Evaluation of endometriosis-associated pain and influence of conventional treatment: a systematic review

Avaliação da dor associada à endometriose e influência do tratamento convencional: uma revisão sistemática

Alessandra Bernadete Trovó de Marqui About the author

SUMMARY

Endometriosis is a chronic gynecological disease characterized by sustained painful symptoms that are responsible for a decline in the quality of life of sufferers. Conventional treatment includes surgical and pharmacological therapy aiming at reducing painful symptoms. This study aimed to evaluate pain levels in women with endometriosis, focusing on the influence of conventional treatment in controlling this variable. To do so, a literature search was conducted in the Medline/Pubmed databases, with 119 scientific articles found. After applying the inclusion and exclusion criteria, 27 were selected for reading and elaboration of this review. Thus, 9 studies evaluated the contribution of surgery, 17 the use of drugs to reduce pain levels in patients with endometriosis and one assessed surgical and medical treatment. The main results of these searches are presented and discussed in this revision. Surgery and the use of drugs provided reduced pain scores in patients with endometriosis but nevertheless exhibit disadvantages, such as risk of recurrence and side effects, respectively. Treatment of endometriosis is, therefore, a challenge for gynecologists and patients, as they must select the best therapeutic approach for this disease. However, improved quality of life in these patients has been obtained with the use of conventional treatment.

Keywords:
endometriosis; pelvic pain; therapeutics; quality of life

RESUMO

A endometriose é uma doença ginecológica crônica caracterizada por quadros álgicos constantes responsáveis pela redução da qualidade de vida das portadoras. O tratamento convencional, que inclui o cirúrgico e farmacológico, tem por finalidade reduzir os sintomas de dor. Este estudo teve por objetivo avaliar os níveis de dor nas mulheres com endometriose, com enfoque na influência do tratamento convencional no controle dessa variável. Para isso, foi realizada uma pesquisa bibliográfica no Medline/PubMed e foram encontrados 119 artigos científicos, sendo que, após a aplicação dos critérios de inclusão e exclusão, 27 foram selecionados para leitura e elaboração desta revisão. Desse modo, nove estudos avaliaram a contribuição da cirurgia; dezessete, o uso de medicamentos para redução nos níveis de dor em pacientes com endometriose; e um, o tratamento cirúrgico e medicamentoso. Os principais resultados dessas pesquisas estão apresentados e discutidos nesta revisão. A cirurgia e o uso de medicamentos proporcionaram redução nos escores de dor nas pacientes com endometriose, no entanto, exibem desvantagens como risco de recorrência e efeitos colaterais, respectivamente. Assim, o tratamento para endometriose é um desafio para ginecologistas e pacientes, uma vez que é necessário selecionar a melhor abordagem terapêutica para essa doença. Entretanto, melhora na qualidade de vida das pacientes foi obtida com o emprego do tratamento convencional.

Palavras-chave:
endometriose; dor pélvica; terapêutica; qualidade de vida

Introduction

Endometriosis is a gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity.11 Bulun SE. Endometriosis. Review. N Engl J Med. 2009; 360(3):268-79. Treatment consists in relieving chronic pelvic pain (CPP) and recovering fertility, through medication and/or surgery.22 Nácul AP, Spritzer PM. Aspectos atuais do diagnóstico e tratamento da endometriose. Rev Bras Ginecol Obstet. 2010; 32(6):298-307.

Patients with endometriosis display the following types of pain: CPP, dysmenorrhea, dyspareunia, dyschezia and dysuria.11 Bulun SE. Endometriosis. Review. N Engl J Med. 2009; 360(3):268-79. CPP is defined as non-menstrual or non-cyclical pain, lasting at least six months, strong enough to interfere with daily activities and requiring medical or surgical treatment. Dysmenorrhea, also known as menstrual cramps, is pelvic pain occurring before or during a menstrual period. Pain during intercourse is called dyspareunia and pain when defecating and urinating are known as dyschezia and dysuria, respectively.

