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Human Reproduction Update, Vol.22, No.6 pp. 665–686, 2016
Advanced Access publication on July 27, 2016 doi:10.1093/humupd/dmw023
GRAND THEME REVIEW
Uterine fibroid management:
from the present to the future
Jacques Donnez
1,*
and Marie-Madeleine Dolmans
2
1
Professor EM, Catholic University of Louvain, Director, Société de Recherche pour l’Infertilité (SRI), 143 Avenue Grandchamp,
B-1150 Brussels, Belgium
2
Gynecology Department, Cliniques Universitaires St-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium;
Pôle de Gynécologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Avenue Mounier 52,
bte B1.52.02, 1200 Brussels, Belgium
*Correspondence address. E-mail: jacques.donnez@gmail.com
Submitted on February 2, 2016; resubmitted on May 12, 2016; accepted on May 27, 2016
TABLE OF CONTENTS
• Introduction
Risk factors
Classifications
Symptoms
Diagnosis
• Current surgical management strategies
Hysteroscopic myomectomy
Laparoscopic myomectomy
Laparoscopic hysterectomy
Laparoscopic cryomyolysis and thermo-coagulation
Laparoscopic occlusion of the uterine arteries
• Alternatives to surgical intervention
Uterine artery embolization
High-frequency magnetic resonance-guided focused ultrasound surgery
Vaginal occlusion of the uterine arteries
• Why we need new options
• Current medical therapy
GnRH agonists
• The future of medical therapy
Evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids by use of
selective progesterone receptor modulators
SPRMs and fibroids: what we know so far
Long-term intermittent administration of SPRMs, opening up new treatment perspectives
Novel approaches and algorithms, with a special emphasis on infertility
Uterine fibroid associated pathologies
Future prospectives for medical therapy
• Conclusion
ABSTRACT: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical pre-
sentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.
Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve
surgical interventions, but the choice of treatment is guided by patient’s age and desire to preserve fertility or avoid ‘radical’ surgery such
© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
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as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and
non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization
and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.
There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of
concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic
impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical
intervention.
There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of
selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA
was recently demonstrated by randomized controlled studies.
The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now
exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium,
opening up novel strategies for the management of uterine fibroids.
Key words: uterine fibroids / leiomyomas / selective progesterone receptor modulators / ulipristal acetate / surgery / medical therapy /
myomectomy
Introduction
Uterine fibroids (also known as leiomyomas or myomas) are the
most common form of benign uterine tumors (
Stewart, 2001;
Donnez and Jadoul, 2002; Bulun, 2013; Islam et al., 2013; Drayer and
Catherino, 2015
). They are monoclonal tumors of uterine smooth
muscle, thus originating from the myometrium (
Kim and Sefton,
2012
; Bulun, 2013; Islam et al., 2013). They are composed of large
amounts of extracellular matrix (ECM) containing collagen, fibronec-
tin and proteoglycans (
Parker, 2007; Sankaran and Manyonda, 2008;
Kim and Safton, 2012). Leiomyomas occur in 50–60% of women, ris-
ing to 70% by the age of 50 (
Baird et al., 2003), and, in 30% of cases,
cause morbidity due to abnormal uterine bleeding (heavy menstrual
bleeding inducing anemia) and pelvic pressure (urinary symptoms,
constipation and tenesmus) (
Donnez and Jadoul, 2002; Donnez et al.,
2014a
,b). Clinical presentations of uterine leiomyomas include pelvic
masses, pelvic pain, infertility and obstetric complications (
Donnez
and Jadoul, 2002
).
Risk factors
The risk factors for uterine fibroids are illustrated in Fig. 1.
