# Abstract

 

## Context: Resveratrol has been used for the treatment of endometriosis. 

## Objective: To compare resveratrol (40 mg/d) with monophasic contraceptive pill (COC) to COC with placebo for the reduction of pain scores. 

## Design: A randomized clinical trial. 

## Setting: University Hospital. 

## Patients: Women (ages 20 to 50) with laparoscopic diagnosis of endometriosis were eligible for the study. Exclusion criteria: pregnancy, allergy to resveratrol, or contraindications to COC, use of agonists of gonadotropin release hormone or danazol in the last month, or had used depot medroxyprogesterone acetate or Mirena®. 

## Intervention: Subjects were randomized using a computer-generated randomization list to receive COC for 42 days to be taken with identical capsules containing 40 mg of resveratrol or placebo in coded bottles (1:1 ratio). Allocation was concealed in coded, sequenced, opaque-sealed envelopes. 

## Main Outcome: Median pain scores measured with a visual analog scale on day 42. 

## Results: Between 18 June and 6 November 2015, 44 subjects were enrolled. Mean [95% confidence interval (CI)] pain scores on day 0 were 5.4 (4.2 to 6.6) in the placebo group and 5.7 (4.8 to 6.6) in resveratrol groups. After treatment, pain values were [3.9 (2.2 to 5); n = 22] and [3.2 (2.1 to 4.3); n = 22] in the placebo and resveratrol groups, respectively ( *P* = 0.7; Mann-Whitney *U* test). Median (95% CI) difference between groups was 0.75 (--1.6 to 2.3). 

## Conclusion: Resveratrol is not superior to placebo for treatment of pain in endometriosis. Resveratrol, a natural phytoestrogen, has been suggested as a possible treatment option for women with endometriosis. This study is a randomized, double-blinded, placebo-controlled clinical trial. # 2. Results 

## A. Participants Two hundred and forty-three women with diagnosis of endometriosis were screened for acceptance into the study between 18 June and 6 November 2015. Of these, 199 were excluded for not meeting the inclusion criteria. Forty-four subjects were randomly assigned to one of the two treatment regimens. Forty-three women received treatment as allocated. Five women were removed from the PP analysis. One discontinued the study after signing the informed consent, one was removed from the study for intense abnormal uterine bleeding that stopped after medical intervention, and three were lost to follow-up ( [Fig. 1](#) ). <figure> <p><img src="" /></p> <figcaption>Flow diagram of study population randomized to two treatment groups.</figcaption> </figure> For each group, 22 subjects were analyzed as ITT. Outcomes PP were analyzed in 21 and 18 subjects in the resveratrol and placebo arms, respectively. Baseline data of the studied population are depicted in [Table 1](#) . ::::table-wrap

::: caption
**Demographic and Clinical Characteristic of the Studied Population**
:::

Characteristic Resveratrol (n = 220) Placebo (n = 22) *P*Value

______________________________________________________________________

Mean age ± standard deviation (y) 35.4 ± 7.1 32.4 ± 7 0.1 [*^c^*](#)
Ethnic group (n [%]) 1 [*^d^*](#)
White 16 (72) 15 (68)\
Black 6 (28) 7 (32)\
Baseline levels (mean ± standard deviation)\
Pain score (VAS) 5.4 ± 2.6 5.7 ± 2 0.6 [*^e^*](#)
CA-125 (U/mL) [*^a^*](#)^,^[*^b^*](#) 14.1 (3.3 to 49.5) 18.7 (5.7 to 123.6) 0.2 [*^c^*](#)
Prolactin (ng/mL) [*^b^*](#) 12.65 ± 5.9 14.27 ± 6.6 0.4 [*^c^*](#)

Raw values are median (range). Analysis after transformation using *Y* =
log( *Y* ) was performed, and no difference was found using Student *t*
test. Transformed data are shown in [Figure 2](#) .

n = 21 for serum levels; one case of the placebo group dropped out
before collecting blood.

Mann-Whitney *U* test.

Fisher's exact test.