As the disease and the pain are chronic conditions, there is significant interference in the quality of life of these women, in their professional performance, and significant costs to health services.

Regarding professional activity, a multicenter study showed that symptoms of endometriosis have a negative impact on productivity at work, with the loss of approximately one working day per week.33 Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011; 96(2):366-73. Another study showed that 85% of patients with endometriosis perceived an evident decrease in the quality of their work, 19% reported being unable to work due to pain and 69% of patients reported that they continue to work despite the painful sensation.44 Fourquet J, Gao X, Zavala D, Orengo JC, Abac S, Ruiz A, et al. Patients' report on how endometriosis affects health, work, and daily life. Fertil Steril. 2010; 93(7):2424-8.

With respect to health expenditure, there is the need for surgery for definitive diagnosis of the disease or even to assess recurrences, as well as hospital admissions due to pain. According to a multicenter study carried out by Simoens et al.,55 Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012; 27(5):1292-9. health care costs associated with endometriosis were mainly due to surgery (29%), monitoring tests (19%), hospitalization (18%) and medical appointments (16%). These high costs have been associated with severity of the endometriosis, the presence of pelvic pain, infertility, and a large number of years before diagnosis.55 Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012; 27(5):1292-9.

Given the above, the symptoms of this painful gynecological condition interfere with the professional and personal life of patients and, therefore, control of this variable is essential in order to provide a better quality of life for such women. As such, this study aimed to evaluate the levels of pain in women with endometriosis, focusing on the influence of conventional treatment in controlling this variable.

Methods

A literature search was conducted in September 2013 in the Medline/PubMed databases without restriction by period, using the keywords "endometriosis" and "intensity of pain". PubMed was the database of choice for this systematic review as it is more comprehensive, used internationally in health care research and, therefore, provides the most complete indexing of scientific studies. 119 articles were found and 27 were retrieved and analyzed in full. The inclusion criteria for selection of the articles were: 1) those closely related to the theme, with selection based on titles and/or abstracts; 2) articles written in English or Portuguese; 3) the possibility of obtaining the full version of the article; 4) those that were original/research articles. In endometriosis, conventional treatment includes laparoscopic surgery and pharmacological treatment. The title and/or abstract of 27 articles presented information about the method of treatment used to control the symptoms of pain caused by endometriosis. Review articles or letters to the editor were excluded, as well as those without any relationship with the subject of the review, and those that did not offer access to the full article and those published in other foreign languages. The reference lists of articles identified in the electronic search were also reviewed in order to find potentially important studies for inclusion in this literature review. The selection of articles included in the review was carried out by a single examiner, following the previously defined criteria. Ten other references were also used to help compose the introduction and discussion of the results.

Results

After applying the pre-established inclusion and exclusion criteria, 27 studies that evaluated pain levels in patients with endometriosis were selected for the development of this literature review.66 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.

7 Garry R, Clayton R, Hawe J. The effect of endometriosis and its radical laparoscopic excision on quality of life indicators. BJOG. 2000; 107(1):44-54.

8 Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2-5 year follow-up. Hum Reprod. 2003; 18(9):1922-7.

9 Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004; 82(4):878-84.

10 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.

11 Lyons SD, Chew SS, Thomson AJ, Lenart M, Camaris C, Vancaillie TG, et al. Clinical and quality-of-life outcomes after fertility-sparing laparoscopic surgery with bowel resection for severe endometriosis. J Minim Invasive Gynecol. 2006; 13(5):436-41.

12 Remorgida V, Abbamonte HL, Ragni N, Fulcheri E, Ferrero S. Letrozole and norethisterone acetate in rectovaginal endometriosis. Fertil Steril. 2007; 88(3):724-6.

13 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.

14 Fabbri E, Villa G, Mabrouk M, Guerrini M, Montanari G, Paradisi R, et al. McGill Pain Questionnaire: a multi-dimensional verbal scale assessing postoperative changes in pain symptoms associated with severe endometriosis. J Obstet Gynaecol Res. 2009; 35(4):753-60.

