Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

Adenomyosis: a systematic review of medical

treatment

A. Pontis, M. N. D'Alterio, S. Pirarba, C. de Angelis, R. Tinelli & S. Angioni

To cite this article: A. Pontis, M. N. D'Alterio, S. Pirarba, C. de Angelis, R. Tinelli & S. Angioni
(2016): Adenomyosis: a systematic review of medical treatment, Gynecological Endocrinology

To link to this article: http://dx.doi.org/10.1080/09513590.2016.1197200

Published online: 05 Jul 2016.

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ISSN: 0951-3590 (print), 1473-0766 (electronic)

Gynecol Endocrinol, Early Online: 1–5

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/09513590.2016.1197200

REVIEW ARTICLE

Adenomyosis: a systematic review of medical treatment

A. Pontis1, M. N. D’Alterio2, S. Pirarba2, C. de Angelis3, R. Tinelli4, and S. Angioni2
1
U.O.C. Gynecology and Obstetrics, Ospedale San Francesco, Nuoro, Italy, 2Department of Surgical Sciences, Section of Obstetrics & Gynecology,
University of Cagliari, Monserrato, Italy, 3Casa di Cura Accreditata Fabia Mater, Roma, Italy, and 4Department of Obstetrics and Gynecology,
Perrino Hospital, Brindisi, Italy

Abstract Keywords
Adenomyosis is a heterogeneous gynaecologic condition with a range of clinical presentations, Adenomyosis, aromatase inhibitors, danazol,
the most common being heavy menstrual bleeding and dysmenorrhoea; however, patients can endometriosis, GnRH agonist,
also be asymptomatic. Several studies support the theory that adenomyosis results from levonorgestrel-releasing intrauterine
Downloaded by [La Trobe University] at 00:41 06 July 2016

invasion of the endometrium into the myometrium, causing alterations in the junctional zone. device, oral contraceptive, progestins
These changes are commonly seen on imaging studies, such as transvaginal ultrasound and
magnetic resonance imaging. The aim of this review is to discuss the medical approach to History
the management of adenomyosis symptoms, including pain and abnormal uterine bleeding.
The standard treatment of adenomyosis is hysterectomy, but there is no medical therapy to Received 28 April 2016
treat the symptoms of adenomyosis while still allowing patients to conceive. Medical therapies Revised 5 May 2016
using suppressive hormonal treatments, such as continuous use of oral contraceptive pills, Accepted 31 May 2016
high-dose progestins, selective oestrogen receptor modulators, selective progesterone Published online 4 July 2016
receptor modulators, the levonorgestrel-releasing intrauterine device, aromatase inhibitors,
danazol, and gonadotrophin receptor hormone agonists can temporarily induce regression of
adenomyosis and improve the symptoms.

