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A Review of Evidence-Based Management Ofuterinefibroids PDF
A Review of Evidence-Based Management Ofuterinefibroids PDF
12223 2016;18:33–42
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Please cite this paper as: Younas K, Hadoura E, Majoko F, Bunkheila A. A review of evidence-based management of uterine fibroids. The Obstetrician &
Gynaecologist 2016;18:33–42. DOI: 10.1111/tog.12223
Pharmacological treatment
Pharmacological options are available for short-term use to
Figure 1. A description of fibroids in relation to their location in treat problems associated with fibroids. These options were
the uterus. used more frequently in the following situations:
in perimenopausal women whose problems were likely to
resolve with the onset of the menopause
has been reported.7 Treatment options for fibroids have been in women who were not suitable for surgery and in some
the subject of Cochrane reviews, but research is still needed to women receiving fertility treatment
determine the most appropriate treatment options for preoperatively to reduce the size of the fibroid and to
women with fibroids. reduce menstrual bleeding to improve haemoglobin levels
The aim of this review was to assess the clinical before surgery. Ulipristal acetate (UA) and
effectiveness of treatments for symptomatic uterine fibroids gonadotrophin-releasing hormone (GnRH) analogues
in premenopausal women. We focused on the effectiveness of may be used prior to surgery for a fibroid uterus.
treatment in reducing menstrual loss and fibroid size as well
as improvement in symptoms. In Table S1, we provide a descriptive summary of available
medical treatment options for uterine fibroids and their
effects on menstrual loss, fibroid size and quality of life.
Methods
In defining our question for the review we used the PICO
Nonhormonal treatment for heavy periods
(participants, intervention, comparison and outcome) tool.8
associated with fibroids
We searched the Medline, PubMed, Ovid and Cochrane
Library databases using the following keywords: ‘fibroid’, Tranexamic acid is frequently used in treating heavy
‘leiomyomata’, ‘leiomyoma’, ‘leiomyofibromas’, menstrual bleeding in women who have uterine fibroids.
‘menorrhagia due to fibroids’, ‘menometrorrhagia, Tranexamic acid is an antifibrinolytic drug that reduces
symptomatology and management’, ‘treatment of fibroids’, menstrual loss. A review of the use of tranexamic acid in
and ‘medical and surgical management of fibroid uterus’. women with fibroids concluded that it may reduce
Studies of premenopausal women in which the outcome menorrhagia as well as perioperative blood loss in
measures were either change in menstrual loss, uterine or myomectomy.10 Necrosis and infarcts in fibroids (especially
fibroid size (volume) or improvement in quality of life were in large fibroids) have been reported following use of
included. All studies from 1990 onwards were included and tranexamic acid.10,11
we placed no limits on language of publications. Relevant
papers in foreign languages were translated into English
Hormonal treatments
through the library services. When considering procedures
that are current standard practice, we included only Published data for the outcome of treatment with the
randomised controlled trials, meta-analyses and systematic combined pill or progesterone-only pill in women with a
reviews. For newer treatments, we included all the available fibroid uterus are inconclusive. Fibroids have estrogen
literature, including case series. We also looked for and progesterone receptors and both estrogen and
unpublished work discussed in international and national progesterone may promote their growth.12 These hormonal
treatments can also induce endometrial atrophy, which can et al.17 reported low expulsion rates. An online survey for the
result in reduced menstrual loss.12 A small observational Uterine Bleeding and Pain Women’s Research Study found
study reported a reduction in menstrual blood loss and that 10.3% of women in the UK and France used the
fibroid volume after 6 months of treatment with depot LNG-IUS for menorrhagia associated with fibroids.4
medroxyprogesterone acetate.13 The LNG-IUS reduces menstrual blood loss from
fibroids by inducing endometrial atrophy. A review by
Levonorgestrel intrauterine system Sangkomkamhang et al.16 included a randomised controlled
The levonorgestrel intrauterine system (LNG-IUS) has been trial of 58 women assigned to either a combined oral
widely accepted as an effective treatment of heavy menstrual contraceptives treatment group (n = 29) or a LNG-IUS
bleeding. There is general agreement among several reviews (n = 29) treatment group. The trial showed that the LNG-IUS
that use of the LNG-IUS in women with fibroids is successful was more effective than combined oral contraceptives in
in reducing menstrual blood loss, increasing haemoglobin reducing menstrual blood loss and improving haemoglobin
and relieving symptoms.14–17 There are conflicting results levels.18 The LNG-IUS group showed an increase in
regarding its effect on fibroid or uterine volume and device haemoglobin levels from 9.7 1.9 g/dL to 11.7 1.2 g/dL
expulsion rates. Jiang et al.17 reported no effect on fibroid (P <0.001) and a reduced number of days of menstrual loss.18