15 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.

16 Jedrzejczak P, Sokalska A, Spaczynski RZ, Duleba AJ, Pawelczyk L. Effects of presacral neurectomy on pelvic pain in women with and without endometriosis. Ginekol Pol. 2009; 80(3):172-8.

17 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.

18 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.

19 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.

20 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.

21 Bassi MA, Podgaec S, Dias Jr JA, D'Amico Filho N, Petta CA, Abrão MS. Quality of life after segmental resection of the rectosigmoid by laparoscopy in patients with deep infiltrating endometriosis with bowel involvement. J Minim Invasive Gynecol. 2011; 18(6):730-3.

22 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.

23 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.

24 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.

25 Mabrouk M, Montanari G, Guerrini M, Villa G, Solfrini S, Vicenzi C, et al. Does laparoscopic management of deep infiltrating endometriosis improve quality of life? A prospective study. Health Qual Life Outcomes. 2011; 9:98.

26 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.

27 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.

28 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.

29 Setälä M, Härkki P, Matomäki J, Mäkinen J, Kössi J. Sexual functioning, quality of life and pelvic pain 12 months after endometriosis surgery including vaginal resection. Acta Obstet Gynecol Scand. 2012; 91(6):692-8.

30 Mabrouk M, Montanari G, Di Donato N, Del Forno S, Frascà C, Geraci E, et al. What is the impact on sexual function of laparoscopic treatment and subsequent combined oral contraceptive therapy in women with deep infiltrating endometriosis? J Sex Med. 2012; 9(3):770-8.

31 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.
-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.

Nine studies assessed the contribution of surgery to reduce pain levels in patients with endometriosis77 Garry R, Clayton R, Hawe J. The effect of endometriosis and its radical laparoscopic excision on quality of life indicators. BJOG. 2000; 107(1):44-54.

8 Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2-5 year follow-up. Hum Reprod. 2003; 18(9):1922-7.
-99 Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004; 82(4):878-84.,1111 Lyons SD, Chew SS, Thomson AJ, Lenart M, Camaris C, Vancaillie TG, et al. Clinical and quality-of-life outcomes after fertility-sparing laparoscopic surgery with bowel resection for severe endometriosis. J Minim Invasive Gynecol. 2006; 13(5):436-41.,1414 Fabbri E, Villa G, Mabrouk M, Guerrini M, Montanari G, Paradisi R, et al. McGill Pain Questionnaire: a multi-dimensional verbal scale assessing postoperative changes in pain symptoms associated with severe endometriosis. J Obstet Gynaecol Res. 2009; 35(4):753-60.,1616 Jedrzejczak P, Sokalska A, Spaczynski RZ, Duleba AJ, Pawelczyk L. Effects of presacral neurectomy on pelvic pain in women with and without endometriosis. Ginekol Pol. 2009; 80(3):172-8.,2121 Bassi MA, Podgaec S, Dias Jr JA, D'Amico Filho N, Petta CA, Abrão MS. Quality of life after segmental resection of the rectosigmoid by laparoscopy in patients with deep infiltrating endometriosis with bowel involvement. J Minim Invasive Gynecol. 2011; 18(6):730-3.,2525 Mabrouk M, Montanari G, Guerrini M, Villa G, Solfrini S, Vicenzi C, et al. Does laparoscopic management of deep infiltrating endometriosis improve quality of life? A prospective study. Health Qual Life Outcomes. 2011; 9:98.,2929 Setälä M, Härkki P, Matomäki J, Mäkinen J, Kössi J. Sexual functioning, quality of life and pelvic pain 12 months after endometriosis surgery including vaginal resection. Acta Obstet Gynecol Scand. 2012; 91(6):692-8. and one assessed the combination of surgical and drug treatments (combined oral contraceptives - COC).3030 Mabrouk M, Montanari G, Di Donato N, Del Forno S, Frascà C, Geraci E, et al. What is the impact on sexual function of laparoscopic treatment and subsequent combined oral contraceptive therapy in women with deep infiltrating endometriosis? J Sex Med. 2012; 9(3):770-8. The individual values and frequency for each type of pain before and after the surgical procedure are presented in Tables 1 and 2. Also, Garry et al.77 Garry R, Clayton R, Hawe J. The effect of endometriosis and its radical laparoscopic excision on quality of life indicators. BJOG. 2000; 107(1):44-54. showed that of the 53 patients with dysmenorrhea, 43 reported improvement in this symptom 4 months after surgery, while 4 did not notice changes and 6 reported worsening after surgery. Non-menstrual pelvic pain was reported by 48 women, 34 of which reported an improvement after surgery, with four reporting no change and 10 feeling worse. Dyspareunia was reported by 41 patients, 32 of which reported improvement, while 5 and 4 patients reported no change and worsening of symptoms, respectively. Rectal pain was cited by 41 patients with 35 of them reporting improvement after surgery.