Introduction frequent symptom is dysmenorrhoea (15–30%) [8]. Adenomyosis

has a significant impact on fertility status and IVF outcomes.
Uterine adenomyosis and/or adenomyoma are characterised by
Mechanisms that account for the negative impact of adenomyosis
the presence of heterotopic endometrial glands and stroma within
on fertility may include impairment of the uterine system of
the myometrium. The diagnosis is based on a myometrial depth of
sperm transport, uterine dysperistalsis (which may be responsible
42.5 mm or of more on one microscopic field at 10 times
for reduced embryo implantation), abnormal concentrations of
magnification from the endometrium–myometrium junction, and
free radicals in the uterine environment, and altered endometrial
a variable degree of adjacent myometrial hyperplasia, causing
vascularisation [9,10]. The diagnosis of adenomyosis is based on
globular and cystic enlargement of the myometrium, with some
transvaginal ultrasonography (TVUS) and magnetic resonance
cysts filled with extravasated, haemolysed red blood cells and
imaging (MRI). TVUS is observer-dependent, but it has a
siderophages [1–3]. In 1972, adenomyosis was clearly defined by
sufficiently high diagnostic accuracy in clinically suspect cases
Bird et al. [4] as ‘‘benign invasion of endometrium in the
[11]. Both TVUS and transabdominal sonography characterise
myometrium, producing a diffusely enlarged uterus, which
adenomyosis by identifying myometrial cysts (1–7 mm round
microscopically exhibits ectopic, non-neoplastic, endometrial
anechoic areas), a distorted and heterogeneous myometrial
glands and stroma surrounded by hypertrophic and hyperplastic
echotexture, and poorly defined foci of an abnormal myometrial
myometrium’’. Adenomyosis remains an enigmatic disease and a
echotexture [12,13]. Findings on MRI include a large asymmetric
cause of abnormal uterine bleeding (AUB) and dysmenorrhoea,
uterus without leiomyomas, thickening of the junctional zone to
resulting in chronic pelvic pain and infertility [5]. Similar
8–12 mm, or an abnormal ratio (440%) of junctional zone to
symptoms are reported in patients with endometriosis, and the
myometrial thickness. The junctional zone is the innermost
two diseases are associated in many cases, negatively affecting
myometrial layer, which is distinct on light optic microscopy but
quality of life [5–7]. The prevalence of adenomyosis varies
lacks histologic distinction [14]. A direct visualisation of the
widely, with an average rate of 20%–25%. Approximately 20% of
uterine cavity by means of outpatient diagnostic hysteroscopy
adenomyosis cases involve women of reproductive age (540
using a miniature hysteroscope with a 3.5-mm sheath and saline
years), with the remaining 80% occurring in women of late
uterine distension may offer more accurate information about the
reproductive age (40–50 years). One-third of women affected by
intracavitary pathology [15]. Although adenomyosis represents a
adenomyosis are asymptomatic. In the remaining cases, the most
rare finding, particularly in young women, some suggestive
hysteroscopic images have been described [16]. Like endometri-
osis, adenomyosis is an oestrogen-dependent condition that
Address for correspondence: Prof. Stefano Angioni, M.D., Ph.D.,
Department of Surgical Sciences, Section of Obstetrics & Gynecology,
responds to medical treatment with anti-oestrogenic drugs and
University of Cagliari, Azienda Ospedaliero Universitaria, Blocco Q, gonadotropin-releasing hormone agonist (GnRh-a), which often
09124 Monserrato, Italy. Tel: +3907051093399. E-mail: result in temporary improvement of symptoms [17,18].
sangioni@yahoo.it Unfortunately, medical approaches can be ineffective, and relapse
 2 A. Pontis et al.
of symptoms frequently occurs. Total or subtotal hysterectomy is
considered the definitive therapy for uterine adenomyosis [19].
Unfortunately, the management of these patients is difficult,
especially when they are symptomatic but have a strong desire to
preserve their uterus. Conservative treatment is required for
patients that require preservation of fertility and improvement of
quality of life. Minimally invasive surgical procedures enable
conservative options, including endometrial ablation and resec-
tion, laparoscopic excision of adenomyosis and MRI-guided
focused ultrasound [2,20,21]. The objectives of medical treatment
are the inhibition of ovulation, abolition of menstruation, and
achievement of a stable steroid hormonal milieu, based on the
