| Miller66 Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin-releasing hormone agonist therapy: a double-blind, randomized, placebo-controlled trial. Am J Obstet Gynecol. 2000; 182(6):1483-8.
|
120 women with endometriosis |
Leuprolide acetate |
60 control group (treated with placebo) |
VAS (pain levels measured before the start of the study, 2 and 4 weeks after treatment) |
Compared with the control women treated with a placebo, those treated with GnRHa exhibited a statistically (p <0.0001) and clinically significant increase in pain levels, showing that this therapy is associated with an increase in pain associated with endometriosis. |
| 60 treatment group (leuprolide acetate) Double-blind study |
| Petta et al.1010 Petta CA, Ferriani RA, Abrão MS, Hassan D, Rosa E Silva JC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005; 20(7):1993-8.
|
82 women with endometriosis |
LNG-IUS GnRHa |
Final sample: 71 |
VAS (pain levels measured before and during the 6 months of treatment) |
CPP decreased from the first month and continued to decline over the six months with the two forms of treatment, with no difference between groups (p>0.999). In both groups, the women with stage III and IV endometriosis showed a faster improvement in VAS pain scores than those at stages I and II (p <0.002). |
| 34 – LNG-IUS |
Both treatments were effective in reducing the CPP associated with endometriosis. The advantage of LNG-IUS is that it requires a single medical intervention for insertion into the womb every five years and may be the treatment of choice for women who do not want to become pregnant. |
| 37 – GnRHa |
| Remorgida et al.1212 Remorgida V, Abbamonte HL, Ragni N, Fulcheri E, Ferrero S. Letrozole and norethisterone acetate in rectovaginal endometriosis. Fertil Steril. 2007; 88(3):724-6.
|
12 women with recto-vaginal endometriosis |
Letrozole Norethisterone acetate |
Letrozole and norethisterone acetate for 6 months |
VAS (dysmenorrhea, deep dyspareunia and CPP). Pain symptoms were measured before starting the treatment, each month during treatment (6 months) and 3, 6 and 12 months after completion of treatment (follow-up) |
100% of women with dysmenorrhea; 83.3% with deep dyspareunia and 83.3% with CPP. |
| After completion of treatment, all symptoms of pain were significantly less intense than baseline (dysmenorrhea: 8.8±1.0 versus 3.7±2.2; dyspareunia: 7.6±1.5 versus 2.2±2.0 and CPP: 5.6±0.9 versus 2.4±1.6). Symptoms of pain returned rapidly after 3 months of follow-up and, after six months, no significant difference was observed in the intensity of dysmenorrhea, deep dyspareunia, and CPP compared to baseline values. |
| Side effects reported by patients: weight gain (n=4), mood changes (n=4), weakness (n=3), bone and joint pain (n=3), vaginal bleeding (n=2), muscle pains (n=2), headache (n=2), depression (n=2), hot flashes (n=1), nausea (n=1), decreased libido (n=1). |
| Due to the persistence of symptoms of pain, 41.7% of patients underwent surgery after an average (± standard deviation) of 7 (± 2.5) months after the end of medical treatment, that is, 5 patients had surgery during the follow-up. The combined use of letrozoleand norethisterone acetate quickly and effectively reduces the intensity of the symptoms of pain caused by recto-vaginal endometriosis without significant side effects, though pain symptoms returned quickly after stopping treatment. |
| Figueiredo and Nascimento1313 Figueiredo J, Nascimento R. Avaliação da qualidade de vida de pacientes portadoras de endometriose após inserção do sistema intra-uterino liberador de levonorgestrel (SIU-LNg). ACM Arq Catarin Med. 2008; 37(4):20-6.
|
10 women with endometriosis |
LNG-IUS |
10 |
VAS (pelvic pain before and after insertion of the LNG-IUS with 6 months of monitoring) |
Before insertion of the LNG-IUS, the average pain score was 8.9 and, after insertion, there was a decrease over the year, reaching an average of 1.8 in 6 months. At the end of treatment, the average satisfaction score given by the patients was 9.8. This study showed that LNG-IUS was effective in reducing the pelvic pain associated with endometriosis. |
| Ferrero et al.1515 Ferrero S, Camerini G, Seracchioli R, Ragni N, Venturini PL, Remorgida V. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod. 2009; 24(12):3033-41.