TABLE 1
Pain scores before (pre-op) and after (post-op) laparoscopic surgery for endometriosis regarding the following pain symptoms: dysmenorrhea, pelvic pain, dyspareunia, dyschezia and dysuria.
TABLE 2
Frequency and pain scores before surgery (pre-op) and postoperatively (post-op) regarding the following pain symptoms: dysmenorrhea, chronic pelvic pain (CPP), dyspareunia, dysuria and dyschezia.

Other studies aimed at checking if there was a decrease in pain levels after surgery were performed by Fabbri et al.1414 Fabbri E, Villa G, Mabrouk M, Guerrini M, Montanari G, Paradisi R, et al. McGill Pain Questionnaire: a multi-dimensional verbal scale assessing postoperative changes in pain symptoms associated with severe endometriosis. J Obstet Gynaecol Res. 2009; 35(4):753-60. and Jdrzejczak et al.1616 Jedrzejczak P, Sokalska A, Spaczynski RZ, Duleba AJ, Pawelczyk L. Effects of presacral neurectomy on pelvic pain in women with and without endometriosis. Ginekol Pol. 2009; 80(3):172-8. The first study used the McGill Pain Questionnaire (MPQ) in 55 women with severe endometriosis who underwent laparoscopy. The pain intensity ratio before surgery was 3, falling to 1 after surgery (6 months), that is, the intensity of the pain significantly decreased after laparoscopic treatment of endometriosis (p<0.0005). A significant reduction was also observed (p<0.05) on all individual pain indexes; however, 18.2% of those women showed no improvement in the symptoms of pain after laparoscopic surgery. Possible explanations for this include recurrence of the disease after surgery, incomplete excision of endometriotic lesions or pain unrelated to endometriosis. Jdrzejczak et al.1616 Jedrzejczak P, Sokalska A, Spaczynski RZ, Duleba AJ, Pawelczyk L. Effects of presacral neurectomy on pelvic pain in women with and without endometriosis. Ginekol Pol. 2009; 80(3):172-8. evaluated the effects of pre-sacral neurectomy in the treatment of CPP in 23 women, 16 of whom had endometriosis, while 7 did not. The symptoms of pain evaluated were dysmenorrhea, CPP and dyspareunia, with intensity determined by the visual analogue scale (VAS) before surgery, and 3 and 12 months postoperatively. The results show a significant improvement in pain symptoms after three months and this remained significant 12 months postoperatively. Furthermore, at the end of the study 79% of the patients reported general satisfaction in relation to pain relief.

The referred studies have shown that the severity of all kinds of pain was diminished after surgery, as well as the prevalence of such, thus demonstrating the effectiveness of surgery for pain relief, and consequently for the quality of life of women with endometriosis.

Seventeen studies published in the literature evaluated the use of drugs to treat pain associated with endometriosis.66 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.,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.,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.,1313 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.,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.,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.

18 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.

19 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.
-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.,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.

23 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.
-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.,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.

27 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.
-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.,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.,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. The main results of these studies are summarized in Table 3.

