriosis-associated pelvic pain (EAPP).

      Study design

      The present was a 24-week, randomized, double-blind, placebo-controlled trial that included 50 women aged 18–45 years old with diagnosis of deeply infiltrating endometriosis based on magnetic resonance imaging or transvaginal ultrasound after bowel preparation, and score ≥ 5 on a visual analogue scale (VAS: range 0 to 10) for endometriosis-associated pelvic pain. Potentized estrogen (12cH, 18cH and 24cH) or placebo was administered twice daily per oral route. The primary outcome measure was change in the severity of EAPP global and partial scores (VAS) from baseline to week 24, determined as the difference in the mean score of five modalities of chronic pelvic pain (dysmenorrhea, deep dyspareunia, non-cyclic pelvic pain, cyclic bowel pain and/or cyclic urinary pain). The secondary outcome measures were mean score difference for quality of life assessed with SF-36 Health Survey Questionnaire, depression symptoms on Beck Depression Inventory (BDI), and anxiety symptoms on Beck Anxiety Inventory (BAI).

      Results

      The EAPP global score (VAS: range 0 to 50) decreased by 12.82 (P< 0.001) in the group treated with potentized estrogen from baseline to week 24. Group that used potentized estrogen also exhibited partial score (VAS: range 0 to 10) reduction in three EAPP modalities: dysmenorrhea (3.28; P< 0.001), non-cyclic pelvic pain (2.71; P = 0.009), and cyclic bowel pain (3.40; P< 0.001). Placebo group did not show any significant changes in EAPP global or partial scores. In addition, the potentized estrogen group showed significant improvement in three of eight SF-36 domains (bodily pain, vitality and mental health) and depression symptoms (BDI). Placebo group showed no significant improvement in this regard. These results demonstrate superiority of potentized estrogen over placebo. Few adverse events were associated with potentized estrogen.

      Conclusions

      Potentized estrogen (12cH, 18cH and 24cH) at a dose of 3 drops twice daily for 24 weeks was significantly more effective than placebo for reducing endometriosis-associated pelvic pain.
      Trial registration: ClinicalTrials.gov Identifier: NCT02427386.