|
82 patients with recto-vaginal endometriosis |
Letrozole Norethisterone acetate |
41 from the L group (letrozole, norethisterone acetate) |
VAS (dysmenorrhea, deep dyspareunia assessed before, 3 and 6 months during treatment and 3, 6 and 12 months after completion of treatment) |
Intensity of CPP and deep dyspareunia was significantly lower in the L group compared with the N group. At the end of treatment 63.4% of patients in the N group were more satisfied with the treatment compared to 56.1% in the L group (p=0.49). Adverse effects were more frequent in the L group than in the N group (p=0.02). The combined use of drugs was more effective in reducing painful symptoms; however, letrozole caused a high incidence of side effects, its cost is higher and it did not improve patient satisfaction or influence the recurrence of pain. |
| 41 from the N group (isolated norethisterone acetate) |
| Walch et al.1717 Walch K, Unfried G, Huber J, Kurz C, van Trotsenburg M, Pernicka E, et al. Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis-a pilot study. Contraception. 2009; 79(1):29-34.
|
41 women with endometriosis |
Implanon DMPA |
21 – treated with implanon |
VAS (dysmenorrhea, non-menstrual pelvic pain and dyspareunia assessed before and after 3, 6, 9 and 12 months of treatment) |
The level of patient satisfaction with treatment was similar in both groups (57% implanon versus 58% DMPA). During the period of 1 year of treatment, there was an improvement in pain intensity for both treatments. After 6 months, the mean decrease in pain was 68% in the group treated with Implanon and 53% in the DMPA group, but this difference was not statistically significant (p=0.36). The results showed that in relation to pain relief, the therapeutic efficacy of Implanon was not lower than DMPA, that is, both were effective in reducing the pain associated with endometriosis. |
| 20 – treated with DMPA |
| Indraccolo et al.1818 Indraccolo U, Barbieri F. Effect of palmitoylethanolamide-polydatin combination on chronic pelvic pain associated with endometriosis: preliminary observations. Eur J Obstet Gynecol Reprod Biol. 2010; 150(1):76-9.
|
4 patients with endometriosis and CPP |
N-palmitoylethanolamide Polydatin |
Palmitoylethanolamide and polydatin for 90 days Pilot study |
VAS (CPP, deep dyspareunia, dyschezia, dysuria and dysmenorrhea) before and 1, 2 and 3 months after treatment |
Preliminary results showed that the patients reported pain relief after one month of treatment. The palmitoylethanolamide/polydatin combination was effective in controlling CPP associated with endometriosis. |
| Ferrero et al.1919 Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, Seracchioli R, et al. Letrozole and norethisterone acetate in colorectal endometriosis. Eur J Obstet Gynecol Reprod Biol. 2010; 150(2):199-202.
|
6 women with colorectal endometriosis |
Letrozole Norethisterone acetate |
Letrozole and norethisterone acetate for 6 months Pilot study |
VAS (dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia, dyschezia and gastrointestinal symptoms) presence and intensity of symptoms assessed before starting treatment and after 3 and 6 months of treatment |
Prevalence and mean intensity (standard deviation) of symptoms before and 3 and 6 months after treatment. |
| Dysmenorrhea: 100% |
| 7.6±1.8 NI NI |
| Non-menstrual pelvic pain: 83% |
| 6±1.1 3.2±0.5 2.2±0.4 |
| Deep dyspareunia: 83% |
| 5.1±1.9 1.7±1.2 1.2±1.0 |
| Dyschezia: 67% |
| 5.1±2.0 2.0±1.5 1.2±0.9 |
| Intensity of symptoms decreased 3 months after treatment and even further after 6 months. |
| 67% of patients reported being satisfied/very satisfied with respect to the overall assessment of the effects of the treatment on symptoms. 4 patients reported side effects of treatment but due to their mild severity, there was no interruption of treatment: bleeding (n=1), weight gain (n=1), joint pain (n=1), and decreased libido (n=1). |
| The combined use of letrozole and norethisterone acetate reduces pain and gastrointestinal symptoms. |
| Ferrero et al.2020 Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, Remorgida V. Norethisterone acetate in the treatment of colorectal endometriosis: a pilot study. Hum Reprod. 2010; 25(1):94-100.