Race
Race constitutes an important risk factor for leiomyoma development
(
Marshall et al., 1997 ; Wise et al., 2004; Stewart et al., 2013; El
Toukhi et al., 2014
). An US study found that the incidence of uterine
fibroids was 60% by age 35 among African-American women,
increasing to >80% by age 50, while Caucasian women showed a
rate of 40% by age 35, increasing to 70% by age 50 (
Baird et al.,
2003
). Differences in gene expression in uterine fibroids between
these two groups may influence these growth rates (
Davis et al.,
2013
). Nevertheless, it is clear that African-American women have a
greater chance of being affected by uterine fibroids, particularly at an
earlier age (
Wise et al., 2004, 2005; Wise and Laughlin-Tommaso,
2016
). Among women of African origin living in Europe, a similar
trend has been observed, with more severe symptoms and surgery
required at a younger age. Moreover, recurrence rates after surgery
(myomectomy) may be as high as 59% after an interval of 4–5 years
(
Malone, 1969; Donnez et al., 2014a,b) for women of African origin.
Age
Peddada et al. (2008) followed the size of 262 leiomyomas from
72 women for up to 12 months using magnetic resonance imaging
(MRI). The average growth rate was 9% over 6 months, but growth
rates differed between races when age was taken into account.
White women under 35 years of age had faster-growing tumors than
white women over 45, who exhibited a comparatively slow growth
rate. On the other hand, women of African origin did not show any
decrease in myoma growth rates with age.
Figure 1 Risk factors for uterine fibroid. These include race, age,
delayed pregnancy, early menarche, parity (protective effect), caf-
feine, genetic alterations, and others, such as obesity and a diet rich
in red meat.
666 Donnez and Dolmans
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Moreover, delaying the first pregnancy until the third decade of life
also places women at higher risk of uterine fibroids (
Petraglia et al.,
2013
).
Early menarche
Menarche at an early age increases the risk of developing fibroids and
is also considered a risk factor for other hormonally mediated dis-
eases, such as endometrial and breast cancers (
Kim and Sefton,
2012
; Khan et al., 2014).
Parity
Pregnancy has been found to have a protective effect on the develop-
ment of uterine fibroids, but the mechanism remains unclear. It has
been suggested that during post-partum uterine remodeling, small
lesions may be subject to selective apoptosis. Furthermore fibroid tis-
sue may be highly susceptible to ischemia during both uterine remod-
eling and parturition (
Baird and Dunson, 2003; Laughlin et al., 2010).
Caffeine and alcohol
An association has been reported between alcohol and caffeine
intake and an increased risk of developing uterine fibroids in a study
concerning the health of women of African origin (
Wise et al., 2004;
Wise and Laughlin-Tommaso, 2016).
Genetic factors
Some specific genetic alterations are linked to fibroid growth
(
Mäkinen et al., 2011; Eggert et al., 2012; Islam et al., 2013; Mittal
et al., 2015
; Styer and Rueda, 2015). Mehine et al. (2013) performed
whole genome sequencing and gene expression profiling of 38 uterine
leiomyomas and corresponding myometrium. The common occur-
rence of chromothripsis in uterine fibroids suggests that it also plays a
role in their genesis and progression (
Mehine et al., 2013, 2014).
Other factors
General health status may also be predictive of leiomyoma growth,
with factors such as obesity and high blood pressure playing a role. A
diet rich in red meat appears to increase the risk of developing leio-
myomas, while smoking decreases the risk, for unknown reasons
(
Kim and Sefton, 2012; Islam et al., 2013).
Classifications
Numerous classifications of myomas can be found in the literature
(
Lasmar et al., 2005; Stamatellos and Bontis, 2007). All of them take
into account the degree of intramural extension and/or uterine cavity
distortion. The fibroid classification adopted by the ESGE (European
Society for Gynecological Endoscopy) has the advantage of being very
simple (G0 is a pedunculated intrauterine myoma, G1 has its largest
part (>50%) in the uterine cavity, and G2 has its largest part (>50%)
in the myometrium).
More recently, the FIGO classification was published (
Munro et al.,
2011
), describing eight types of fibroids as well as a hybrid class (asso-
ciation of two types of myomas) (Fig.
2). As different types of fibroids
are often present at the same time (depending on the site), this classi-
fication offers a more representative ‘map’ of fibroid distribution and
will be used further for the establishment of new algorithms.
