Clinical Review & Education
JAMA Clinical Evidence Synopsis
An Overview of Treatments for Endometriosis Julie Brown, PhD; Cynthia Farquhar, MD
CLINICAL QUESTION What treatments are associated with improved outcomes for women with endometriosis? BOTTOM LINE The levonorgestrel-releasing intrauterine system (LNG-IUD), gonadotropin-releasing hormone analogues (GnRHa; nafarelin, leuprolide, buserelin, goserelin, triptorelin), laparoscopic ablation, and excision are associated with relief of pain due to endometriosis. Gonadotropin-releasing hormone analogues and laparoscopic ablation or excision are associated with increased clinical pregnancy rates in women with endometriosis. Gonadotropin-releasing hormone analogues, danazol, and depot progestagens are associated with a higher incidence of adverse events.
Countries: Worldwide
Gonadotropin-releasing hormone analogues (GnRHa) were associated with relief of pelvic tenderness compared with placebo and relief of painful periods compared with no treatment (Table). There was very low-quality evidence for studies that compared excisional vs ablative surgery, danazol vs placebo, and acupuncture vs Chinese herbal medicine. Laparoscopic surgery (ablation and excision; ablation and uterine nerve transection) was associated with increased live births and ongoing pregnancies compared with diagnostic laparoscopy. Laparoscopic excision of the endometrioma cyst wall was associated with increased clinical pregnancy rates compared with ablation. Prior to in vitro fertilization, GnRHa was associated with increased clinical pregnancies compared with no GnRHa (Table). There were no differences in pregnancy rates between groups in trials that compared the following: ovulation suppression vs placebo; Chinese herbal medicine vs gestrinone; postsurgical medical therapy vs placebo or no treatment; pentoxifylline vs placebo; aspiration or cystectomy of endometriomata vs expectant management.4 Gonadotropin-releasing hormone analogue therapy was associated with higher rates of adverse effects compared with placebo (sleep disturbances, 20 of 24 women [83%] vs 9 of 24 women [38%]). Danazol was associated with higher rates of adverse effects compared with GnRHa (hot flashes, 1410 of 1646 women [86%] vs 537 of 991 women [54%]; vaginitis, 444 of 1266 women [35%] vs 146 of 802 women [18%]; sleep disturbances, 186 of 550 women [34%] vs 58 of 399 women [15%]; headaches, 380 of 1303 women [29%] vs 173 of 1799 women [22%]). Depot progestagens were associated with higher rates of adverse effects (nausea, 12 of 40 women [30%] vs 4 of 40 women [10%]; weight gain, 21 of 40 women [53%] vs 12 of 40 women [30%]; bleeding, 39 of 176 women [22%] vs 5 of 178 women [3%]) compared with other treatments.4
Comparison: Treatment vs placebo or no treatment; one treatment vs another treatment
Discussion
Primary outcomes: Self-reported pain relief for dysmenorrhea and live birth rate
Limitations
Secondary outcomes: Clinical improvement or resolution of endometriosis-related pain, pain recurrence, clinical pregnancy, ongoing pregnancy, miscarriage, and adverse events
There is limited evidence to guide clinical decisions for endometriosis therapy. Evidence is especially limited for preventing recurrence. There are insufficient data to reach definitive conclusions about the superiority of any one treatment for endometriosis. The
Endometriosis is a common gynecological condition characterized by deposits of endometrial tissue outside the endometrial cavity, such as the liver, diaphragm, umbilicus, and pleural cavity.1 The prevalence is as high as 10% in the general population and as high as 40% in subfertile women.2 Pain is the common presenting feature and often recurs, even after treatment.3 This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 to assess treatments that are associated with improved outcomes for women with endometriosis.
Summary of Findings The levonorgestrel-releasing intrauterine system (LNG-IUD) was associated with fewer painful symptoms compared with usual care. Laparoscopic surgery (ablation and excision; ablation and uterine nerve transection) was associated with reduced pain at 6 months compared with diagnostic laparoscopy. Laparoscopic excision of the endometrioma cyst wall was associated with decreased recurrence of dysmenorrhea after 2 years compared with ablation.