      Keywords

      Introduction

      Endometriosis is an estrogen-dependent condition characterized by presence of extrauterine endometrial tissue and it affects 10 to 15% of women of reproductive age [
      • Bellelis P.
      • Dias Jr., J.A.
      • Podgaec S.
      • Gonzalez M.
      • Baracat E.C.
      • Abrao M.S.
      Epidemiological and clinical aspects of pelvic endometriosis − a case series.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Peterson C.M.
      • et al.
      Pain typology and incident endometriosis.
      ]. While diagnostic certainty requires surgery, the accuracy of non-invasive methods for diagnosis of deep endometriosis, such as magnetic resonance imaging (MRI) and transvaginal ultrasound (TVU), is quite high when performed by experienced professionals [
      • Chapron C.
      • Fauconnier A.
      • Dubuisson J.B.
      • Barakat H.
      • Vieira M.
      • Bréart G.
      Deep infltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease.
      ,
      • Fauconnier A.
      • Chapron C.
      Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
      ,
      • Abrao M.S.
      • Gonçalves M.O.
      • Dias Jr., J.A.
      • Podgaec S.
      • Chamie L.P.
      • Blasbalg R.
      Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis.
      ,
      • Goncalves M.O.
      • Dias Jr., J.A.
      • Podgaec S.
      • Averbach M.
      • Abrão M.S.
      Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis.
      ,
      • Goncalves M.O.
      • Podgaec S.
      • Dias Jr., J.A.
      • Gonzalez M.
      • Abrao M.S.
      Transvaginal ultrasonography with bowel preparation is able to predict the number of lesions and rectosigmoid layers affected in cases of deep endometriosis, defining surgical strategy.
      ,
      • Hudelist G.
      • English J.
      • Thomas A.E.
      • Tinelli A.
      • Singer C.F.
      • Keckstein J.
      Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis.
      ,
      • Vimercati A.
      • Achilarre M.T.
      • Scardapane A.
      • et al.
      Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance-colonography for the presurgical staging of deep infiltrating endometriosis.
      ,
      • Menakaya U.
      • Infante F.
      • Condous G.
      Consensus on current management of endometriosis.
      ].
      Endometriosis-associated pelvic pain (EAPP) encompasses dysmenorrhea, deep dyspareunia, non-cyclic pelvic pain, cyclic bowel pain and/or cyclic urinary pain. The most common treatment includes nonsteroidal anti-inflammatory drugs, combined oral contraceptives, and progestins. Although partially effective, most of these options are associated with systemic side effects, while the need for repeated or regular administration impairs long-term acceptability, resulting in decreased efficacy [
      • Rodgers A.K.
      • Falcone T.
      Treatment strategies for endometriosis.
      ,
      • Dunselman G.A.
      • Vermeulen N.
      • Becker C.
      • et al.
      ESHRE guideline: management of women with endometriosis.
      ].
      Just as other complementary and alternative therapies [
      • Johnson N.P.
      • Hummelshoj L.
      World endometriosis society montpellier consortium: consensus on current management of endometriosis.
      ], homeopathy might represent an option for women with symptomatic endometriosis. The theoretical-practical model underlying homeopathic therapeutics is based on four pillars: therapeutic similitude (similia similibus curentur, likes heal likes); homeopathic pathogenetic trials (similar to phase 1 clinical pharmacological trials); use of potentized medicines (prepared through serial dilution and agitation); and individualization of treatment (drug selection based on the full picture of signs and symptoms exhibited by each patient). In clinical practice, patients are prescribed medicines previously shown to elicit similar signs and symptoms on healthy subjects (so-called primary, direct or pathogenetic effects of medicines) to trigger a homeostatic reaction (secondary, rebound or paradoxical effect) in the body against its ongoing disorders [
      • Teixeira M.Z.
      Scientific evidence of the homeopathic epistemological model.
      ,
      • Teixeira M.Z.
      Rebound effect of modern drugs: serious adverse event unknown by health professionals.
      ]. Any (natural or synthetic) substance might be used as homeopathic medicine provided it elicits similar pathogenetic effects (or adverse events, in the terms of modern pharmacology) on healthy subjects.
      To broaden the scope of action of similitude-based treatment, starting 2003, we developed a systematic method of application of the curative rebound effect of modern drugs. Within this context, we suggest giving patients drugs that induce adverse events similar to the full picture of their signs and symptoms, but in highly diluted doses (i.e., homeopathic potencies) to trigger a curative (homeostatic, rebound or homeopathic) reaction [
      • Teixeira M.Z.
      Homeopathic use of modern medicines: utilisation of the curative rebound effect.
      ,
      • Teixeira M.Z.
      New homeopathic medicines: use of modern drugs according to the principle of similitude.
      ,
      • Teixeira M.Z.
      ‘New Homeopathic Medicines’ database: a project to employ conventional drugs according to the homeopathic method of treatment.
      ]. The resulting proposal is available at an open-access website (http://www.newhomeopathicmedicines.com) [
      • Teixeira M.Z.
      New Homeopathic Medicines: use of modern drugs according to the principle of similitude.
      ].
      In the present article, we describe the results of the just mentioned method to individualized homeopathic treatment of EAPP according to a pre-set protocol [
      • Teixeira M.Z.
      • Podgaec S.
      • Baracat E.C.
      Homeopathic treatment of chronic pelvic pain in women with endometriosis.
      ,
      • Teixeira M.Z.
      • Podgaec S.
      • Baracat E.C.
      Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis.
      ]. There we consider using potentized estrogen for EAPP treatment, because this hormone elicits, as adverse events (or pathogenetic effects), a set of signs and symptoms very similar to the one of endometriosis, including endometrial hyperplasia, pelvic pain, depression, anxiety, insomnia and migraine, among others.

      Materials and methods

      Study design

      The study consisted of a 24-week randomized clinical trial in which we investigated the efficacy and safety of three homeopathic potencies of estrogen (12cH, 18cH and 24cH) or placebo (1:1 ratio). The potencies were administered sequentially every eight weeks to women with pelvic pain associated with deep endometriosis lesions (totally or partially) refractory to conventional treatment (hormonal therapy and/or nonsteroidal anti-inflammatory drugs). The participants were recruited in 2014 at Endometriosis Unit of Gynecology Division, Clinical Hospital, School of Medicine, University of Sao Paulo, which was the study setting. The study protocol had institutional research ethics committee approval and all the participants provided written informed consent.