concept that the responses of the eutopic and ectopic endomet-
rium are substantially similar. Medical therapies commonly used
in the treatment of adenomyosis are similar to those for
endometriosis and include GnRH-a, oral contraceptives (OCs),
progestins, danazol, and, more recently, selective oestrogen
receptor modulators (SERMs), selective progesterone receptor
modulators (SPRMs), and aromatase inhibitors (AIs) [17,22–24].
The aim of this review is to discuss the medical approach for the
management of adenomyosis symptoms, including infertility,
pain, and AUB.
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Methods
A literature search was performed in the PubMed database,
spanning 1990 to 2015. The applied search heading included
combinations of the following terms: ‘‘adenomyosis’’, ‘‘GnRH
agonist’’, ‘‘SERMS’’, ‘‘SPRMS’’, ‘‘progestins’’, ‘‘aromatase
inhibitors’’, ‘‘danazol’’, ‘‘levonorgestrel-releasing intrauterine
device’’ (LNG–IUD) and ‘‘oral contraceptive’’. The search was
limited to clinical studies published in English. Titles and
abstracts were screened to identify relevant articles. References
and related articles were checked. Observational studies (such as
cohort or case control studies), randomised controlled trials,
prospective clinical trials, and case reports were included. For
multiple publications of the same data set, only the most relevant
studies were included.
Results
Oral contraceptives
OCs are used in the management of adenomyosis to induce a
decreased menstruation, particularly when given continuously,
and a pseudogestational status, which causes decidualisation and
subsequent atrophy of the endometrium. Patients with dysmen-
orrhoea and menorrhagia may benefit from the resulting amen-
orrhoea, which may provide relief of symptoms. Monophasic,
low-dose OCs show overall safety, good efficacy, high tolerability
and low cost, and may be the best choice for adenomyosis-related
pain. Their continuous use is suggested, with the aim of
abolishing uterine flow. Medical therapy with OCs enables
satisfactory long-term pain control in two-thirds of women with
symptomatic endometriosis or adenomyosis [25]. However, many
patients report irregular bleeding and it should be emphasised that
OCs have been often associated with an increased risk of venous
thrombosis, and are not suggested in patients with other risk
factors (thrombophilia or hypertension).
Danazol
Danazol is an isoxazole derivative of 12 aloha-ethinyl testoster-
one. It has strong antigonadotrophic properties and has been
widely used as a treatment for adenomyosis and AUB [26].
Danazol can act directly on endometriotic tissue in vitro to inhibit
DNA synthesis and induce apoptosis. Experience with the use of
systemic danazol therapy in patients with adenomyosis is limited.
Gynecol Endocrinol, Early Online: 1–5
This is likely due to the adverse effect profile of the drug, which
includes weight gain, muscle cramps, reduced breast size, acne,
hirsutism, oily skin, decreased high-density lipoprotein levels,
increased liver enzymes, hot flashes, mood changes, depression,
and deepening of the voice. After systemic treatment with
danazol, oestrogen receptors are decreased, which may contribute
to reduced uterine size and improvement of symptoms [27].
Igarashi et al. [28] reported that adenomyosis could be treated
with 300–400 mg of danazol loaded onto an intrauterine contra-
ceptive device (IUCD). In their study, they treated 14 adeno-
myosis patients with dysmenorrhoea, hypermenorrhoea or
infertility. During the treatment, blood danazol levels were
undetectable, ovulation was not inhibited, and no side effects
were reported. The danazol-loaded vaginal ring and IUCD have
also been tested in patients with endometriosis, with encouraging
results [29]. A prospective study demonstrates that long-term
vaginal administration of one 200-mg danazol tablet every day is
both efficacious and safe for reducing heavy menstrual bleeding
(HMB) in premenopausal women [30]. In addition, cervical
injections of danazol have also been successfully used.
Takebayashi et al. injected 10 mg of danazol into the cervix in
22 patients at 2 week intervals for 12 weeks. There was 60%
improvement in subjective symptoms of bleeding, pain and
dyspareunia, and a mean decrease in uterine size from
334.6 ± 211.9 cm3 to 243.1 ± 11.9 cm3. No adverse effects were
noted as a result of local administration of this hormone [31].
Progestins