volume but a decrease in uterine volume; however,
Sangkomkamhang et al.16 and Kim and Seong15 reported Gonadotropin-releasing hormone analogues
no change in both uterine and fibroid volume. Zapata et al.14 GnRH analogues were approved by the Food and Drug
and Kim and Seong15 reported higher device expulsion rates Administration in 1995 for preoperative management of
that appear to increase with uterine volume. However, Jiang uterine fibroids. GnRH analogue treatment induces a
menopausal state with low estrogen levels that may result in endometrium. Some reports suggest no effect on fibroid
intolerable side effects and bone loss. The hypoestrogenic side volume23 while others show a reduction in fibroid or uterine
effects could be minimised by adding low dose estrogen and volume.24,25 A systematic review of three clinical trials
progestin or tibolone after initial phase of downregulation. including 112 women treated with 5–50 mg of mifepristone
GnRH analogue treatment is therefore limited to a maximum for 3–6 months reported a significant reduction in menstrual
of 6 months. A Cochrane review that evaluated the role of blood loss and an improvement of symptoms (OR 17.84;
preoperative GnRH analogue treatment in women 95% CI 6.72–47.38), but no change in uterine volume.23
undergoing hysterectomy or myomectomy suggested a 36% Mifepristone has been associated with development of
reduction in leiomyoma size and an improvement in endometrial changes in some reports22–25 and its use in
symptoms after 12 weeks.19 After discontinuation of treatment of fibroids is currently restricted to research
treatment, menstruation returned in 4–8 weeks and fibroid settings.22–24
size returned to pretreatment levels within 4–6 months.19,20
Preoperative use of a GnRH analogue may reduce fibroid Ulipristal acetate
volume sufficiently to make vaginal hysterectomy or UA is a new SPRM that is considered effective in the
transverse incision for the abdominal approach feasible. treatment of uterine fibroids. It induces apoptosis in uterine
Preoperative treatment with a GnRH analogue appears to fibroid cells and inhibits proliferation of cells.27 In the first
make hysterectomy easier, with reduced operating time and a trial (PEARL I),27 5 mg and 10 mg UA doses were compared
shorter hospital stay. with placebo for 13 weeks. Both doses of UA were effective in
There have been concerns about difficulties during reducing menstrual blood loss in over 90% of patients after
myomectomy in obtaining an appropriate plane for 13 weeks of treatment.27 Amenorrhoea was noted within 10
dissection between the fibroid capsule and myometrium days in three-quarters of patients receiving UA. The median
and that small fibroids were often poorly defined and change in uterine fibroid volume was 41% compared with
therefore were missed in women pretreated with GnRH 18% (P = 0.0100) and this reduction was maintained for at
analogues. Deligdisch et al.21 reported the blurred interface least 6 months after discontinuation of treatment.27
between myoma and myometrium and obliteration of The PEARL II trial28 was a noninferiority, double-blind 13
cleavage plan on anatomical and histopathologic findings weeks comparison of UA with a GnRH analogue (monthly
with GnRH analogue use before the surgery. injection of leuprolide acetate). There was no difference in
the control of menstrual bleeding between UA and
Progesterone-mediated medical treatment leuprolide. However, UA was tolerated better and
Progesterone binds to progesterone receptors to mediate its controlled bleeding more rapidly than leuprolide. Uterine
effects in tissues. It has been established that progesterone volume change was greater with leuprolide than UA, but
acting through its receptors enhances the proliferative activity ultrasound assessment showed no difference in fibroid
of fibroids. Antiprogestins and agents that modulate volume change.28 UA use was associated with benign
progesterone receptor activity, collectively termed selective endometrial changes termed progesterone-receptor-
progesterone-receptor modulators (SPRMs), could be useful modulator-associated endometrial changes. These changes
in the treatment of fibroids. Several SPRMs, including were noted in up to two-thirds of women during treatment
mifepristone, telapristone, asoprisnil and UA, have been and resolved within 6 months of discontinuation
used in clinical trials for the treatment of uterine of treatment.
fibroids.22–29 The PEARL III and extension trials were performed to
investigate long-term use of UA with repeated treatment
Selective progesterone-receptor modulators cycles. In PEARL III, 209 patients used 10 mg of UA for 12
weeks and results were similar to those of PEARL I and II. In
Mifepristone the PEARL III extension, a subsample of 107 women received
Mifepristone, a synthetic steroid, works by modulating four courses of UA as well as norethisterone acetate between
progesterone receptors and has been used to alleviate the courses.29 The use of norethisterone acetate between courses
symptoms of fibroids. In one double-blind, randomised of UA had no effect on progesterone-receptor-modulator-
clinical trial comparing 10 mg of mifepristone with placebo associated endometrial changes.