      Participants

      Table 1 shows the primary (endometriosis-related) inclusion criteria. Patients who met these criteria were analyzed for secondary (homeopathic-related) inclusion criteria (a priori or pre-individualization of patients vis-a-vis the adverse events caused by estrogen, i.e., pathogenetic effects of estrogen). Among patients who met the primary inclusion criteria, only the ones who exhibited a set of signs and symptoms similar to the one corresponding to the adverse events caused by estrogen (anxiety, depression, insomnia, migraine and constipation, among others) were selected to participate in the study. Described in full detail in the aforementioned protocol [
      • Teixeira M.Z.
      • Podgaec S.
      • Baracat E.C.
      Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis.
      ], individualization of treatment according to similarity of signs and symptoms is a sine qua non requisite for the development of curative homeostatic response (clinical efficacy) and must mandatorily be included in all homeopathic clinical trials [
      • Teixeira M.Z.
      • Guedes C.H.
      • Barreto P.V.
      • Martins M.A.
      The placebo effect and homeopathy.
      ].
      Table 1Primary (endometriosis-related) inclusion criteria.
      Age 18–45 years old.
      Diagnosis of deeply infiltrating endometriosis based on clinical history and demonstration of lesions on MRI or TVU after bowel preparation.
      Absence of clinical or laboratory signs of menopause or premature ovarian failure.
      Presence of chronic pelvic pain refractory to conventional therapy (one year of use at least).
      Score ≥ 5 on a visual analogue scale (VAS: range 0 to 10; were 0 represents absence of pain and 10 indicates unbearable pain) for EAPP.
      MRI, magnetic resonance imaging; TVU, transvaginal ultrasound; VAS, visual analogue scale; EAPP, endometriosis-associated pelvic pain.

      Preparation of the homeopathic medicine (potentized estrogen)

      Potentized estrogen was prepared from 17-beta-estradiol valerate (batch #12030691A, Pharma Nostra, Sao Paulo, Brazil, 2011) in compliance with the Brazilian Homeopathic Pharmacopeia [
      Farmacopeia Homeopatica Brasileira [Brazilian homeopathic pharmacopoeia].
      ]. The first three steps consisted in serial grinding of 17-beta-estradiol mixed with lactose, followed by dilution 1:100 (each dilution agitated 100 times) until reaching potencies 12cH, 18cH and 24cH. The medication was delivered as drops (30% hydroalcoholic solution) in 30-ml vials including a dropper.

      Randomization and blinding

      The participants were randomly allocated to receive potentized estrogen or placebo in 1:1 ratio. The randomization sequence was created by an independent supervisor using a random number generator. Both physician-investigator and participants were blinded as to the interventions (potentized estrogen or placebo) for the full duration of the study and throughout data analysis. To preserve blinding, both interventions were indistinguishable in appearance and taste.

      Interventions

      Each participant allocated to active treatment group (verum) was scheduled to receive a vial of potentized 17-beta-estradiol, while participants in the placebo group were given identical vials containing hydroalcoholic solution only. After initial assessment and delivery of the first vial of homeopathic medication (potency 12cH) or placebo on visit 1, the participants were evaluated by the physician-investigator every eight weeks (visits 2, 3 and 4) along the duration of the study (24 weeks). On visits 2 and 3 the participants were given new vials of homeopathic medicine (visit 2, week 8, potency 18cH; visit 3, week 16, potency 24cH) or placebo. The study finished on week 24 (visit 4), when the final outcomes were assessed. Potentized estrogen or placebo was administered in a dose of three drops twice daily (every 12 h). Compliance with treatment was assessed based on the return of the used vials.
      All the participants remained under the care of their gynecologists and no changes in the concomitant medication (hormonal therapy and/or nonsteroidal anti-inflammatory drugs) were allowed along the study period to avoid a possible interference of this variable with the assessed outcomes.

      Outcome measures

      Primary outcome measure was change in severity of pelvic pain as determined by modifications of the VAS score (range 0 to 10) for five modalities of EAPP (dysmenorrhea, deep dyspareunia, non-cyclic pelvic pain, cyclic bowel pain and/or cyclic urinary pain). The score was analyzed per individual modalities (EAPP partial score: range 0 to 10) and globally (EAPP global score: range 0 to 50) at baseline (visit 1) and weeks 8 (visit 2), 16 (visit 3) and 24 (visit 4).
      Secondary outcome measures were changes in the scores for quality of life, assessed with SF-36 Health Survey Questionnaire [
      • Ware J.E.
      • Sherbourne C.D.
      The MOS 36-Item short-Form health survey (SF-36). I. conceptual framework and item selection.
      ,
      • Ciconelli R.M.
      • Ferra M.B.
      • Santos W.
      • Meinão I.
      • Quaresma M.R.
      Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36) [Brazilian-Portuguese version of the SF-36. A reliable and valid quality of life outcome measure].
      ]; depressive symptoms on Beck Depression Inventory (BDI; range 0 to 63) [
      • Beck A.T.
      • Steer R.A.
      • Brown G.K.
      Manual of beck depression inventory − II.
      ]; and anxious symptoms on Beck Anxiety Inventory (BAI; range 0 to 63) [
      • Beck A.T.
      • Steer R.A.
      Beck anxiety inventory manual.
      ]. The secondary outcomes were assessed at baseline and at the end of the study (week 24).