Progestins’ action involves the decidualisation and subsequent
atrophy of endometrial tissue. There is only limited evidence to
support the use of progesterone for endometriosis and adeno-
myosis-associated pain, and randomised clinical trials addressing
quality of life have had a high withdrawal rate [23,32]. A
retrospective study evidenced a marked relief from adenomyosis
associated menorrhagia and pain can be obtained with the use of
norethindrone acetate [33]. A prospective clinical trial compared
the efficacy of oral dienogest (82 mg/day orally) versus
triptorelin acetate injections (3.75 mg/4 weeks subcutaneously)
for the treatment of premenopausal menorrhagia and pelvic pain
in women with uterine adenomyosis. Significant reductions in
pelvic pain after 16 weeks of treatment were obtained in both
groups, demonstrating the equivalence of dienogest relative to
triptorelin acetate. Triptorelin acetate was more effective at
controlling menorrhagia and reducing uterine volume [34]. A
drawback of progestin therapy is reduced libido in about one-
fifth of women, and, compared with other medical treatments,
amenorrhoea and bleeding have been more frequently reported
with progestin.
Levonorgestrel-releasing intrauterine device
The LNG-IUS releases 20 mg of levonorgestrel per day and is an
effective treatment for adenomyosis. The use of LNG-IUS is
associated with decidualisation of the endometrium and
decreased bleeding, and is also thought to act directly on
adenomyotic deposits by downregulating the oestrogen recep-
tors. This reduces the size of the foci, improves contractility of
the uterus to decrease blood loss, and improves dysmenorrhoea
by reducing prostaglandin production within the endometrium
and inducing amenorrhoea [35]. The benefits of the LNG-IUS,
particularly its effects on dysmenorrhoea and HMB, have been
proven to be effective against adenomyosis in many clinical
trials. In a prospective randomised clinical trial, Ozdegirmenci
et al. compared the LNG-IUS with hysterectomy in adenomyosis
patients, to study the effect of both treatments on quality of life
(QoL). The LNG-IUS increased the haemoglobin levels at the
 DOI: 10.1080/09513590.2016.1197200
sixth month and first year of the treatment, comparable to levels
obtained with hysterectomy. When the pre-treatment and post-
treatment QoL scores of the groups were compared, three of the
five mean domains scores were increased in patients treated with
hysterectomy, while in patients managed with the LNG-IUS,
all five mean domain scores were increased. LNG-IUS
demonstrated significant and comparable improvements in
haemoglobin levels compared to hysterectomy in treating
adenomyosis-associated menorrhagia during the first year.
Although both treatments led to improvements in health-related
QoL, the LNG-IUS seemed to have superior effects on patients’
psychological and social lives [36]. Cho et al. evaluated, in a
prospective study, the long-term clinical effects of the LNG-IUS
on adenomyosis. LNG-IUS devices were inserted into 47
patients who had been diagnosed with adenomyosis. Uterine
volume, uterine artery blood flow, pictorial blood loss assess-
ment chart (PBAC) scores, and the degree of dysmenorrhoea
were evaluated before and 36 months after insertion of the
LNG-IUS. The LNG-IUS, in patients with clinical diagnosis of
adenomyosis, was effective for the reduction of uterine volume,
with improvement of vascularity and relief of symptoms. The
efficacy of the LNG-IUS on uterine volume may begin to
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decrease two years after insertion [37]. Sheng et al. evaluated
the efficacy of the LNG-IUS after use for 36 months in 94
women with moderate to severe dysmenorrhoea associated with
adenomyosis diagnosed with TVUS. The rate of pain measured
using a visual analogue scale decreased from a mean baseline
score of 77.9 ± 14.7 to 11.8 ± 11.8, with 25% of patients
reporting amenorrhoea. Uterine volume decreased significantly
as did CA-125 levels. The overall patient-satisfaction rate with
the treatment was 72.5% [38]. The efficacy of the LNG-IUS for
reducing uterine volume in cases of adenomyosis is controver-
sial. Significant uterine volume reductions associated with the
LNG-IUS were reported by Cho et al. and Sheng et al., but not
by Bragheto et al. [39], who evaluated the effect of the LNG-
IUS on adenomyotic lesions diagnosed and monitored with MRI,
and reported a significant reduction of 24.2% in junctional zone