Evidence Profile No. of randomized clinical trials: 140 (included in 18 Cochrane systematic reviews) Study years: Published, 1979-2012; literature search conducted to July 2013 No. of patients: 13 599 Women: 100% Race/ethnicity: Unavailable Age: Women of reproductive age Settings: Gynecology and fertility clinics
296
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JAMA Clinical Evidence Synopsis Clinical Review & Education
Table. Outcomes Following Treatment for Women Diagnosed With Endometriosisa Absolute Event Rates, No. of Events/Total Patients (%) Treatment Comparison LNG-IUD vs expectant management
Outcome Painful symptoms
Resolution of Laparoscopic ablation or excision pain at 6 mo vs diagnostic laparoscopy
Relative Association (95% CI)
No. of Participants
No. of Trials
Control Group
Intervention Group
Risk Ratio
95
2
18/47 (38)
4/48 (8)
0.22 (0.08 to 0.60)
171
3
25/78 (32)
70/93 (75)
Odds Ratio
6.58 (3.31 to 13.10)
Strength of the Evidence7
Reasons for Evidence Rating
Moderate
No blinding in 1 trial; blinding was unclear in other trial
Moderate
No blinding; allocation concealment and randomization unclear in 2 trials
GnRHa vs no treatment
Relief of dysmenorrhea
35
1
3/16 (18)
14/19 (74)
3.93 (1.37 to 11.28)
Low
No blinding; evidence based on a single trial
GnRHa vs no treatment
Relief of pelvic tenderness
49
1
4/25 (16)
16/24 (67)
4.17 (1.62 to 10.68)
Low
No blinding; evidence based on a single trial
Recurrence of Laparoscopic dysmenorrhea excision of endometrioma cyst at 2 y wall vs ablation
104
2
26/47 (55)
9/57 (16)
0.15 (0.06 to 0.38)
Moderate
1 trial in abstract only
Pregnancy Laparoscopic ablation or excision vs diagnostic laparoscopy
381
2
34/190 (18)
57/192 (30)
1.94 (1.20 to 3.16)
Moderate
1 trial in abstract only; minimal data on live birth
Excisional vs ablative surgery for endometriomata
Pregnancy
88
2
11/47 (23)
25/41 (61)
5.21 (2.04 to 13.29)
Low
No blinding in 1 trial; small sample sizes
GnRHa prior to IVF vs no GnRHa
Pregnancy
165
3
25/77 (32)
53/88 (60)
4.28 (2.0 to 9.15)
Very low
No blinding or details for allocation concealment; statistical imprecision
Abbreviations: GnRHa, gonadotropin-releasing hormone analogues; IVF, in vitro fertilization; LNG-IUD, levonorgestrel-releasing intrauterine system. a
Source: Data have been adapted with permission from Wiley.4
available evidence was limited by the number of randomized trials reporting relevant data and high risk of bias, specifically poor reporting of methods of randomization, allocation concealment, small sample sizes, and wide confidence intervals.
(COCP), laparoscopic excision, and nonsteroidal anti-inflammatory drugs (NSAIDS) as first-line treatments and GnRHa (for cases in which alternative first-line treatment interventions have failed), NSAIDS, COCP, and LNG-IUD as second-line treatments.
Comparison of Findings and Current Guidelines
Areas in Need of Future Study
The European Society of Human Reproduction and Embryology5 recommends GnRHa, laparoscopic ablation or excision, progestagens, or LNG-IUD as first-line treatments for endometriosis based on patient preferences, adverse effects, efficacy, costs, and availability. The American College of Obstetrics and Gynecology6 recommends GnRHa, progestagens, danazol, combined oral contraceptive pill
Direct comparisons of medical therapy with surgical interventions may identify optimal treatments for relieving pain associated with endometriosis. Randomized clinical trials are needed to determine whether surgical interventions in women with endometriomata reduce the capacity of the ovary to produce egg cells that are capable of fertilization, resulting in a healthy pregnancy with a live birth.
ARTICLE INFORMATION Author Affiliations: Liggins Institute, University of Auckland, New Zealand (Brown); Department of Obstetrics and Gynaecology, University of Auckland, New Zealand (Farquhar). Corresponding Author: Julie Brown, PhD, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Both Drs Brown and Farquhar report being authors on some of the source reviews. Funder/Sponsor: The Auckland District Health Board Trust funded the salary of Dr Brown.
jama.com
Role of the Funder/Sponsor: The Auckland District Health Board Trust had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES
5. Dunselman GA, Vermeulen N, Becker C, et al; European Society of Human Reproduction and Embryology. ESHRE guideline. Hum Reprod. 2014; 29(3):400-412. 6. American College of Obstetrics and Gynecology. Practice bulletin No. 114. Obstet Gynecol. 2010;116 (1):223-236. 7. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE. BMJ. 2008;336(7650): 924-926.
1. Hickey M, Ballard K, Farquhar CM. Endometriosis. BMJ. 2014;348:g1752. 2. Ozkan S, Murk W, Arici A. Endometriosis and infertility. Ann N Y Acad Sci. 2008;1127:92-100. 3. Guo S-W. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441-461. 4. Brown J, Farquhar C. Endometriosis. Cochrane Database Syst Rev. 2014;3(3):CD009590.