      Adverse events

      The incidence and severity of adverse events were assessed at each visit and registered in an ad hoc form. Only adverse events absent in the participants’ previous medical history were considered as potentially related to the drugs and/or withdrawal of treatment.

      Sample size

      Sample size was calculated based on the primary outcome, namely, changes in VAS score for EAPP from baseline (visit 1) to week 24 (visit 4). With conventional treatment [
      • Bayoglu Tekin Y.
      • Dilbaz B.
      • Altinbas S.K.
      • Dilbaz S.
      Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue.
      ] the score reduced by 2.58, on average. In the present (placebo-controlled) study, the pain score ought to decrease by 2.16 to obtain the same difference. With 80% power and 5% significance level the minimum number of participants for a two-tailed test [
      • Kirwood B.R.
      • Sterne J.A.C.
      Essential medical statistics.
      ] ought to be 23 per group. Considering an expected dropout rate of 10% the final sample size was estimated as 50 participants (25 patients per group).

      Data analysis

      Data were analyzed by means of descriptive statistics, and a CONSORT-like flowchart [
      • Begg C.
      • Cho M.
      • Eastwood S.
      • et al.
      Improving the quality of reporting of randomized controlled trials e The CONSORT statement.
      ,
      • Dean M.E.
      • Coulter M.K.
      • Fisher P.
      • Jobst K.A.
      • Walach H.
      Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT.
      ] was plotted to describe the flow of participants through the study. The data were subjected to intention-to-treat (ITT) analysis and per-protocol (PP) analysis at 5% significance level (95% confidence interval). The primary outcome measure was average variation of pain score from first (baseline) to last (week 24) assessment, which was assessed by means of analysis of covariance adjusted to the scores at baseline. The same method was used for evaluation of the secondary outcomes (scores on SF-36, BDI and BAI).
      The data were analyzed per group and along follow up using mean and standard deviation [
      • Kirwood B.R.
      • Sterne J.A.C.
      Essential medical statistics.
      ]. Comparison between groups and time points was performed by means of generalized estimating equations with first-order autoregressive structure, normal marginal distribution and identity link function [
      • McCullagh P.
      • Nelder J.A.
      Generalized linear models.
      ]. Outcome measures that showed statistical significance were subjected to Bonferroni test [
      • Neter J.
      • Kutner M.H.
      • Nachtsheim C.J.
      • Wasserman W.
      Applied linear statistical models.
      ] to establish between which groups and time-points differences in symptoms and scales occurred. The results are described as mean (mean difference − MD) and standard deviation unless stated otherwise.

      Results

      Participants’ characteristics

      A total of 1112 medical records were analyzed and 170 patients met the primary inclusion criteria. Fifty of them also met the secondary inclusion criteria and were randomized to receive treatment (n = 23, potentized estrogen; n = 27, placebo). Of these, 44 participants were included in ITT analysis (n = 19, potentized estrogen; n = 25, placebo). With a dropout rate of 18%, the study was completed by 41 participants (n = 17, potentized estrogen; n = 24, placebo) who were included in PP analysis. Fig. 1 shows the main reasons for study discontinuation.
      Fig. 1
      Fig. 1Flowchart showing the intervention arms of the randomized clinical trial.
      Demographic and disease characteristics, including mean VAS scores (EAPP global and partial scores) were broadly similar at baseline between the two groups (Table 2). Most participants from both groups exhibited high pain scores and deep endometriosis lesions affecting the rectosigmoid. The participants exhibited complete compliance with treatment, as evidenced by the returned vials.
      Table 2Demographic characteristics and disease severities at baseline.
      ParametersPotentized estrogen (n = 23)Placebo (n = 27)
      Age (years, mean ± SD)34.3 ± 5.035.3 ± 4.9
      Main site of endometriotic lesions (% women)
      Retrocervical3041
      Rectosigmoid7059
      EAPP partial scores (VAS: 0–10 points; mean ± SD)
      Dysmenorrhea8.3 ± 2.57.6 ± 2.2
      Deep dyspareunia8.0 ± 2.76.9 ± 2.0
      Acyclical pelvic pain8.1 ± 2.57.1 ± 1.7
      Cyclical bowel pain7.7 ± 2.35.9 ± 3.2
      Cyclical urinary pain4.1 ± 3.63.9 ± 3.6
      EAPP global score (VAS: 0–50 points; mean ± SD)33.7 ± 8.529.4 ± 7.7
      SF-36 (points, mean ± SD)
      Physical functioning46.3 ± 23.654.6 ± 21.9
      Role physical40.2 ± 40.422.2 ± 32.8
      Bodily pain23.4 ± 15.328.3 ± 11.6
      General health34.5 ± 14.535.9 ± 14.6
      Vitality26.5 ± 17.125.6 ± 12.0
      Social functioning32.1 ± 19.940.7 ± 15.7
      Role emotional26.1 ± 34.825.9 ± 37.4
      Mental health30.6 ± 18.536.9 ± 14.5
      BDI (0–63 points, mean ± SD)30.0 ± 13.222.8 ± 6.6
      BAI (0–63 points, mean ± SD)27.0 ± 11.126.1 ± 12.2
      Concomitant medication (% women)
      Hormonal therapy8378
      NSAIDs100100
      EAPP score, endometriosis-associated pelvic pain score; VAS, visual analogue scale; SD, standard deviation; SF-36, SF-36 Health Survey Questionnaire; BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; NSAIDs, nonsteroidal anti-inflammatory drugs.