Symptoms
Many fibroids are asymptomatic, but in 30–40% of cases, they show
a variety of symptoms, depending on the location and size. Fibroids
can cause heavy menstrual bleeding with subsequent anemia, which
could be life-threatening (
Parker, 2007; Nelson and Ritchie, 2015).
African-American women have more severe symptoms in terms of
heavy bleeding and anemia compared to white women (
Stewart
et al., 2013
). Large fibroids can also result in pressure symptoms
(bulk symptoms) that may be responsible for bowel and bladder dys-
function, including urgency, increased daytime urinary frequency and
urinary incontinence (
Gupta et al., 2008). Abdominal distention or
distortion and pelvic pressure on the ureters (causing hydronephro-
sis) and pelvic blood vessels (particularly pelvic veins) could also inter-
fere with quality of life (QoL) (
Spies et al., 2002; Donnez et al.,
2014a
,b).
Dysmenorrhea and pelvic pain are frequently encountered, impact-
ing on QoL and impairing daily activities (
Spies et al., 2002). Infertility
and recurrent miscarriage may also be symptoms of fibroids, depend-
ing on their location and size, especially for submucous and intra-
mural myomas distorting the uterine cavity (
Pritts et al., 2009;
Sunkara et al., 2010, Yan et al., 2014; Zepiridis et al., 2015).
Fibroids can impair fertility through several possible mechanisms,
including: (1) alteration of the local anatomy (anatomic distortion of
the uterine cavity), with subsequent alterations to endometrial func-
tion (
Somigliana et al., 2007); (2) functional changes, such as
increased uterine contractility and impairment of the endometrial
and myometrial blood supply (
Donnez and Jadoul, 2002) and (3)
changes to the local hormone milieu and paracrine molecular
changes induced by fibroids, which could impair gamete transport
Figure 2 FIGO classification of uterine fibroids according to
Munro et al. (2011). Fibroid types range from 0 to 8.
0 = Pedunculated, intracavitary; 1 = Submucosal, <50% intramural;
2 = Submucosal, ≥50% intramural; 3 = Contact with endometrium,
100% intramural; 4 = Intramural; 5 = Subserosal, ≥50% intramural;
6 = Subserosal, <50% intramural; 7 = Subserosal, pedunculated;
8 = Other (e.g. cervical, parasitic). Where two numbers are given
(e.g. 2–5), the first number refers to the relationship with the endo-
metrium, while the second number refers to the relationship with
the serosa; e.g. 2–5 = Submucosal and subserosal, each with less
than half the diameter in the endometrial and peritoneal cavities
respectively. Fibroid classification cartoon republished with permis-
sion from
Munro et al. (2011).
667Management of Uterine Fibroids
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and/or reduce blastocyst implantation (Sinclair et al., 2011; Galliano
et al., 2015
).
Moreover, fibroids can affect obstetric outcomes. Inflammatory
pathways, associated or not with other reproductive disorders, may
impair pregnancy outcomes (
Vannuccini et al., 2016). Fibroids are
significantly associated with preterm delivery (<37 weeks), primary
cesarean section, breech presentation and lower birthweight infants
(
Shavell et al., 2012; Lam et al., 2014, Parazzini et al., 2015; Blitz
et al., 2016
). Very recently, a higher incidence of short cervix was
also observed during pregnancy in women with fibroids (
Blitz et al. ,
2016
).
Diagnosis
Pelvic examination
Examination of the pelvis may reveal an enlarged uterus or mass. If
fibroids are suspected and a woman reports heavy menstrual
bleeding, a hemoglobin evaluation will allow detection of iron defi-
ciency anemia.