TABLE 3
Main results of 17 studies that evaluated the effect of drugs on pain scores.

Discussion

This study shows that the scientific literature is vast as to the number of scientific articles published on the prevalence and levels of pain in patients with endometriosis. The painful symptoms attributed to endometriosis include CPP, dysmenorrhea, dyspareunia, dyschezia and dysuria. Pain restricts and modifies the daily routine of these patients, directly affecting their quality of life. Despite the use of instruments to measure pain, such analysis is complex due to its subjective nature and the influence of factors such as personality, psychiatric disorders (depression) and psychosocial factors. The severity of pain may be related to the degree of depression and anxiety, present in 90% of women with endometriosis. Some authors indicate that depression is a direct consequence of pain, but there is no consensus on this temporal issue when defining which condition precedes the other. However, it is possible to affirm that the two conditions coexist, and that one worsens the experience of the other.3333 Lorençatto C, Vieira MJN, Pinto CLB, Petta CA. Avaliação da frequência de depressão em pacientes com endometriose e dor pélvica. Rev Assoc Med Bras. 2002; 48(3):217-21. Whenever endometriosis patients exhibit depression, it is clinically important to assess the condition and start appropriate treatment as soon as possible. Depression, if left untreated, has a negative effect on the patient's ability to deal with the pain, daily functioning, and especially their quality of life. In addition, the impact of a chronic disease, such as endometriosis, associated with persistent painful symptoms, causes the patient to become isolated, damaging relationships given that women with endometriosis are labeled as "hypochondriac" and their circle of friends ends up getting tired of so many complaints. This favors the emergence of depressive symptoms.3333 Lorençatto C, Vieira MJN, Pinto CLB, Petta CA. Avaliação da frequência de depressão em pacientes com endometriose e dor pélvica. Rev Assoc Med Bras. 2002; 48(3):217-21.

In relation to the instruments for measuring pain, the VAS has prevailed as the most frequently applied questionnaire for analysis of endometriotic pain. It is a onedimensional instrument that quantifies pain according to intensity. It consists of a line of 10 or 100 cm, which contains the number 0 on the left and the number 10 or 100 at the other end. Patients are advised to mark the position that reflects the degree of pain, with 0 being no pain and 10 or 100 considered the worst pain experienced.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.,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.

One way to reduce the painful symptoms in patients with endometriosis is to use conventional treatment including surgery and/or medication.

The data presented in Tables 1 and 2 show that surgical treatment for endometriosis was effective in relieving dysmenorrhea, dyspareunia, pelvic pain, dyschezia and dysuria. These studies show that laparoscopic excision reduces pain levels after surgery, ranging from 4 months,77 Garry R, Clayton R, Hawe J. The effect of endometriosis and its radical laparoscopic excision on quality of life indicators. BJOG. 2000; 107(1):44-54. to 6 months,2525 Mabrouk M, Montanari G, Guerrini M, Villa G, Solfrini S, Vicenzi C, et al. Does laparoscopic management of deep infiltrating endometriosis improve quality of life? A prospective study. Health Qual Life Outcomes. 2011; 9:98.,3030 Mabrouk M, Montanari G, Di Donato N, Del Forno S, Frascà C, Geraci E, et al. What is the impact on sexual function of laparoscopic treatment and subsequent combined oral contraceptive therapy in women with deep infiltrating endometriosis? J Sex Med. 2012; 9(3):770-8. 12 months99 Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004; 82(4):878-84.,1111 Lyons SD, Chew SS, Thomson AJ, Lenart M, Camaris C, Vancaillie TG, et al. Clinical and quality-of-life outcomes after fertility-sparing laparoscopic surgery with bowel resection for severe endometriosis. J Minim Invasive Gynecol. 2006; 13(5):436-41.,2121 Bassi MA, Podgaec S, Dias Jr JA, D'Amico Filho N, Petta CA, Abrão MS. Quality of life after segmental resection of the rectosigmoid by laparoscopy in patients with deep infiltrating endometriosis with bowel involvement. J Minim Invasive Gynecol. 2011; 18(6):730-3.,2929 Setälä M, Härkki P, Matomäki J, Mäkinen J, Kössi J. Sexual functioning, quality of life and pelvic pain 12 months after endometriosis surgery including vaginal resection. Acta Obstet Gynecol Scand. 2012; 91(6):692-8. and 2-5 years.88 Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2-5 year follow-up. Hum Reprod. 2003; 18(9):1922-7.