      Primary outcome measure

      Potentized estrogen was significantly superior to placebo in reducing the EAPP global and partial scores on ITT and PP analysis.

      Change in EAPP global score (VAS: range 0 to 50)

      On ITT analysis for the full treatment period (from baseline to week 24), potentized estrogen was associated with clinically significant reduction of the EAPP global score (MD 12.82; 95% CI 6.74-18.89; P< 0.001). Placebo was not associated with any significant change. Similar results were also observed on PP analysis (MD 12.03; 95% CI 5.32-18.74; P< 0.001) (Fig. 2).
      Fig. 2
      Fig. 2Change in EAPP global score (mean difference − MD) from baseline to week 24 in groups potentized estrogen and placebo (intention-to-treat analysis).
      Also in the intermediate assessments, potentized estrogen was associated with reduction of the EAPP global score on ITT analysis: 0–8 weeks (MD 9.93; 95% CI 6.23-13.63; P< 0.001), and 0–16 weeks (MD 10.60; 95% CI 5.51-15.68; P< 0.001). Similar results were observed also on PP analysis. Placebo showed no significant changes.

      Changes in EAPP partial scores (VAS: range 0 to 10)

      On ITT analysis of the full course of treatment (24 weeks), potentized estrogen was associated with clinically significant reduction of the partial scores in dysmenorrhea (MD 3.28; 95% CI 1.04-5.52; P< 0.001), non-cyclic pelvic pain (MD 2.71; 95% CI 0.36-5.05; P = 0.009), and cyclic bowel pain (MD 3.40; 95% CI 1.12-5.68; P< 0.001). Similar results were also observed on PP analysis. Placebo showed no significant changes (Fig. 3).
      Fig. 3
      Fig. 3Changes in partial scores (mean difference − MD) of three EAPP modalities from baseline to week 24 in groups potentized estrogen and placebo (intention-to-treat analysis): (A) dysmenorrhea, (B) non-cyclic pelvic pain, and (C) cyclic bowel pain.

      Secondary outcome measures

      The secondary outcome measures were subjected to PP analysis (0 and 24 weeks).
      Regarding quality of life, the potentized estrogen group exhibited improvement in three out of eight SF-36 domains: bodily pain (MD −13.71; 95% CI −25.49 to −1.92; P = 0.013), vitality (MD −13.82; 95% CI −26.38 to −1.27; P = 0.022), and mental health (MD −14.35; 95% CI −27.58 to −1.12; P = 0.025). Placebo group showed no significant improvement (Fig. 4).
      Fig. 4
      Fig. 4Changes in scores (mean difference − MD) of three SF-36 domains from baseline to week 24 in groups potentized estrogen and placebo (per-protocol analysis): (A) bodily pain, (B) vitality, and (C) mental health.
      Depression symptoms (BDI score) showed significant improvement in the potentized estrogen group only (MD 11.53; 95% CI 4.16-18.90; P< 0.001) (Fig. 5). It is worth stressing that this group presented significantly higher score on BDI at baseline compared to placebo group (MD 10.13; 95% CI −18.04 to −2.21; P = 0.004). Anxiety symptoms (BAI score) showed significant improvement in both groups (MD 5.43; 95% CI 2.11-8.74; P = 0.001).
      Fig. 5
      Fig. 5Change in the score (mean difference − MD) of depression symptoms (BDI) from baseline to week 24 in groups potentized estrogen and placebo (per-protocol analysis).

      Adverse events

      Adverse event-related withdrawal occurred in only one patient from the potentized estrogen group (spotting). Possible drug-related adverse events occurred in four patients from the potentized estrogen group (nasopharyngitis, leucorrhea and diarrhea) and 11 patients from placebo group (headache, nasopharyngitis, canker sores, nausea, stomach pain, leucorrhea, cystitis, constipation, lichen planus and herpes simplex).

