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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
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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. Gynecol Endocrinol, Early Online: 1–5

of symptoms frequently occurs. Total or subtotal hysterectomy is This is likely due to the adverse effect profile of the drug, which
considered the definitive therapy for uterine adenomyosis [19]. includes weight gain, muscle cramps, reduced breast size, acne,
Unfortunately, the management of these patients is difficult, hirsutism, oily skin, decreased high-density lipoprotein levels,
especially when they are symptomatic but have a strong desire to increased liver enzymes, hot flashes, mood changes, depression,
preserve their uterus. Conservative treatment is required for and deepening of the voice. After systemic treatment with
patients that require preservation of fertility and improvement of danazol, oestrogen receptors are decreased, which may contribute
quality of life. Minimally invasive surgical procedures enable to reduced uterine size and improvement of symptoms [27].
conservative options, including endometrial ablation and resec- Igarashi et al. [28] reported that adenomyosis could be treated
tion, laparoscopic excision of adenomyosis and MRI-guided with 300–400 mg of danazol loaded onto an intrauterine contra-
focused ultrasound [2,20,21]. The objectives of medical treatment ceptive device (IUCD). In their study, they treated 14 adeno-
are the inhibition of ovulation, abolition of menstruation, and myosis patients with dysmenorrhoea, hypermenorrhoea or
achievement of a stable steroid hormonal milieu, based on the infertility. During the treatment, blood danazol levels were
concept that the responses of the eutopic and ectopic endomet- undetectable, ovulation was not inhibited, and no side effects
rium are substantially similar. Medical therapies commonly used were reported. The danazol-loaded vaginal ring and IUCD have
in the treatment of adenomyosis are similar to those for also been tested in patients with endometriosis, with encouraging
endometriosis and include GnRH-a, oral contraceptives (OCs), results [29]. A prospective study demonstrates that long-term
progestins, danazol, and, more recently, selective oestrogen vaginal administration of one 200-mg danazol tablet every day is
receptor modulators (SERMs), selective progesterone receptor both efficacious and safe for reducing heavy menstrual bleeding
modulators (SPRMs), and aromatase inhibitors (AIs) [17,22–24]. (HMB) in premenopausal women [30]. In addition, cervical
The aim of this review is to discuss the medical approach for the injections of danazol have also been successfully used.
management of adenomyosis symptoms, including infertility, Takebayashi et al. injected 10 mg of danazol into the cervix in
pain, and AUB. 22 patients at 2 week intervals for 12 weeks. There was 60%
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improvement in subjective symptoms of bleeding, pain and


Methods dyspareunia, and a mean decrease in uterine size from
334.6 ± 211.9 cm3 to 243.1 ± 11.9 cm3. No adverse effects were
A literature search was performed in the PubMed database,
noted as a result of local administration of this hormone [31].
spanning 1990 to 2015. The applied search heading included
combinations of the following terms: ‘‘adenomyosis’’, ‘‘GnRH
Progestins
agonist’’, ‘‘SERMS’’, ‘‘SPRMS’’, ‘‘progestins’’, ‘‘aromatase
inhibitors’’, ‘‘danazol’’, ‘‘levonorgestrel-releasing intrauterine Progestins’ action involves the decidualisation and subsequent
device’’ (LNG–IUD) and ‘‘oral contraceptive’’. The search was atrophy of endometrial tissue. There is only limited evidence to
limited to clinical studies published in English. Titles and support the use of progesterone for endometriosis and adeno-
abstracts were screened to identify relevant articles. References myosis-associated pain, and randomised clinical trials addressing
and related articles were checked. Observational studies (such as quality of life have had a high withdrawal rate [23,32]. A
cohort or case control studies), randomised controlled trials, retrospective study evidenced a marked relief from adenomyosis
prospective clinical trials, and case reports were included. For associated menorrhagia and pain can be obtained with the use of
multiple publications of the same data set, only the most relevant norethindrone acetate [33]. A prospective clinical trial compared
studies were included. the efficacy of oral dienogest (82 mg/day orally) versus
triptorelin acetate injections (3.75 mg/4 weeks subcutaneously)
Results for the treatment of premenopausal menorrhagia and pelvic pain
in women with uterine adenomyosis. Significant reductions in
Oral contraceptives
pelvic pain after 16 weeks of treatment were obtained in both
OCs are used in the management of adenomyosis to induce a groups, demonstrating the equivalence of dienogest relative to
decreased menstruation, particularly when given continuously, triptorelin acetate. Triptorelin acetate was more effective at
and a pseudogestational status, which causes decidualisation and controlling menorrhagia and reducing uterine volume [34]. A
subsequent atrophy of the endometrium. Patients with dysmen- drawback of progestin therapy is reduced libido in about one-
orrhoea and menorrhagia may benefit from the resulting amen- fifth of women, and, compared with other medical treatments,
orrhoea, which may provide relief of symptoms. Monophasic, amenorrhoea and bleeding have been more frequently reported
low-dose OCs show overall safety, good efficacy, high tolerability with progestin.