Surgical treatment for endometriosis consists of excision of endometriotic lesions by laparoscopy. Laparotomy can also be used in the treatment of this disease; however, laparoscopy is more widely employed because it is minimally invasive compared to the first, and has the following advantages: less blood loss, shorter postoperative recovery time, less postoperative pain and early hospital discharge.22 Nácul AP, Spritzer PM. Aspectos atuais do diagnóstico e tratamento da endometriose. Rev Bras Ginecol Obstet. 2010; 32(6):298-307. A recent review addressed the surgical treatment of endometriosis in terms of improvement in pain and infertility. The authors conclude that surgical treatment seems to be the definitive therapy for women with exacerbated painful symptoms.3434 Kondo W, Zomer MT, Amaral VF. Tratamento cirúrgico da endometriose baseado em evidências. Femina. 2011; 39(3):143-8.

According to Nácul and Spritzer,22 Nácul AP, Spritzer PM. Aspectos atuais do diagnóstico e tratamento da endometriose. Rev Bras Ginecol Obstet. 2010; 32(6):298-307. pharmacological treatments for pain associated with endometriosis include estro-progesterone combinations (birth control), isolated progestins (norethindrone acetate, dienogest, medroxyprogesterone acetate - DMPA, intrauterine systems with levonorgestrel - LNG-IUS), gonadotropin releasing hormone analogues (GnRHa - nafarelin acetate, leuprolide acetate, triptorelin), danazol and gestrinone and aromatase inhibitors (letrozole and anastrozole). The costs and side effects of these drugs differ significantly. Of the 17 studies that evaluated the influence of medication on decreasing pain levels, seven evaluated one drug alone66 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.,1313 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.,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.,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.

27 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.
-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.,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. and 10 evaluated drugs in combination.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.,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.,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.,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.

18 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.
-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.,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.

23 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.
-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.,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. Thus, 3 studies employed contraceptives;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.,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.,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. 10 used isolated progestins;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.,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.,1313 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.,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.,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.,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.,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.,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.,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.,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. 5 used GnRHa,66 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.,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.,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.,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.,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. one used danazol2323 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. and 4 used aromatase inhibitors.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.,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.,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.,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. The use of aromatase inhibitors for the treatment of endometriosis and its associated symptoms is justified by the fact that endometriotic tissue over-expresses aromatase, an enzyme key for the production of estrogen, noting that endometriosis is an estrogen-dependent gynecological condition. However, they exhibit poor tolerability and high costs compared to more conventional therapies.3535 Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011; 9:87. Review. Among the therapeutic options for treatment of endometriotic pain, estrogen-progestin combinations are the 1st line therapy, with progestins as 1st or 2nd line therapy, and GnRHa and danazol/gestrinone as 2nd and 3rd line treatments, respectively.22 Nácul AP, Spritzer PM. Aspectos atuais do diagnóstico e tratamento da endometriose. Rev Bras Ginecol Obstet. 2010; 32(6):298-307. An interesting finding in relation to GnRHa (triptorelin) was reported by 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. who also evaluated the effect of letrozole (aromatase inhibitor) and norethisterone acetate (isolated progestin). In their study, about 80% of patients who received letrozole and triptorelin reported side effects and 45% discontinued treatment as a result. Side effects of GnRHa include dry vagina, decreased libido, depression, irritability, fatigue and bone mineral loss, which limits its use.22 Nácul AP, Spritzer PM. Aspectos atuais do diagnóstico e tratamento da endometriose. Rev Bras Ginecol Obstet. 2010; 32(6):298-307. Danazol is another drug that has limited use due to adverse androgenic effects, such as changes in lipid profile, weight gain, edema, acne, vaginal dryness, hot flashes, liver toxicity, breast atrophy, voice alteration, hirsutism, and oily skin; however, vaginal use has shown satisfactory results.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. Accordingly, while indicating a drug for treatment of pain associated with endometriosis, one must consider the adverse effects and investigate the patient's satisfaction with the treatment. It is also recommended to inform women with endometriosis of the benefits, limitations and costs of each drug. In relation to dienogest (DNG), a scientific paper recently published presented the results of nine studies using DNG, short and long term, in the treatment of endometriosis. This drug proved to be effective in reducing pain symptoms associated with endometriosis.3636 Bahamondes L, Camargos AF. Dienogest: uma nova opção terapêutica em endometriose. Femina. 2012; 40(3):155-9.