thickness (p50.0001). However, no significant decrease in
uterine volume was observed between baseline and the 6-month
evaluation. In this study, the insertion of an LNG-IUS led to a
reduction in pain and abnormal bleeding. Park et al., in a
retrospective study of 48 patients, reported significant improve-
ment in dysmenorrhoea and HMB, but no significant change in
uterine volume. The most common side effects were prolonged
vaginal spotting (58.3%) and LNG-IUS expulsion (37.5%). Five
(10.4%) patients underwent premature LNG-IUS removal, and
eight (16.7%) patients underwent hysterectomy. The overall
success rate of the LNG-IUS was 68.8% [40].
GnRH agonists
GnRH agonists are derived from native GnRH by amino acid
substitution, which renders the agonist resistant to degradation
and increases its half-life. GnRH agonists (GnRH-a) work by
temporarily ‘‘switching off’’ the ovaries. Hypogonadic side
effects caused by GnRH agonists, including vasomotor syndrome,
genital atrophy, mood instability, a negative impact on bone
health and a possible negative influence on cardiovascular health
can be managed with ‘‘add-back therapy’’. Goserelin, leuprolide
and nafarelin are commonly used in clinical practice, in particular
for the treatment of endometriosis [18,41]. The first reported case
of biopsy-proven adenomyosis treated using a GnRH analogue
was published in 1991. The results demonstrated a reduction in
uterine volume from 440 to 150 cm3, decreased amenorrhoea,
and relief of severe dysmenorrhoea. However, on discontinu-
ation of therapy, the symptoms recurred and uterine volume
Treatment of adenomyosis 3
increased [42]. GnRH agonists are very effective against
adenomyosis-related pain, and consequently contribute to the
achievement of many successful pregnancies and live deliveries
[43–45]. However, long-term GnRH agonist therapy is not
practical because of side effects associated with a hypoestrogenic
state, the most serious being bone loss. Consequently, GnRH
agonist plus add back therapy should be used only in carefully
selected women unresponsive to other medications, or in surgical
high-risk patients.
Selective oestrogen receptor modulators
SERMs are associated with beneficial oestrogen agonist effects in
certain tissues without undesirable effects in others. In post-
menopausal patients, the SERM raloxifene shows beneficial
effects of oestrogens on bone density, but stimulates neither the
endometrium nor the breasts. In menstruating women, at a daily
dose of 200 mg, raloxifene did not alter menstrual cycle length or
stimulate endometrial growth, despite elevated plasma oestrogen
levels. The beneficial effect on bone density without endometrial
stimulation suggested that raloxifene might be an effective
medical therapy for women with endometriosis. In the first
placebo-controlled study of SERMs to treat women with pain
from endometriosis after complete excision of disease, raloxifene
was associated with the return of pain earlier than the placebo,
and that effect was independent of the return of endometriosis
[46]. Moreover, the rate of adenomyosis described among
postmenopausal breast cancer patients treated with the SERM
tamoxifen is nearly 3–4 times higher than the rate reported in the
literature for pre- and postmenopausal women [47]. Consequently,
it seems that SERMs are not indicated for the treatment of
adenomyosis.
Selective progesterone receptor modulators
SPRMs are defined as a new class of progesterone receptor
ligands, which exhibit both progesterone agonist and antagonist
activities. In the absence of progesterone, SPRMs act as weak
progestins. In the presence of progesterone, they may also show
weak antiprogestagenic properties in some tissues, particularly
the endometrium. This property justifies their use in the
treatment of myomas and endometriosis [23]. Only two drugs
are currently approved for gynaecologic use. Mifepristone is
approved for the termination of pregnancy, cervical dilatation
and medical termination of pregnancy during the second
trimester. Ulipristal acetate has been approved in Europe and
the United States as an emergency contraceptive, and recently
for the preoperative treatment of uterine fibroids. Wang et al., in
a recent study, discussed the influence of mifepristone on
caspase 3 expression in adenomyosis tissue. The expression of
caspase 3 was examined with the immunohistochemical method
in both the eutopic and ectopic endometrium. Compared with
the placebo group, the expression of caspase 3 was significantly