|
40 women with colorectal endometriosis |
Norethisterone acetate |
Norethisterone acetate for 12 months |
VAS (dysmenorrhea, CPP, deep dyspareunia, and dyschezia), and gastrointestinal symptoms measured before and after 6 and 12 months of treatment |
85% dysmenorrhea, 73% CPP, 67% deep dyspareunia and 68% dyschezia. |
| 60% of patients reported being satisfied/very satisfied with respect to the overall assessment of the effects of the treatment on symptoms at the end of treatment. |
| 53% of patients reported improvement in gastrointestinal symptoms. |
| The administration of norethisterone acetate promoted a significant improvement in the intensity of CPP, deep dyspareunia and dyschezia. |
| Values expressed as a mean (± standard deviation) before the beginning of treatment and after 6 and 12 months. |
| Dysmenorrhea: 6.8±1.9/not available/not available |
| Initial sample: n=40 |
CPP: 5.5±1.3/4.1±1.8/3.5±1.6 |
| 6 months: n=38 |
Deep dyspareunia: 5.7±1.4/3.1±1.1/2.8±1.2 |
| 12 months: n=32 |
Dyschezia: 5.1±1.9/3.2±1.2/2.5±1.4 |
| Ferrero et al.2222 Ferrero S, Venturini PL, Gillott DJ, Remorgida V. Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial. Reprod Biol Endocrinol. 2011; 9:88.
|
35 patients with recto-vaginal endometriosis |
Letrozole Norethisterone acetate Triptorelin |
17 from the N group (letrozole, norethisterone acetate) 18 from the T group (letrozole, triptorelin) |
VAS and Multidimensional Categorical Classification Scale (dysmenorrhea, non-menstrual pelvic pain and deep dyspareunia assessed before, and after 3 and 6 months of treatment) |
64.7% of patients in the N group reported being satisfied or very satisfied with the treatment compared with 22.2% from the T group. |
| 77.8% of the T group patients reported adverse effects versus 35.3% from the N group. |
| 44.4% of the T group patients stopped treatment due to adverse effects versus 5.9% from the N group. |
| During treatment, the bone mineral density significantly decreased in the T group but not the N group. |
| Pain intensity decreased significantly during treatment in both groups. |
| This study demonstrated the effectiveness of the aromatase inhibitor in the treatment of pain associated with endometriosis. |
| Ferrero et al.2323 Ferrero S, Tramalloni D, Venturini PL, Remorgida V. Vaginal danazol for women with rectovaginal endometriosis and pain symptoms persisting after insertion of a levonorgestrel-releasing intrauterine device. Int J Gynaecol Obstet. 2011; 113(2):116-9.
|
15 women with recto-vaginal endometriosis |
LNG-IUS Danazol |
Vaginal danazol applied for 6 months |
VAS and Multidimensional Categorical Classification Scale (symptoms evaluated: dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia and dyschezia) Intensity of the symptoms evaluated in three different situations: isolated use of LNG-IUS and after 3 and 6 months of treatment with vaginal danazol |
Intensity of the symptoms of pain significantly decreased after administration of danazol for 3 months and continued to decrease even after 6 months of treatment. |
| 80% of patients were satisfied with the treatment. |
| Minimal adverse effects of LNG-IUS and vaginal danazol treatment: seborrhea, oily hair or acne (n=4), headache (n=3), weight gain > 3 kg (n=2) and vaginal irritation (n=2). |
| Vaginal danazol reduced the severity of the painful symptoms related to endometriosis that persisted after insertion of LNG-IUS. |
| Guzick et al.2424 Guzick DS, Huang LS, Broadman BA, Nealon M, Hornstein MD. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril. 2011; 95(5):1568-73.
|
47 women with endometriosis and CPP |
Leuprolide Continuous oral contraceptives (COC) |
21 – leuprolide |
Biberoglu & Behrman/B & B and Numerical Scale measured before treatment, and after 4, 12, 24, 36 and 48 weeks of treatment |
Both products were equally effective in treating the pelvic pain associated with endometriosis. |
| 26 – continuous oral contraceptives |
| Mabrouk et al.2626 Mabrouk M, Frascà C, Geraci E, Montanari G, Ferrini G, Raimondo D, et al. Combined oral contraceptive therapy in women with posterior deep infiltrating endometriosis. J Minim Invasive Gynecol. 2011; 18(4):470-4.
|
106 women with endometriosis |
COCs |
75 – use of COCs |
VAS (dysmenorrhea, dyspareunia, CPP and dyschezia) |
The comparison of VAS scores between the two groups showed that during the preoperative period, dysmenorrhea and dyspareunia symptoms had higher VAS scores (p=0.02 and p=0.005, respectively) in the untreated group, with worsening of the intensity of the pain. The data suggest that therapy with combined oral contraceptive may have a role in limiting the progression of dysmenorrhea and dyspareunia associated with endometriosis. |
| 31 – non users of COCs |
| Ferrari et al.2727 Ferrari S, Persico P, Di Puppo F, Vigano P, Tandoi I, Garavaglia E, et al. Continuous low-dose oral contraceptive in the treatment of colorectal endometriosis evaluated by rectal endoscopic ultrasonography. Acta Obstet Gynecol Scand. 2012; 91(6):699-703.