there was a reduction in uterine and fibroid volume as well as Progesterone plays an important role in normal
decreased menstrual blood loss in the mifepristone group.22 physiological function of reproductive organs, mammary
The reduction in menstrual loss and improvement in glands, and bone, brain and endothelial cells in vessels and
symptoms in women treated with mifepristone appears to the central nervous system. Studies are needed to evaluate the
be a consistent finding.23–25 However, there is no consensus effects of SPRMs on other body systems, especially after
about the effect of mifepristone on fibroid volume and the prolonged use.
Gupta et al.35 Review 7 studies UAE versus abdominal Higher rate of minor complications in UAE group.
793 women hysterectomy No difference in major complications.
UAE versus myomectomy UAE associated with higher rate of need for further interventions.
Insufficient evidence on fertility outcomes but suggestion that
myomectomy may have advantage over UAE.
UAE had shorter hospital stay, reduced need for blood transfusion.
produce heat to denature proteins leading to cell death and however, MRgFUS was associated with a seven-fold need for
shrinkage of fibroids. MRI is used to target the fibroids and reintervention within 12 months.44
treatment is monitored by assessing the temperature of The newer uterus-preserving fibroid treatments need
treated tissue. The major advantages of MRgFUS are quick further research to determine their safety for future child
recovery and very low morbidity. This treatment is not yet bearing. Around a quarter (21–28%) of women needed
recommended for women wishing to preserve fertility.40 The further intervention after treatment of fibroids with
Food and Drug Administration approved this treatment in MRgFUS.41–44
2004 but the National Institute for Health and Care
Excellence advises its use only in research and
Surgical treatments of fibroids
audit settings.32
In one study, 91.5% of 54 patients who completed a fibroid Surgical management of uterine fibroids may be required in
symptom and quality of life questionnaire, both before and women with severe pressure symptoms, unresponsiveness to
after MRgFUS treatment, reported satisfaction with other therapies (medical, UAE) or in large pedunculated
treatment and a significant reduction in fibroid-related subserosal or submucous fibroids. Surgical treatment can be
symptoms at 12 months.41 either hysterectomy or myomectomy. The size and location
Machtinger et al.42 reported the outcome of telephone of the fibroid in the uterus and the desire for future fertility
interviews at 33 months ( 15 months) with 81 women affects the choice of surgical procedure. Hysteroscopic,
treated with MRgFUS. Most women (69%) did not need laparoscopic, vaginal or laparotomy routes may be used to
further surgical intervention, but 24% needed further remove fibroids. Myomectomy may alleviate symptoms in
treatment, especially women with hyperintense fibroids (on most women with uterine fibroids but complications (e.g.
ultrasound the fibroid is whiter than the myometrium); the severe haemorrhage that is difficult to control), may lead to
OR was 2.96 (95% CI 1.01–8.71).42 Less vascular fibroids hysterectomy. The need for careful counselling prior to
with low signal intensity on MRI were more likely to surgical interventions cannot be overemphasised.45,46
respond to treatment than high signal intensity vascular
fibroids.41,42 The incidence of side effects was generally low. Myomectomy
Transient adverse effects included mild skin burn, nausea,
short-term buttock or leg pain and transient sciatic nerve Hysteroscopic myomectomy
palsy.41–43 One case of severe skin burn needing skin graft Hysteroscopic myomectomy for submucous and intracavity
has been reported.43 A systematic review including 2500 fibroids is an established procedure for heavy menstrual
patients in 38 studies concluded that MRgFUS was a safe, bleeding, recurrent miscarriages and infertility.45,47
cost-effective, minimally invasive technique for treatment of Submucous fibroids have been reported in 6–34% of
fibroids. Further research is needed regarding its effect women with abnormal uterine bleeding, in 2–7% of
on fertility.43 women undergoing infertility investigations and in 1–5% of
A small clinical trial comparing MRgFUS with UAE in asymptomatic women who had hysteroscopic sterilisation.45
fibroid treatment found no difference in relief of symptoms; Classification systems have been devised to enable accurate
Figure 3. Saline sonography for submucous fibroids. (a) Grade 0, (b) Grade 1, (c) Grade 2.
Reproduced with permission from Professor A Abdel-Gadir, www.gynaecologist4u.com.