Ultrasonography
An ultrasound is the gold standard test for uterine fibroids. Its wide-
spread availability enables easy and inexpensive confirmation in
almost all instances. Moreover, ultrasonography after infusion of
saline into the uterine cavity can delineate submucous myomas and
indicate the proximity of intramural myomas to the endometrial cav-
ity (
Seshadri et al. , 2015). The advent of 3D imaging technology has
seen 3D ultrasound establishes itself as a useful tool for the investiga-
tion of myometrial pathology due to its ability to reconstruct the
coronal plane of the uterus (
Andreotti and Fleischer, 2014; Wong
et al., 2015
).
Hysteroscopy
A hysteroscopy may be required to di fferentiate intracavitary myo-
mas and large endometrial polyps (Bett occhi et al., 2003; Di
Spiezio Sard o et al.,2010
; Parazzini et al., 2015). Hysteros copy is
usually performed in an outpat ient setting and does not require
any anesthesia (
Bettocchi et al.,2003). Ultrasonography with saline
infusion and diagnostic hysteroscopy should be considered more as
complementary ex aminations when hysteroscopic myo mectomy is
indicated. Of course, in case of irregular bleeding or if the patient
has risk factors for endometrial hyperplasia (obesity, chronic ano-
vulation), hysteroscopy may be combined with an endometrial
biopsy.
Magnetic Resonance Imaging
MRI can provide information on the number of fibroids, their size,
vascularization, relationship with the endometrial cavity and serosal
surface, and boundaries with normal myometrium (Fig.
3). It should
nevertheless be stressed that like ultrasonography, MRI cannot
diagnose malignancy with any certainty (
Lumsden et al., 2015;
Stewart, 2015). While MRI findings can suggest a diagnosis of sar-
coma, there is currently no form of preoperative testing which can
definitively rule it out (
Lin et al., 2015). Possibly in the future, new
types of imaging will improve the accuracy of detecting sarcoma,
which remains a very infrequent condition (1/1500 in women aged
<40 years and 1/1100 in women aged 40–44) (
Wright et al., 2014).
Current surgical management
strategies
As stressed by Stewart (2015), there are areas of uncertainty sur-
rounding the management of myomas, as only a few randomized
trials have compared different therapies for fibroids. Moreover, data
on their comparative effectiveness in terms of future fertility are lack-
ing. There are also inadequate data on long-term outcomes in
women who have undergone hysterectomy according to indication
(
Stewart, 2015). Prospective data and studies are essential to com-
pare different options and evaluate long-term outcomes with regard
to QoL, recurrence of symptoms (bleeding, bulk symptoms), fertility
and even complications.
Indeed, in a cohort study of 30 117 Nurse’s Health Study partici-
pants undergoing hysterectomy for benign disease, bilateral oophor-
ectomy was found to be associated with increased mortality in
patients under 50 years of age who had never used estrogen therapy
(
Parker et al., 2013).
While guidelines exist in the literature (
ACOG, 2008; ASRM,
2008
; Marret et al., 2012; Stewart, 2015), the risks and benefits of
each option should be discussed with the patient. It should also be
stressed that many other factors need to be taken into account,
including the skill of the surgeons involved, as well as the experience
of different centers in the available techniques.
Current management strategies involve mainly surgical interven-
tions, but the choice of treatment is guided by the patient’s age and
desired to preserve fertility or avoid ‘radical’ surgery such as
hysterectomy (
Donnez and Jadoul, 2002; Practice Committee of the
American Society for Reproductive Medicine, 2008
; Lumsden et al.,
2015
). Other surgical and non-surgical approaches include myomect-
omy by hysteroscopy, myomectomy by laparotomy or laparoscopy,
uterine artery embolization (UAE) and other interventions performed
under radiologic or ultrasound guidance (Fig.
4)(Donnez and Jadoul,
2002
; Practice Committee of the American Society for Reproductive
Medicine, 2008
; Lumsden et al., 2015; Stewart, 2015; Zupi et al.,
2015
).
Hysteroscopic myomectomy
Over the last 30 years, advances in instruments and techniques have
promoted hysteroscopic myomectomy to the rank of a standard
minimally invasive surgical procedure for submucous myomas. Small
fibroids (<2 cm) are now routinely removed in an outpatient setting
according to the technique described by Bettocchi (
Bettocchi et al.,
2003
, 2004; Di Spiezio Sardo et al., 2010; Casadio et al., 2011;
Mazzon et al., 2015; Vilos et al., 2015).