(Reprinted) JAMA January 20, 2015 Volume 313, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
297
JAMA Clinical Evidence Synopsis
An Overview of Treatments for Endometriosis Julie Brown, PhD; Cynthia Farquhar, MD
CLINICAL QUESTION What treatments are associated with improved outcomes for women with endometriosis? BOTTOM LINE The levonorgestrel-releasing intrauterine system (LNG-IUD), gonadotropin-releasing hormone analogues (GnRHa; nafarelin, leuprolide, buserelin, goserelin, triptorelin), laparoscopic ablation, and excision are associated with relief of pain due to endometriosis. Gonadotropin-releasing hormone analogues and laparoscopic ablation or excision are associated with increased clinical pregnancy rates in women with endometriosis. Gonadotropin-releasing hormone analogues, danazol, and depot progestagens are associated with a higher incidence of adverse events.
Countries: Worldwide
Gonadotropin-releasing hormone analogues (GnRHa) were associated with relief of pelvic tenderness compared with placebo and relief of painful periods compared with no treatment (Table). There was very low-quality evidence for studies that compared excisional vs ablative surgery, danazol vs placebo, and acupuncture vs Chinese herbal medicine. Laparoscopic surgery (ablation and excision; ablation and uterine nerve transection) was associated with increased live births and ongoing pregnancies compared with diagnostic laparoscopy. Laparoscopic excision of the endometrioma cyst wall was associated with increased clinical pregnancy rates compared with ablation. Prior to in vitro fertilization, GnRHa was associated with increased clinical pregnancies compared with no GnRHa (Table). There were no differences in pregnancy rates between groups in trials that compared the following: ovulation suppression vs placebo; Chinese herbal medicine vs gestrinone; postsurgical medical therapy vs placebo or no treatment; pentoxifylline vs placebo; aspiration or cystectomy of endometriomata vs expectant management.4 Gonadotropin-releasing hormone analogue therapy was associated with higher rates of adverse effects compared with placebo (sleep disturbances, 20 of 24 women [83%] vs 9 of 24 women [38%]). Danazol was associated with higher rates of adverse effects compared with GnRHa (hot flashes, 1410 of 1646 women [86%] vs 537 of 991 women [54%]; vaginitis, 444 of 1266 women [35%] vs 146 of 802 women [18%]; sleep disturbances, 186 of 550 women [34%] vs 58 of 399 women [15%]; headaches, 380 of 1303 women [29%] vs 173 of 1799 women [22%]). Depot progestagens were associated with higher rates of adverse effects (nausea, 12 of 40 women [30%] vs 4 of 40 women [10%]; weight gain, 21 of 40 women [53%] vs 12 of 40 women [30%]; bleeding, 39 of 176 women [22%] vs 5 of 178 women [3%]) compared with other treatments.4
Comparison: Treatment vs placebo or no treatment; one treatment vs another treatment
Discussion
Primary outcomes: Self-reported pain relief for dysmenorrhea and live birth rate
Limitations
Secondary outcomes: Clinical improvement or resolution of endometriosis-related pain, pain recurrence, clinical pregnancy, ongoing pregnancy, miscarriage, and adverse events
There is limited evidence to guide clinical decisions for endometriosis therapy. Evidence is especially limited for preventing recurrence. There are insufficient data to reach definitive conclusions about the superiority of any one treatment for endometriosis. The
Endometriosis is a common gynecological condition characterized by deposits of endometrial tissue outside the endometrial cavity, such as the liver, diaphragm, umbilicus, and pleural cavity.1 The prevalence is as high as 10% in the general population and as high as 40% in subfertile women.2 Pain is the common presenting feature and often recurs, even after treatment.3 This JAMA Clinical Evidence Synopsis summarizes a Cochrane review1 to assess treatments that are associated with improved outcomes for women with endometriosis.
Summary of Findings The levonorgestrel-releasing intrauterine system (LNG-IUD) was associated with fewer painful symptoms compared with usual care. Laparoscopic surgery (ablation and excision; ablation and uterine nerve transection) was associated with reduced pain at 6 months compared with diagnostic laparoscopy. Laparoscopic excision of the endometrioma cyst wall was associated with decreased recurrence of dysmenorrhea after 2 years compared with ablation.