|
26 women with colorectal endometriosis |
Continuous oral contraceptives |
26 patients on continuous oral contraceptives |
VAS (dysmenorrhea, non-menstrual pelvic pain, dyspareunia and dyschezia with pain scores measured before and 12 months after administration of the drug) |
The symptoms evaluated and their scores before and after treatment were: dysmenorrhea (90.4±9.9 versus 26.9±29.2), non-menstrual pelvic pain (65.0±27.3 versus 18.5±19.1), dyspareunia (63.1±22.8 versus 18.5±24.3) and pain on defecation (57.7±28.2 versus 13.1±17.6). The values are expressed as mean ± standard deviation and show that there was a significant decline in intensity of symptoms after 12 months of treatment (p<0.01). At the end of the study, 69% of patients were satisfied with the treatment. The following adverse effects were noted: 38% uterine bleeding, 23% moderate weight gain, 11% headache and 7% decreased libido, although none of the women discontinued treatment due to the effects. |
| Petraglia et al.2828 Petraglia F, Hornung D, Seitz C, Faustmann T, Gerlinger C, Luisi S, et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet. 2012; 285(1):167-73.
|
168 women with endometriosis |
Dienogest |
Initial sample: 168 Final sample: 152 |
VAS (CPP – 65 weeks, that is, 53 weeks in the group treated with dienogest and 12 weeks in the placebo group) |
The mean VAS score was significantly reduced by 43.2 mm (standard deviation ± 21.7) in the total period of 65 weeks of treatment (that is, the study group versus placebo group, p<0.001), meaning that a significant decrease pelvic pain was observed during continuous treatment with dienogest (p<0.001). Adverse effects related to medication were noted in 27/168 patients (16.1%) during the study, with the intensity of adverse events related to treatment ranging from mild to moderate in the majority of cases (92.5%). Only 4 patients (2.4%) discontinued treatment due to side effects. Long term treatment with dienogest was effective and the reduction of pelvic pain persisted for at least 24 weeks after the end of treatment. |
| Giugliano et al.3131 Giugliano E, Cagnazzo E, Soave I, Lo Monte G, Wenger JM, Marci R. The adjuvant use of N-palmitoylethanolamine and transpolydatin in the treatment of endometriotic pain. Eur J Obstet Gynecol Reprod Biol. 2013; 168(2):209-13.
|
47 patients with endometriosis |
N-palmitoylethanolamide Trans-polydatin |
47 patients divided into two groups according to the ED site |
VAS (dyspareunia, dyschezia, dysmenorrhea and CPP) before, 1, 2 and 3 months after treatment |
Endometriotic pain intensity decreased significantly in both groups (p<0.0001). The efficacy of treatment was significant after 30 days. Pain intensity also decreased in both groups, except for dysmenorrhea, which was reduced faster in group B. The combination of N-palmitoylethanolamide and trans-polydatin reduced pain related to endometriosis, regardless of the site affected. |
| 19 – Group A (ED of the rectovaginal septum) |
| 28 – Group B (ED of the ovary) |
| Morelli et al.3232 Morelli M, Rocca ML, Venturella R, Mocciaro R, Zullo F. Improvement in chronic pelvic pain after gonadotropin releasing hormone analogue (GnRH-a) administration in premenopausal women suffering from adenomyosis or endometriosis: a retrospective study. Gynecol Endocrinol. 2013;29(4):305-8.
|
63 women |
GnRHa (leuprolide acetate) |
15 – adenomyosis (group A) |
VAS (before and 3 months after administration of GnRHa) |
Before using the drug, the scores were 72.5±18.5 versus 68.5±19.9 in groups A and B, respectively, and this difference was not statistically significant (p=0.48). After three months of treatment, the VAS scores decreased significantly in patients with adenomyosis (23.3±16.7 vs. 31.8±10.0 for groups A and B, respectively; p<0.05). The values are expressed as mean ± standard deviation. When comparing both groups, the reduction in CPP intensity, expressed as ΔVAS (difference between VAS scores prior to and after the use of GnRHa), was significantly higher in patients with adenomyosis compared to those with endometriosis (49.3±16 8 versus 36.7±15.6 for group A and B, respectively; p<0.001), showing greater effectiveness of GnRHa in the reduction of CPP in adenomyosis. In summary, a significant reduction in CPP intensity was observed in both groups (p<0.05), but was significantly higher in group A compared with B (p<0.001). |
| 48 – endometriosis (group B) |