      Discussion

      In the present study, both intention-to-treat and per-protocol analysis demonstrated significant reduction of EAPP in women with endometriosis after 24 weeks of treatment with three homeopathic potencies of 17-beta-estradiol (12cH, 18cH and 24cH) compared to placebo based on the VAS results (EAPP global and partial scores). Presence of deep endometriosis, high EAPP scores at baseline and refractoriness to conventional treatment denote a high degree of severity of disease before treatment and also point to the relevance of the therapeutic response obtained.
      As a function of the need for global treatment of endometriosis [
      • Kennedy S.
      • Bergqvist A.
      • Chapron C.
      • et al.
      ESHRE guideline for the diagnosis and treatment of endometriosis.
      ], the improvement found in the participants’ quality of life (SF-36) and depression symptoms (BDI) indicate that potentized estrogen might be beneficial for the treatment of this condition. Taking also the safety (few adverse events with mild-to-moderate intensity) and low cost of homeopathic treatment, homeopathy might be added to routine conventional treatment of endometriosis as a complementary therapeutic resource [
      • Johnson N.P.
      • Hummelshoj L.
      World endometriosis society montpellier consortium: consensus on current management of endometriosis.
      ], analogous to what occurs with other disorders (upper respiratory tract infections, respiratory allergies, childhood diarrhea, acute otitis media, premenstrual syndrome, menopause, fibromyalgia, chronic fatigue syndrome, attention deficit hyperactivity disorder, among others) and in accordance with favorable evidences demonstrated in systematic reviews and meta-analysis [
      • Linde K.
      • Clausius N.
      • Ramirez G.
      • et al.
      Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials.
      ,
      • Jacobs J.
      • Jonas W.B.
      • Jiménez-Pérez M.
      • Crothers D.
      Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials.
      ,
      • Coulter M.K.
      • Dean M.E.
      Homeopathy for attention deficit/hyperactivity disorder or hyperkinetic disorder.
      ,
      • Davidson J.R.
      • Crawford C.
      • Ives J.A.
      • Jonas W.B.
      Homeopathic treatments in psychiatry: a systematic review of randomized placebo-controlled studies.
      ,
      • Hahn R.G.
      Homeopathy: meta-analyses of pooled clinical data.
      ,
      • Mathie R.T.
      • Lloyd S.M.
      • Legg L.A.
      • et al.
      Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis.
      ].
      Relative to the therapeutic response to the three assessed potencies of 17-beta estradiol used consecutively, we found initial greater improvement (12cH) followed by continuous and progressive effect (18cH and 24cH), indicating therapeutic efficacy regardless of the potency used.
      As study limitations, sample size was small and duration of treatment and follow up was short. Another point concerns the inclusion criteria, as they required diagnosis of endometriosis based on imaging methods, namely, TVU after bowel preparation or MRI, which were selected as a function of their high accuracy when performed by experienced radiologists [
      • Abrao M.S.
      • Gonçalves M.O.
      • Dias Jr., J.A.
      • Podgaec S.
      • Chamie L.P.
      • Blasbalg R.
      Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis.
      ,
      • Goncalves M.O.
      • Dias Jr., J.A.
      • Podgaec S.
      • Averbach M.
      • Abrão M.S.
      Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis.
      ,
      • Goncalves M.O.
      • Podgaec S.
      • Dias Jr., J.A.
      • Gonzalez M.
      • Abrao M.S.
      Transvaginal ultrasonography with bowel preparation is able to predict the number of lesions and rectosigmoid layers affected in cases of deep endometriosis, defining surgical strategy.
      ,
      • Hudelist G.
      • English J.
      • Thomas A.E.
      • Tinelli A.
      • Singer C.F.
      • Keckstein J.
      Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis.
      ,
      • Vimercati A.
      • Achilarre M.T.
      • Scardapane A.
      • et al.
      Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance-colonography for the presurgical staging of deep infiltrating endometriosis.
      ,
      • Menakaya U.
      • Infante F.
      • Condous G.
      Consensus on current management of endometriosis.
      ]. While the limitations derived from the small sample size might be minimized by replicating the protocol used in larger and/or multicenter studies, the dropout rate (18%) points to the difficulty of keeping patients with severe disease and refractory to treatment in a randomized clinical trial over a long period of time. Future observational studies with larger samples and conducted over longer periods of time might consolidate the results found. In addition, imaging methods might also be included in longer lasting studies to quantify the possible reduction of lesions along treatment.
      While the lack of similar studies in the literature made the calculation of sample size difficult, the results reported here will facilitate this estimation in future studies. As a particular strength, we might stress our concern with the methodological quality of the assessed protocol, which led us to strictly comply with inclusion/exclusion criteria, randomization/blinding methods and techniques for data collection, record and analysis.
      To conclude, in the present 24-week, randomized, double-blind, placebo-controlled study, potentized estrogen was associated with significant improvement of EAPP, quality of life and depression symptoms among women with endometriosis. Potentized estrogen might represent an effective and well-tolerated complementary treatment for the pain and mental symptoms of endometriosis.