increased in three groups that were treated, respectively, with 5,
10 and 15 mg of mifepristone. Mifepristone can increase the
expression of caspase 3 in both the eutopic and ectopic
endometrium, initiate cell apoptosis, and inhibit the emergence
and development of adenomyosis [48]. A small number of
clinical studies have also demonstrated that SPRMs have
potential in the treatment of adenomyosis. Mifepristone 50 mg
daily has been shown to improve pain and cause regression of
endometriosis implants [49]. Asoprisnil and telapristone acetate
have also been reported to relieve adenomyosis-associated pain
[50,51]. Nevertheless, SPRMs require further investigations to
assess their long-term effects and their clinical use in patients
with adenomyosis.
 4 A. Pontis et al.
Aromatase inhibitors
Aromatase is a key enzyme in the synthesis of oestrogens from
androgens, involving the conversion of androstenedione and
testosterone to oestrone and oestradiol, respectively [52]. Several
studies suggest that aromatase is inappropriately expressed in the
eutopic endometrium and ectopic endometrial implants in
women with endometriosis, as well as in several types of
malignant tumours [53]. Badawy et al., in a prospective
randomised trial, compared the efficacy of AIs versus GnRh-a
in treating premenopausal women with uterine adenomyosis.
The patients were randomly allocated to receive oral letrozole
(2.5 mg/day) or subcutaneous GnRh-a (goserelin 3.6 mg) for 12
weeks. There was no significant difference in total uterine size
based on post-treatment uterine volumes in the two groups. Total
adenomyoma volume decreased in both groups. AIs demon-
strated the same efficacy as GnRH-a in reducing adenomyoma
volume and improving symptoms [54]. Another study reported
the effect of AIs with GnRH-a for severe symptomatic
adenomyosis that was refractory to GnRH-a and danazol,
demonstrating reduction of uterine volume as estimated by
MRI, ultrasonography, and symptom improvement [55]. The side
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effects most commonly associated with AI treatment are
headaches, hot flashes, mood changes, muscle aches and
breakthrough bleeding. Oestradiol levels are significantly sup-
pressed with this treatment [56]. The European Society of
Human Reproduction and Embryology (ESHRE), in their latest
guidelines, recommends the use of AIs associated with another
hormonal treatment (OC pills, progestins or GnRH analogs) only
in women in whom all surgical and medical treatments have
failed [57].
Conclusion
Adenomyosis is a common condition that is asymptomatic in
one-third of cases, while in the remainder, it can cause
dysmenorrhoea and/or menometrorrhagia. Imaging is performed
to make the diagnosis, to determine the extent of disease spread,
and to look for any associated pathologies, especially endomet-
riosis. The goal of therapy for adenomyosis is important, and
can include symptom relief and possibly increased fertility. The
results of published studies have consistently demonstrated that,
as long as amenorrhoea is achieved, there are no statistical
differences between the various available drugs in terms of pain
relief. However, tolerability, side effects and costs vary widely.
The most promising medical therapy, based on the literature, is
the LNG-IUS due to its ability to provide hormone suppression
to improve symptoms with a low profile of adverse effects,
while enabling women to maintain future fertility. The LNG-IUS
has been proven to decrease or eliminate the symptoms of
dysmenorrhoea and to decrease menorrhagia, increasing the
haematocrit concentration after only three months of treatment.
Even GnRHa treatment has shown efficacy and good results on
fertility after treatment but is associated to many side effects in
long-term users [43–45]. In women who have completed
childbearing, less invasive surgical procedures, such as endo-
metrial ablation and resection, have been demonstrated to
improve the symptoms of menorrhagia, with a mean failure
rate of 20% [58]. Higher failure rates are noted if adenomyosis
has penetrated more than 2.5 mm from the basalis layer.
Treatment should be tailored to the specific symptoms, such
as pain severity, or the special requests of individual patients.
Future research on this subject will be worthwhile.
Declaration of interest
The authors report no conflicts of interest.
Gynecol Endocrinol, Early Online: 1–5
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