ESGE = European Society of Gynaecological Endoscopy; FIGO = International Federation of Gynaecology and Obstetrics.
description of submucous fibroids (Figure 3) and assist serosa is an important factor in determining the safety of
clinicians in determining the likelihood of successful hysteroscopic resection in Grade 2 cases.
hysteroscopic surgery. The most widely used classification When fertility is not a concern, the combination of
is that adopted by the European Society of Gynaecological hysteroscopic fibroid resection with endometrial ablation
Endoscopy (ESGE);48 the International Federation of may be performed. In one study, 90% of women showed a
Gynaecology and Obstetrics (FIGO) have a more extensive decrease in menstrual blood loss at 1-year follow-up.52
classification system for fibroids49 (Table 2 contains details of One review of different techniques used for hysteroscopic
the FIGO and ESGE classification systems). There are myomectomy has suggested that resectoscopic slicing is the
limitations in using these classifications to predict operative gold standard for intracavity fibroids (Grade 0), although there
outcomes; therefore, another classification was introduced to is no single proven technique for fibroid treatment with an
improve the outcome in hysteroscopic myomectomy. This is intramural component (Grades 1 and 2).53 Figure 4 shows a
called STEPW (size, topography, extension, penetration and resection of a Grade 0 submucous fibroid using a resectoscope.
lateral wall);50 one multicentre study comparing this Traditional methods of fibroid resection may be partly
classification system with the ESGE classification system for replaced by myolysis (in which an electric current is passed
hysteroscopic myomectomy indicated that the former system through a needle to destroy the fibroid) or cryomyolysis
was better at predicting successful myoma resection and (in which a freezing probe is used in a similar manner).
minimising surgical complications.51 Grade 0 and Grade 1 These techniques can be used for all types of fibroids
fibroids can be easily removed hysteroscopically, but through laparoscopic or hysteroscopic routes. They are
difficulties are likely to be encountered with Grade 2 associated with less blood loss but have the disadvantages
fibroids as most of the fibroid is in the myometrium. The of providing no tissue for histology, an increased risk of
thickness of the myometrium between the fibroid and the postoperative adhesions and the need for
reintervention.52,53 Myolysis can be an alternative to hospital stay.46 One meta-analysis showed that the
myomectomy in selected cases. laparoscopic approach is associated with longer operating
times, less blood loss, less postoperative pain and fewer
Laparotomy/laparoscopic myomectomy complications than open conventional myomectomy.57
Myomectomy can be performed either by the laparoscopic The choice of open laparotomy or laparoscopic
route or open laparotomy. Myomectomy may reduce myomectomy depends upon the availability of facilities and
menstrual blood loss and can be considered for women expertise of surgeons. The size and number of fibroids may
who want to preserve the uterus.54 make laparoscopic myomectomy inappropriate.
Women who have laparotomy for hysterectomy or Conventional open myomectomy has advantages in the
myomectomy show similar surgical complications, such presence of huge, multiple fibroids where a laparoscopic
as haemorrhage, unintended repeat surgery and approach is not possible.58
rehospitalisation, while bladder and bowel injuries are more
frequent with hysterectomy.54 One systematic review showed Hysterectomy
that laparoscopic occlusion of the uterine artery is less effective Hysterectomy remains the definitive surgical intervention for
for the treatment of symptomatic uterine fibroids compared uterine fibroids.58,59 It is the permanent treatment that shows
with myomectomy and uterine artery embolisation.55 the highest satisfaction regarding heavy menstrual bleeding
Techniques for reducing blood loss during myomectomy symptoms. In the USA, uterine fibroids are the indication for
include a preoperative course of GnRH analogue or SPRM, use one-third of all hysterectomies.59 Hysterectomy is a major
of vasoconstriction agents (vasopressin) and tourniquets surgical procedure associated with longer hospital stay and
during surgery. Laparoscopic myomectomy is considered increased time off work. Open conventional hysterectomy,
the best treatment option for symptomatic uterine fibroids in vaginal hysterectomy and total laparoscopic hysterectomy
women who wish to retain childbearing capacity.56 A can be performed when there is a fibroid uterus. Walsh
systematic review comparing laparoscopic myomectomy and et al.60 compared open conventional hysterectomy with total
open myomectomy showed that laparoscopic procedures were laparoscopic hysterectomy and reported that the latter
associated with less postoperative pain or fever and shorter resulted in shorter hospital stay, fewer perioperative
Study
Intervention Author design Participants Intervention details Main results
complications and reduced intraoperative blood loss. Table S1. Pharmacological interventions for treatment of
However, feasibility of total laparoscopic hysterectomy for fibroids.
fibroids depends on the size of the fibroids and may be Single Best Answer questions are available for this article at
associated with a longer operating time.60 Surgical https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
interventions are shown in Table 3.
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