Depending on personal experience and available equipment, the
gynecologist has a choice of several alternative procedures.
The first involves cutting the base of pedunculated fibroids with
either the resectoscopic loop or laser fiber (
Stamatellos and Bontis,
2007
; Bettocchi et al., 2004; Di Spiezio Sardo et al., 2008; Tan and
Lethaby, 2013
). The base of the pedicle is cut and the fibroid is
extracted by forceps or may be left in place.
668 Donnez and Dolmans
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The second alternative is a complete excision of fibroids by a
one-step procedure (
Di Spiezio Sardo et al., 2008, 2015). The most
commonly used approach is the slicing technique. Repeated and
progressive passage of the cutting loop allows the surgeon to cut the
myoma into small chips. The operation is considered complete when
the fasciculate fibers of the myometrium are visualized (
Donnez
et al., 1990
; Bettocchi et al., 2004; Di Spiezio Sardo et al., 2015;
Mazzon et al., 2015; Saridogan, 2016 ). Hysteroscopic resection is
effective and safe and should be considered the technique of choice
for type 1 myomas. The development of intrauterine morcellators
has facilitated the implementation of hysteroscopic myomectomy
(
Lee and Matsuzono, 2016; Munro, 2016). If the myoma is large
(>3 cm in diameter), there is an increased risk of operative complica-
tions (perforation, bleeding and fluid intravasation) and damage to
surrounding myometrium due to use of electrosurgery. Interestingly,
Casadio et al., (2011) demonstrated that during surgery, myometrial
thickness increases when myoma slices are removed, leading to pro-
trusion of the intramural component into the uterine cavity.
The third alternative is myomectomy by a two-step procedure
(forlargetype1–3 myomas of acc ording to the FIGO
classification,
Munro et al., 2011). A fter resection or ablation of
the protruded portion of the myoma during first-step hystero-
scopy, the residual intramural component rapidly migrates to the
uterine cavity, with a parallel increase in myometrial thickness,
allowing complete and safe myoma excision during second-step
hysteroscopy (
Donnez et al., 1990; Bettocchi et al., 2004;
Stamatellos and Bontis, 2007; Tan and Lethaby, 2013; Di Spiezio
Sardo et al., 2008
, 2015).
With all the techniques described here, there is risk of fluid (gly-
cine) absorption while using monopolar energy. This risk is avoided
by use of bipolar or laser energy with saline solution.
Hysteroscopic myomectomy is effective for control of bleeding,
but failures are reported and are often related to growth of fibroids
in other sites, association of fibroids with adenomyosis, and incom-
plete treatment of large intramural (partially submucous) myomas
(
Pritts, 2001; Pritts et al., 2009; Donnez and Jadoul, 2002; Donnez
et al., 2014a
; Parazzini et al., 2015).
In terms of reproductive outcomes, most studies are retrospective
(
Bosteels et al., 2010a,b). They report post-surgery pregnancy rates ran-
ging from 16.7% to 76.9%, with a mean of 45% (Donnez et al., 2014a).
Figure 3 Magnetic resonance imaging (MRI) of fibroids. Midline sagittal T2-weighted images show different types of myomas according to
the FIGO classification (
Munro et al., 2011). Fibroids vary in size, number and site in the uterus. (A) Submucosal type 2 myoma. (B) Large type
2–5 myoma (white arrow): submucosal and subserosal, each with less than half the diameter in the endometrial and peritoneal cavities respect-
ively. Subserosal type 5 myomas (subserosal,
>50% intramural) (black arrows). (C) Submucosal type 2 myoma (>50% intramural) (white arrow).
Intramural type 4 myoma (arrowhead). Small type 5 myomas (black arrows). (D) Multiple myomas, three of which are type 0 (intracavitary)
(white arrows).
669Management of Uterine Fibroids
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