and low cost, and may be the best choice for adenomyosis-related
pain. Their continuous use is suggested, with the aim of Levonorgestrel-releasing intrauterine device
abolishing uterine flow. Medical therapy with OCs enables
The LNG-IUS releases 20 mg of levonorgestrel per day and is an
satisfactory long-term pain control in two-thirds of women with
effective treatment for adenomyosis. The use of LNG-IUS is
symptomatic endometriosis or adenomyosis [25]. However, many
associated with decidualisation of the endometrium and
patients report irregular bleeding and it should be emphasised that
decreased bleeding, and is also thought to act directly on
OCs have been often associated with an increased risk of venous
adenomyotic deposits by downregulating the oestrogen recep-
thrombosis, and are not suggested in patients with other risk
tors. This reduces the size of the foci, improves contractility of
factors (thrombophilia or hypertension).
the uterus to decrease blood loss, and improves dysmenorrhoea
by reducing prostaglandin production within the endometrium
Danazol
and inducing amenorrhoea [35]. The benefits of the LNG-IUS,
Danazol is an isoxazole derivative of 12 aloha-ethinyl testoster- particularly its effects on dysmenorrhoea and HMB, have been
one. It has strong antigonadotrophic properties and has been proven to be effective against adenomyosis in many clinical
widely used as a treatment for adenomyosis and AUB [26]. trials. In a prospective randomised clinical trial, Ozdegirmenci
Danazol can act directly on endometriotic tissue in vitro to inhibit et al. compared the LNG-IUS with hysterectomy in adenomyosis
DNA synthesis and induce apoptosis. Experience with the use of patients, to study the effect of both treatments on quality of life
systemic danazol therapy in patients with adenomyosis is limited. (QoL). The LNG-IUS increased the haemoglobin levels at the
DOI: 10.1080/09513590.2016.1197200 Treatment of adenomyosis 3

sixth month and first year of the treatment, comparable to levels increased [42]. GnRH agonists are very effective against
obtained with hysterectomy. When the pre-treatment and post- adenomyosis-related pain, and consequently contribute to the
treatment QoL scores of the groups were compared, three of the achievement of many successful pregnancies and live deliveries
five mean domains scores were increased in patients treated with [43–45]. However, long-term GnRH agonist therapy is not
hysterectomy, while in patients managed with the LNG-IUS, practical because of side effects associated with a hypoestrogenic
all five mean domain scores were increased. LNG-IUS state, the most serious being bone loss. Consequently, GnRH
demonstrated significant and comparable improvements in agonist plus add back therapy should be used only in carefully
haemoglobin levels compared to hysterectomy in treating selected women unresponsive to other medications, or in surgical
adenomyosis-associated menorrhagia during the first year. high-risk patients.
Although both treatments led to improvements in health-related
QoL, the LNG-IUS seemed to have superior effects on patients’
Selective oestrogen receptor modulators
psychological and social lives [36]. Cho et al. evaluated, in a
prospective study, the long-term clinical effects of the LNG-IUS SERMs are associated with beneficial oestrogen agonist effects in
on adenomyosis. LNG-IUS devices were inserted into 47 certain tissues without undesirable effects in others. In post-
patients who had been diagnosed with adenomyosis. Uterine menopausal patients, the SERM raloxifene shows beneficial
volume, uterine artery blood flow, pictorial blood loss assess- effects of oestrogens on bone density, but stimulates neither the
ment chart (PBAC) scores, and the degree of dysmenorrhoea endometrium nor the breasts. In menstruating women, at a daily
were evaluated before and 36 months after insertion of the dose of 200 mg, raloxifene did not alter menstrual cycle length or
LNG-IUS. The LNG-IUS, in patients with clinical diagnosis of stimulate endometrial growth, despite elevated plasma oestrogen
adenomyosis, was effective for the reduction of uterine volume, levels. The beneficial effect on bone density without endometrial
with improvement of vascularity and relief of symptoms. The stimulation suggested that raloxifene might be an effective
efficacy of the LNG-IUS on uterine volume may begin to medical therapy for women with endometriosis. In the first
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decrease two years after insertion [37]. Sheng et al. evaluated placebo-controlled study of SERMs to treat women with pain
the efficacy of the LNG-IUS after use for 36 months in 94 from endometriosis after complete excision of disease, raloxifene
women with moderate to severe dysmenorrhoea associated with was associated with the return of pain earlier than the placebo,
adenomyosis diagnosed with TVUS. The rate of pain measured and that effect was independent of the return of endometriosis
using a visual analogue scale decreased from a mean baseline [46]. Moreover, the rate of adenomyosis described among
score of 77.9 ± 14.7 to 11.8 ± 11.8, with 25% of patients postmenopausal breast cancer patients treated with the SERM
reporting amenorrhoea. Uterine volume decreased significantly tamoxifen is nearly 3–4 times higher than the rate reported in the
as did CA-125 levels. The overall patient-satisfaction rate with literature for pre- and postmenopausal women [47]. Consequently,
the treatment was 72.5% [38]. The efficacy of the LNG-IUS for it seems that SERMs are not indicated for the treatment of
reducing uterine volume in cases of adenomyosis is controver- adenomyosis.
