Pharmacological Treatment for Symptomatic Adenomyosis: A Systematic Review

A search was performed by two authors in the Pubmed, Scopus, and Scielo databases and in the grey literature from inception to March 2018, with no language restriction.

Selection of Studies

We have included prospective randomized studies for treating symptomaticwomen with adenomyosis (abnormal uterine bleeding and/or pelvic pain) diagnosed by ultrasound or magnetic resonance imaging.

Data Collection

Studies were primarily selected by title and abstract. The articles that were eligible for inclusion were evaluated in their entirety, and their data was extracted for further processing and analysis.

Data Synthesis

From567retrieved records only 5 remained for analysis. The intervention groups were: levonorgestrel intrauterine system (LNG-IUS)(n= 2), dienogest (n= 2), and letrozole (n= 1). Levonorgestrel intrauterine system was effective to control bleeding when compared to hysterectomy or combined oral contraceptives (COCs). One study assessed chronic pelvic pain and reported that LNG-IUS was superior to COC to reduce symptoms. Regarding dienogest, it was efficient to reduce pelvic pain when compared to placebo or goserelin, but less effective to control bleeding than gonadotropin-releasing hormone (GnRH) analog. Letrozolewas as efficient asGnRHanalog to relieve dysmenorrhea and dyspareunia, but not for chronic pelvic pain. Reduction of uterine volumewas seen with aromatase inhibitors, GnRH analog, and LGN-IUD.

Conclusion

Levonorgestrel intrauterine system and dienogest have significantly improved the control of bleeding and pelvic pain, respectively, in women with adenomyosis. However, there is insufficient data from the retrieved studies to endorse eachmedication for this disease. Further randomized control tests (RCTs) are needed to address pharmacological treatment of adenomyosis.

Keywords:
adenomyosis; abnormal menstrual bleeding; pelvic pain; systematic review; medical treatment

Author, Year	Country	Study aim	Diagnosis	Sample	Study design	Treatment	Follow-up	Evaluation method	Pain - results	Bleeding loss - results	Uterine volume - results	Quality of life	Other results	Side effects
Ozdegirmenci et al (2011)²¹21 Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril 2011;95(02):497-502. Doi: 10.1016/j.fertnstert.2010.10.009 https://doi.org/10.1016/j.fertnstert.201...	Turkey	To compare LNG-IUS versus hysterectomy	US and MRI criteria	N = 86; 43 in each group	Prospective randomized clinical trial(do not register)	LNG- IUS (final participants, n = 43); Hysterectomy (final participants n = 32)	6 and 12 months	1. Menstrual bleeding (number of pads/day and hemoglobin levels)2. Quality of life (WHOQOL-brief)	Did not assess	LNG-IUS increased the Hb levels to comparable levels with hysterectomy	Did not assess	Both treatments have improved health-related quality of life, but LNG-IUS had a superior effect on psychological and social life		LNG-IUS: headache (11.9%), breast tenderness (7.1%), acne (4.8%), a transient depressive episode (2.4%).Hysterectomies: 1 (3.1%) postoperative infection
Badawy et al (2012)²²22 Badawy AM, Elnashar AM, Mosbah AA. Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial. Acta Obstet Gynecol Scand 2012;91(04):489-495. Doi: 10.1111/j.1600- 0412.2012.01350.x https://doi.org/10.1111/j.1600-...	Egypt	To compare aromatase inhibitor (Letrozole 2.5 mg/d) versus GnRH analog (goserelin 3.6 mg)	US criteria	N = 32	Prospective randomized, non-blind controlled clinical trial (retrospectively registered)	Letrozole 2.5mg/d (final participants n= 15)Goserelin 3.6mg/month (final participants n = 16)	4, 8, and 12 weeks	1. PainPelvic pain, dysmenorrhea, dyspareunia (VAS)2. Menstrual bleeding and subfertility (questionnaire, but it is not clear)3. Uterine volume (TVUS)	Goserelin was more effective in relieving chronic pelvic pain (p= 0.04)	Goserelin was so efficient than letrozole in relieving menorrhagia and metrorrhagia	Reduction in uterine volumes, without difference between the two groups			Hot flashes (0% with letrozole, 81,3% with goserelin),Pregnancy (n = 2 with letrozole)
Shaaban et al (2015)²³23 Shaaban OM, Ali MK, Sabra AM, Abd El Aal DE. Levonorgestrelreleasing intrauterine system versus a low-dose combined oral contraceptive for treatment of adenomyotic uteri: a randomized clinical trial. Contraception 2015;92(04):301-307. Doi: 10.1016/ j.contraception.2015.05.015 https://doi.org/10.1016/...	Egypt	To compare LNG-IUS versus COC	US criteria	N = 62; 31 in each group	Prospective randomized clinical trial, registered	LNG-IUS (final participants n = 29)COC (35mcg of gestodene + 30 mcg of EE, 21/7) (final participants n = 28)	6 months	1. Pain (VAS)2. Menstrual bleeding (menstrual diary, pads/day),3. Uterine volume (TVUS and Doppler)	Both treatments reduced pains, however, the reduction was greater in the LNG-IUS group	Both treatments decreased the number of bleeding days, number of sanitary pads per day, but the reduction was greater with LNG-IUS	Both treatments decreased the uterine volume, but the reduction was greater with LNG-IUS		Uterine arteries and intramyometrial Doppler indices increase in both groups, but the increases were greater with LNG-IUS	LNG-IUS: expulsion (n = 1)
Fawzy and Mesbah (2015)²⁴24 Fawzy M, Mesbah Y. Comparison of dienogest versus triptorelin acetate in premenopausal women with adenomyosis: a prospective clinical trial. Arch Gynecol Obstet 2015;292(06):1267-1271. Doi: 10.1007/s00404-015-3755-5 https://doi.org/10.1007/s00404-015-3755-...	Egypt	To compare dienogest versus triptorelin acetate	US criteria	N = 41; dienogest (n = 22);triptorelin acetate injection (n = 19)	Prospective non- randomized clinical trial(did not register)	Dienogest 2mg/day (final participants n = 19)Triptorelin acetate (final participants n = 18)	16 weeks	1. Pain,dysmenorrhea, dyspareunia and chronic pelvic pain (VAS)2. Menstrual bleeding (3 levels of satisfied, blood cell count, ferritin)3. Uterine volume (TVUS)	Both treatments reduced chronic pelvic pain and dyspareunia. Triptorelin was more effective in relieving dysmenorrhea	Triptorelin was more effective than dienogest (100 and 73.7% respectively) in controlling menstrual bleeding. Both treatments improved Hb levels and ferritin	Triptorelin was more effective in the reduction of uterine volume			Did not assess
Osuga et al (2017)²⁵25 Osuga Y, Fujimoto-Okabe H, Hagino A. Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study. Fertil Steril 2017;108(04): 673-678. Doi: 10.1016/j.fertnstert.2017.07.021 https://doi.org/10.1016/j.fertnstert.201...	Japan	To compare dienogest versus placebo	US and MRI criteria	N = 67	Randomized, double-blind, multicenter, placebo-controlled phase III study	Dienogest 2mg/day (final participants n = 34 Placebo (final participants n = 33)	16 weeks	1. PainPelvic pain (pain severity score in order to access work and analgesics use and VAS)2. Menstrual bleeding Patient diary form, classified by the number of days and severity of bleeding.3. Uterine volume (US and MRI)4. Quality of life (MOS 36-item short-form health survey)	Dienogest reduced pelvic pain and other pain parameters	Dienogest presented a lower number of days with bleeding, and the most was spotting or breakthrough, but the numbers were not statistically compared between the groups	Uterine volumereduction in both groups, but no difference between them	Bodily pain reduction (the item of quality of life)	Reduction of analgesics use score in the Dienogest group	Anemia and menstrual bleeding (placebo) andhot flash (dienogest)