      Competing interests

      The present study is the postdoctoral research project of Marcus Zulian Teixeira at Department of Obstetrics and Gynecology, School of Medicine, University of Sao Paulo.

      Authors’ contributions

      All the authors participated in the study design, manuscript writing and critical discussion, assuming equal responsibility for the manuscript. MZT, SP and ECB performed the applications for required approvals. MZT recruited and treated patients. MZT, SP and ECB have access to all the data and participated in the analysis and interpretation of the data.

      Funding source

      The present study had no funding source.

      Conflict of interest statement

      MZT, SP, and ECB have no commercial interest, financial interest, and/or other relationship with manufacturers of pharmaceuticals, laboratory supplies, and/or medical devices or with commercial providers of medically related services.

      Acknowledgement

      We thank homeopathic pharmacist Marcia Aparecida Gutierrez (Farmacia Homeopatica Sensitiva, Sao Paulo, Brazil) for preparing and providing gratis the homeopathic medicines used in the present study.

      References

        • Bellelis P.
        • Dias Jr., J.A.
        • Podgaec S.
        • Gonzalez M.
        • Baracat E.C.
        • Abrao M.S.
        Epidemiological and clinical aspects of pelvic endometriosis − a case series.
        Rev Assoc Med Bras. 2010; 56: 467-471
        • Schliep K.C.
        • Mumford S.L.
        • Peterson C.M.
        • et al.
        Pain typology and incident endometriosis.
        Hum Reprod. 2015; 30: 2427-2438
        • Chapron C.
        • Fauconnier A.
        • Dubuisson J.B.
        • Barakat H.
        • Vieira M.
        • Bréart G.
        Deep infltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease.
        Hum Reprod. 2003; 18: 760-766
        • Fauconnier A.
        • Chapron C.
        Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications.
        Hum Reprod Update. 2005; 11: 595-606
        • Abrao M.S.
        • Gonçalves M.O.
        • Dias Jr., J.A.
        • Podgaec S.
        • Chamie L.P.
        • Blasbalg R.
        Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis.
        Hum Reprod. 2007; 22: 3092-3097
        • Goncalves M.O.
        • Dias Jr., J.A.
        • Podgaec S.
        • Averbach M.
        • Abrão M.S.
        Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis.
        Int J Gynaecol Obstet. 2009; 104: 156-160
        • Goncalves M.O.
        • Podgaec S.
        • Dias Jr., J.A.
        • Gonzalez M.
        • Abrao M.S.
        Transvaginal ultrasonography with bowel preparation is able to predict the number of lesions and rectosigmoid layers affected in cases of deep endometriosis, defining surgical strategy.
        Hum Reprod. 2010; 25: 665-671
        • Hudelist G.
        • English J.
        • Thomas A.E.
        • Tinelli A.
        • Singer C.F.
        • Keckstein J.
        Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2011; 37: 257-263
        • Vimercati A.
        • Achilarre M.T.
        • Scardapane A.
        • et al.
        Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance-colonography for the presurgical staging of deep infiltrating endometriosis.
        Ultrasound Obstet Gynecol. 2012; 40: 592-603
        • Menakaya U.
        • Infante F.
        • Condous G.
        Consensus on current management of endometriosis.
        Hum Reprod. 2013; 28: 3162-3163
        • Rodgers A.K.
        • Falcone T.
        Treatment strategies for endometriosis.
        Expert Opin Pharmacother. 2008; 9: 243-255
        • Dunselman G.A.
        • Vermeulen N.
        • Becker C.
        • et al.
        ESHRE guideline: management of women with endometriosis.
        Hum Reprod. 2014; 29: 400-412
        • Johnson N.P.
        • Hummelshoj L.
        World endometriosis society montpellier consortium: consensus on current management of endometriosis.
        Hum Reprod. 2013; 28: 1552-1568
        • Teixeira M.Z.
        Scientific evidence of the homeopathic epistemological model.
        Int J High Dilution Res. 2011; 10: 46-64
        • Teixeira M.Z.
        Rebound effect of modern drugs: serious adverse event unknown by health professionals.
        Rev Assoc Med Bras (1992). 2013; 59: 629-638
        • Teixeira M.Z.
        Homeopathic use of modern medicines: utilisation of the curative rebound effect.
        Med Hypotheses. 2003; 60: 276-283
        • Teixeira M.Z.