sial. Significant uterine volume reductions associated with the
LNG-IUS were reported by Cho et al. and Sheng et al., but not
Selective progesterone receptor modulators
by Bragheto et al. [39], who evaluated the effect of the LNG-
IUS on adenomyotic lesions diagnosed and monitored with MRI, SPRMs are defined as a new class of progesterone receptor
and reported a significant reduction of 24.2% in junctional zone ligands, which exhibit both progesterone agonist and antagonist
thickness (p50.0001). However, no significant decrease in activities. In the absence of progesterone, SPRMs act as weak
uterine volume was observed between baseline and the 6-month progestins. In the presence of progesterone, they may also show
evaluation. In this study, the insertion of an LNG-IUS led to a weak antiprogestagenic properties in some tissues, particularly
reduction in pain and abnormal bleeding. Park et al., in a the endometrium. This property justifies their use in the
retrospective study of 48 patients, reported significant improve- treatment of myomas and endometriosis [23]. Only two drugs
ment in dysmenorrhoea and HMB, but no significant change in are currently approved for gynaecologic use. Mifepristone is
uterine volume. The most common side effects were prolonged approved for the termination of pregnancy, cervical dilatation
vaginal spotting (58.3%) and LNG-IUS expulsion (37.5%). Five and medical termination of pregnancy during the second
(10.4%) patients underwent premature LNG-IUS removal, and trimester. Ulipristal acetate has been approved in Europe and
eight (16.7%) patients underwent hysterectomy. The overall the United States as an emergency contraceptive, and recently
success rate of the LNG-IUS was 68.8% [40]. 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
GnRH agonists
caspase 3 was examined with the immunohistochemical method
GnRH agonists are derived from native GnRH by amino acid in both the eutopic and ectopic endometrium. Compared with
substitution, which renders the agonist resistant to degradation the placebo group, the expression of caspase 3 was significantly
and increases its half-life. GnRH agonists (GnRH-a) work by increased in three groups that were treated, respectively, with 5,
temporarily ‘‘switching off’’ the ovaries. Hypogonadic side 10 and 15 mg of mifepristone. Mifepristone can increase the
effects caused by GnRH agonists, including vasomotor syndrome, expression of caspase 3 in both the eutopic and ectopic
genital atrophy, mood instability, a negative impact on bone endometrium, initiate cell apoptosis, and inhibit the emergence
health and a possible negative influence on cardiovascular health and development of adenomyosis [48]. A small number of
can be managed with ‘‘add-back therapy’’. Goserelin, leuprolide clinical studies have also demonstrated that SPRMs have
and nafarelin are commonly used in clinical practice, in particular potential in the treatment of adenomyosis. Mifepristone 50 mg
for the treatment of endometriosis [18,41]. The first reported case daily has been shown to improve pain and cause regression of
of biopsy-proven adenomyosis treated using a GnRH analogue endometriosis implants [49]. Asoprisnil and telapristone acetate
was published in 1991. The results demonstrated a reduction in have also been reported to relieve adenomyosis-associated pain
uterine volume from 440 to 150 cm3, decreased amenorrhoea, [50,51]. Nevertheless, SPRMs require further investigations to
and relief of severe dysmenorrhoea. However, on discontinu- assess their long-term effects and their clinical use in patients
ation of therapy, the symptoms recurred and uterine volume with adenomyosis.
4 A. Pontis et al. Gynecol Endocrinol, Early Online: 1–5

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