In addition to the clinical treatments that reduce estrogenic activity, as presented above, drugs that reduce inflammation are also used in endometriosis (non-steroidal anti-inflammatory drugs - NSAIDs). Two studies have evaluated the combination of N-palmitoyl ethanolamine and transpolydatin/polydatin, drugs that act on inflammation, in the treatment of pain associated with endometriosis.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.,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. Polydatin is a resveratrol glycoside that has antioxidant activities. Therefore, the combination of these drugs work on the inflammatory processes and oxidative stress involved in the development of endometriosis.

The studies presented above show that the pharmacological and surgical treatments for relief of pain associated with endometriosis are effective. Most clinical treatments lead to stabilization or regression of lesions, which usually recur after the medication is stopped, as well as recurrence of the disease after surgery.3434 Kondo W, Zomer MT, Amaral VF. Tratamento cirúrgico da endometriose baseado em evidências. Femina. 2011; 39(3):143-8. There has been predominance in the use of medication to control the pain associated with endometriosis. This is in the premise established by the American Society for Reproductive Medicine (ASRM) which has established that "endometriosis should be viewed as a chronic disease that requires a life-long pain management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures".3737 Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014; 101(4):927-35. Despite the side effects of drugs and their cost, surgery is an invasive procedure with a risk of complications. Thus, surgery is indicated to confirm the diagnosis and to manage the patients that do not respond to medical treatment.3434 Kondo W, Zomer MT, Amaral VF. Tratamento cirúrgico da endometriose baseado em evidências. Femina. 2011; 39(3):143-8. Given the above, the choice of ideal treatment for endometriosis is complex. The data herein presented show that both treatments helped to relieve the pain associated with endometriosis and, consequently, they promoted an improvement in the quality of life of women with this gynecological disease.

Conclusion

Endometriosis is a gynecological disease that has as its main characteristic pain that compromises the sexual, social and professional life of women affected. Thus, painful symptoms have been linked to deterioration in the quality of life of such patients. Treatment for this disease, therefore, focuses on pain relief.

The data herein presented show that patients with endometriosis exhibit high levels of pain. Surgery and the use of drugs provided reduced pain scores in patients with endometriosis, but nevertheless exhibit disadvantages, such as risk of recurrence and side effects, respectively. Treatment of endometriosis is, therefore, a challenge for gynecologists and patients, as they must select the best therapeutic approach for this disease. However, improved quality of life in these patients has been obtained with the use of conventional treatment.

  • 1
    Studed conducted at Universidade Federal do Triângulo Mineiro (UFTM), Uberaba, MG, Brazil
  • Financial support: none

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Publication Dates

  • Publication in this collection
    Nov-Dec 2015

History

  • Received
    15 May 2014
  • Accepted
    23 Sept 2014
Associação Médica Brasileira R. São Carlos do Pinhal, 324, 01333-903 São Paulo SP - Brazil, Tel: +55 11 3178-6800, Fax: +55 11 3178-6816 - São Paulo - SP - Brazil
E-mail: ramb@amb.org.br