        New homeopathic medicines: use of modern drugs according to the principle of similitude.
        Homeopathy. 2011; 100: 244-252
        • Teixeira M.Z.
        ‘New Homeopathic Medicines’ database: a project to employ conventional drugs according to the homeopathic method of treatment.
        Eur J Integr Med. 2013; 5: 270-278
        • Teixeira M.Z.
        New Homeopathic Medicines: use of modern drugs according to the principle of similitude.
        Marcus Zulian Teixeira, São Paulo2010 (Available at)
        • Teixeira M.Z.
        • Podgaec S.
        • Baracat E.C.
        Homeopathic treatment of chronic pelvic pain in women with endometriosis.
        (ClinicalTrials.gov Identifier: NCT02427386. Available at:)
        • Teixeira M.Z.
        • Podgaec S.
        • Baracat E.C.
        Protocol of randomized controlled trial of potentized estrogen in homeopathic treatment of chronic pelvic pain associated with endometriosis.
        Homeopathy. 2016; 105: 240-249
        • Teixeira M.Z.
        • Guedes C.H.
        • Barreto P.V.
        • Martins M.A.
        The placebo effect and homeopathy.
        Homeopathy. 2010; 99: 119-129
      1. Farmacopeia Homeopatica Brasileira [Brazilian homeopathic pharmacopoeia].
        3rd edn. Anvisa, Brasília2011 (Available at:)
        • Ware J.E.
        • Sherbourne C.D.
        The MOS 36-Item short-Form health survey (SF-36). I. conceptual framework and item selection.
        Med Care. 1992; 30 (473e483)
        • Ciconelli R.M.
        • Ferra M.B.
        • Santos W.
        • Meinão I.
        • Quaresma M.R.
        Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36) [Brazilian-Portuguese version of the SF-36. A reliable and valid quality of life outcome measure].
        Rev Bras Reumatol. 1999; 39 (143e150)
        • Beck A.T.
        • Steer R.A.
        • Brown G.K.
        Manual of beck depression inventory − II.
        Psychological Corporation (Harcourt Brace and Company), San Antonio1996
        • Beck A.T.
        • Steer R.A.
        Beck anxiety inventory manual.
        Psychological Corporation (Harcourt Brace and Company), San Antonio1993
        • Bayoglu Tekin Y.
        • Dilbaz B.
        • Altinbas S.K.
        • Dilbaz S.
        Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue.
        Fertil Steril. 2011; 95 (492e496)
        • Kirwood B.R.
        • Sterne J.A.C.
        Essential medical statistics.
        2nd edn. Blackwell Science, Massachusetts2006
        • Begg C.
        • Cho M.
        • Eastwood S.
        • et al.
        Improving the quality of reporting of randomized controlled trials e The CONSORT statement.
        JAMA. 1996; 276 (637e639)
        • Dean M.E.
        • Coulter M.K.
        • Fisher P.
        • Jobst K.A.
        • Walach H.
        Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT.
        Homeopathy. 2007; 96 (42e45)
        • McCullagh P.
        • Nelder J.A.
        Generalized linear models.
        2nd ed. Chapman and Hall, New York1989
        • Neter J.
        • Kutner M.H.
        • Nachtsheim C.J.
        • Wasserman W.
        Applied linear statistical models.
        4th edn. Richard D. Irwin, Illinois1996 (1408)
        • Kennedy S.
        • Bergqvist A.
        • Chapron C.
        • et al.
        ESHRE guideline for the diagnosis and treatment of endometriosis.
        Hum Reprod. 2005; 20: 2698-2704
        • Linde K.
        • Clausius N.
        • Ramirez G.
        • et al.
        Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials.
        Lancet. 1997; 350: 834-843
        • Jacobs J.
        • Jonas W.B.
        • Jiménez-Pérez M.
        • Crothers D.
        Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials.
        Pediatr Infect Dis J. 2003; 22: 229-234
        • Coulter M.K.
        • Dean M.E.
        Homeopathy for attention deficit/hyperactivity disorder or hyperkinetic disorder.
        Cochrane Database Syst Rev. 2007; 4: CD005648
        • Davidson J.R.
        • Crawford C.
        • Ives J.A.
        • Jonas W.B.
        Homeopathic treatments in psychiatry: a systematic review of randomized placebo-controlled studies.
        J Clin Psychiatry. 2011; 72: 795-805
        • Hahn R.G.
        Homeopathy: meta-analyses of pooled clinical data.
        Forsch Komplementmed. 2013; 20: 376-381
        • Mathie R.T.
        • Lloyd S.M.
        • Legg L.A.
        • et al.
        Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis.
        Syst Rev. 2014; 3: 142