Student *t* test.:::: 

## B. Primary Outcome: Pain Score After 7 days of treatment, pain scores were significantly reduced in the resveratrol group, compared with the placebo group. After 42 days of treatment, however, no difference was observed in pain scores between treatment groups. The median difference between groups was 0.75 \[95% confidence interval (CI): --1.6 to 2.3; [Table 2](#) ; ITT results; *P* = 0.7, Mann-Whitney *U* test\]. Subgroup analysis was performed on subjects that followed protocol and did not use any medication for pain. Final pain scores were not significantly different between groups by PP analysis or by use or not of analgesics ( [Table 2](#) ). Similar results were found using a Student *t* test after data normalization (data not shown). ::::table-wrap
::: caption
**Outcomes Measured in Both Groups**
:::

Characteristic Resveratrol (n = 22) Placebo (n = 22) *P*Value

______________________________________________________________________

Subjects that used pain medication (n) 7 8\
Dipyrone, mg: mean (standard deviation) [n] 1944 (1793) [5] 625 (250) [5] 0.09 [*^c^*](#)
Ibuprofen, mg: mean (standard deviation) [n] 1200 (848) [5] 5640 (328) [5] 0.09 [*^c^*](#)
Codeine, mg (n) 0 30 (1)\
Reported side effects (n)\
Diplopia 1 0\
Headache 6 7\
Reduced libido 1 0\
Nausea 1 2\
Breast tenderness 1 0\
Hot flushes 1 0\
Increased uterine bleeding 1 0\
Candidiasis 1 0\
Dyspareunia 0 1\
Pain levels at day 42\
ITT [*^a^*](#) 3.2 (0 to 8) 3.9 (0 to 8.9) 0.7 [*^b^*](#)
Difference between medians (95% CI) 0.75 (--1.6 to 2.3)\
PP [*^a^*](#) 3 (0 to 8) [n = 21] 2.65 (0 to 8.9) [n = 18] 0.9 [*^b^*](#)
Difference between medians (95% CI) 0.35 (--2.3 to 2)\
PP no use of pain medication [*^a^*](#) 3 (0 to 7.7) 2.65 (0 to 8.9) 0.8 [*^b^*](#)
(n = 15) (n = 14)\
Difference between medians (95% CI) 0.35 (--2.3 to 2.8)\
CA-125 (U/mL) at day 42 [*^a^*](#) 11.7 (4.9 to 29.9) 13.7 (5 to 61) 0.1 [*^b^*](#)
Prolactin (ng/mL) at day 42 [*^a^*](#) 12 (4.3 to 32.1) 11.1 (4.2 to 31.6) 0.8 [*^b^*](#)

Values are median (range).

Mann-Whitney *U* test.

Unpaired *t* test with Welch's correction.:::: Further analysis using GEEs and the possible confounding factor (use of medication, time to follow-up) revealed no difference between groups \[ [Fig. 2(a)](#) ; all analyses were made using GEEs\]. Further details are provided in Supplemental Table 1 . <figure> <p><img src="" /></p> <figcaption>(a) Variation of pain scores between groups and compared with baseline; data were analyzed using GEEs. (b) CA-125 and (c) prolactin levels before and after treatment with monophasic contraceptive pill with or without resveratrol. Data were transformed into <em>Y</em> = log( <em>Y</em> ) for achieving normal distribution and analyzed using RM-2 Way ANOVA. Bars represent means for each variable studied.</figcaption> </figure> 

## C. Secondary Outcome 

### C-1. CA-125 and prolactin CA-125 levels were reduced after 42 days of treatment in placebo ( *P* = 0.01; RM-2 Way ANOVA) and the resveratrol group ( *P* = 0.02; RM-2 Way ANOVA). Prolactin levels did not vary by treatment type or over time \[ [Fig. 2(b)](#) and [2(c)](#) \]. 

### C-2. Use of analgesics In both arms, subjects used a similar amount of pain medication. Reported side effects were comparable in both groups and were mild ( [Table 2](#) ).


Extracted trial result:
Outcome: Need for dipyrone (continuous)
Intervention: Resveratrol
Comparator: Placebo
Intervention group size: 22
Intervention mean: 1944
Intervention standard deviation: 1793
Comparator group size: 22
Comparator mean: 625
Comparator standard deviation: 250
Notes: found in table