Certainty assessment - Reduction in uterine volume (ml or cc)							Patients		Effects		Certainty	Importance
Study	Study design	Bias risk	Inconsistency	Indirectness	Imprecision	Other considerations	Group 1	Group 2	Relative(95% CI)	Absolute(95% CI)	Certainty	Importance
Dienogest x Placebo (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	34	33	−	MD 10.4 higher(2.06 lower to 22.86 higher)	⊕⊕⊕○ MODERATE
Letrozole x GnRH analog (12 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	15	16	−	MD 20.6 higher(0.09 lower to 41.29 higher)	⊕⊕⊕○ MODERATE
Dienogest X GnRH analog (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	19	18	−	MD 94 higher(35.68 lower to 223.68 higher)	⊕⊕⊕○ MODERATE
Certainty assessment – Chronic Pelvic Pain (VAS)							Patients		Effects		Certainty	Importance
Study	Study design	Bias risk	Inconsistency	Indirectness	Imprecision	Other considerations	Group 1	Group 2	Relative(95% CI)	Absolute(95% CI)
Dienogest x Placebo (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	34	33	−	MD 37.8 lower(49.1 lower to 26.5 lower)	⊕⊕⊕○ MODERATE
Dienogest x GnRH analog (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	19	18	−	MD 5.3 lower(19.43 lower to 8.83 higher)	⊕⊕⊕○ MODERATE
Certainty assessment – Hemoglobin level (g/dL)							Patients		Effects		Certainty	Importance
Study	Study design	Bias risk	Inconsistency	Indirectness	Imprecision	Other considerations	Group 1	Group 2	Relative(95% CI)	Absolute(95% CI)	Certainty	Importance
Dienogest x GnRH analog (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	19	18	−	MD 1.2 lower(2.46 lower to 0.06 higher)	⊕⊕⊕○ MODERATE
Dienogest x Placebo (16 weeks)
1	Randomized trial	Not serious	Not serious	Not serious	Serious ^a	Undetected	34	33	−	MD 0.4 higher(0.13 lower to 0.93 higher)	⊕⊕⊕○MODERATE
Certainty assessment – Menstrual bleeding (pad/day)							Patients		Effects		Certainty	Importance
Study	Study design	Bias risk	Inconsistency	Indirectness	Imprecision	Other considerations	Group 1	Group 2	Relative(95% CI)	Absolute(95% CI)	Certainty	Importance
LNG-IUS x COC (6 months)
1	Randomized trial	Not serious	Not serious	Not serious	Very serious ^a	Undetected	31	31	−	MD 1.74 lower(2.42 lower to 1.06 lower)	⊕⊕○○ LOW

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[1] Address for correspondence
Cristina Laguna Benetti-Pinto, MD, PhD, Alexander Fleming, 101, 13083-881, Cidade Universitária, Campinas, SP, Brazil (e-mail: laguna.unicamp@gmail.com).