Evidence Profile No. of randomized clinical trials: 140 (included in 18 Cochrane systematic reviews) Study years: Published, 1979-2012; literature search conducted to July 2013 No. of patients: 13 599 Women: 100% Race/ethnicity: Unavailable Age: Women of reproductive age Settings: Gynecology and fertility clinics
296
JAMA January 20, 2015 Volume 313, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
jama.com
JAMA Clinical Evidence Synopsis Clinical Review & Education
Table. Outcomes Following Treatment for Women Diagnosed With Endometriosisa Absolute Event Rates, No. of Events/Total Patients (%) Treatment Comparison LNG-IUD vs expectant management
Outcome Painful symptoms
Resolution of Laparoscopic ablation or excision pain at 6 mo vs diagnostic laparoscopy
Relative Association (95% CI)
No. of Participants
No. of Trials
Control Group
Intervention Group
Risk Ratio
95
2
18/47 (38)
4/48 (8)
0.22 (0.08 to 0.60)
171
3
25/78 (32)
70/93 (75)
Odds Ratio
6.58 (3.31 to 13.10)
Strength of the Evidence7
Reasons for Evidence Rating
Moderate
No blinding in 1 trial; blinding was unclear in other trial
Moderate
No blinding; allocation concealment and randomization unclear in 2 trials
GnRHa vs no treatment
Relief of dysmenorrhea
35
1
3/16 (18)
14/19 (74)
3.93 (1.37 to 11.28)
Low
No blinding; evidence based on a single trial
GnRHa vs no treatment
Relief of pelvic tenderness
49
1
4/25 (16)
16/24 (67)
4.17 (1.62 to 10.68)
Low
No blinding; evidence based on a single trial
Recurrence of Laparoscopic dysmenorrhea excision of endometrioma cyst at 2 y wall vs ablation
104
2
26/47 (55)
9/57 (16)
0.15 (0.06 to 0.38)
Moderate
1 trial in abstract only
Pregnancy Laparoscopic ablation or excision vs diagnostic laparoscopy
381
2
34/190 (18)
57/192 (30)
1.94 (1.20 to 3.16)
Moderate
1 trial in abstract only; minimal data on live birth
Excisional vs ablative surgery for endometriomata
Pregnancy
88
2
11/47 (23)
25/41 (61)
5.21 (2.04 to 13.29)
Low
No blinding in 1 trial; small sample sizes
GnRHa prior to IVF vs no GnRHa
Pregnancy
165
3
25/77 (32)
53/88 (60)
4.28 (2.0 to 9.15)
Very low
No blinding or details for allocation concealment; statistical imprecision
Abbreviations: GnRHa, gonadotropin-releasing hormone analogues; IVF, in vitro fertilization; LNG-IUD, levonorgestrel-releasing intrauterine system. a
Source: Data have been adapted with permission from Wiley.4
available evidence was limited by the number of randomized trials reporting relevant data and high risk of bias, specifically poor reporting of methods of randomization, allocation concealment, small sample sizes, and wide confidence intervals.
(COCP), laparoscopic excision, and nonsteroidal anti-inflammatory drugs (NSAIDS) as first-line treatments and GnRHa (for cases in which alternative first-line treatment interventions have failed), NSAIDS, COCP, and LNG-IUD as second-line treatments.
Comparison of Findings and Current Guidelines
Areas in Need of Future Study
The European Society of Human Reproduction and Embryology5 recommends GnRHa, laparoscopic ablation or excision, progestagens, or LNG-IUD as first-line treatments for endometriosis based on patient preferences, adverse effects, efficacy, costs, and availability. The American College of Obstetrics and Gynecology6 recommends GnRHa, progestagens, danazol, combined oral contraceptive pill
Direct comparisons of medical therapy with surgical interventions may identify optimal treatments for relieving pain associated with endometriosis. Randomized clinical trials are needed to determine whether surgical interventions in women with endometriomata reduce the capacity of the ovary to produce egg cells that are capable of fertilization, resulting in a healthy pregnancy with a live birth.
ARTICLE INFORMATION Author Affiliations: Liggins Institute, University of Auckland, New Zealand (Brown); Department of Obstetrics and Gynaecology, University of Auckland, New Zealand (Farquhar). Corresponding Author: Julie Brown, PhD, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Both Drs Brown and Farquhar report being authors on some of the source reviews. Funder/Sponsor: The Auckland District Health Board Trust funded the salary of Dr Brown.
jama.com
Role of the Funder/Sponsor: The Auckland District Health Board Trust had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES
5. Dunselman GA, Vermeulen N, Becker C, et al; European Society of Human Reproduction and Embryology. ESHRE guideline. Hum Reprod. 2014; 29(3):400-412. 6. American College of Obstetrics and Gynecology. Practice bulletin No. 114. Obstet Gynecol. 2010;116 (1):223-236. 7. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE. BMJ. 2008;336(7650): 924-926.
1. Hickey M, Ballard K, Farquhar CM. Endometriosis. BMJ. 2014;348:g1752. 2. Ozkan S, Murk W, Arici A. Endometriosis and infertility. Ann N Y Acad Sci. 2008;1127:92-100. 3. Guo S-W. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441-461. 4. Brown J, Farquhar C. Endometriosis. Cochrane Database Syst Rev. 2014;3(3):CD009590.
(Reprinted) JAMA January 20, 2015 Volume 313, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
297
