Approach

Key Points

Treatment of symptomatic adenomyosis is individualised according to the type and severity of symptoms, the patient's preference, and any desire to preserve fertility.

For women who are not looking to conceive in the near future, consider a levonorgestrel intrauterine device (IUD) as a first-line treatment. It has proven efficacy for treating dysmenorrhoea and heavy menstrual bleeding and has high rates of patient satisfaction.

Consider alternative oral hormonal treatments (combined oral contraceptive, norethisterone, dienogest) in women with symptomatic adenomyosis who decline or are unsuitable for the levonorgestrel IUD.

A non-steroidal anti-inflammatory drug (NSAID) or tranexamic acid can be used alone for relief of mild symptoms of pain and heavy bleeding, or as an adjunct treatment to hormonal therapy.

In patients who do not desire future fertility, hysterectomy is a definitive treatment option for symptoms of abnormal uterine bleeding, dysmenorrhoea, or bulk symptoms secondary to adenomyosis. Endometrial ablation and uterine artery embolisation are alternative approaches for patients who wish to preserve their uterus or are unsuitable for hysterectomy.

Uterine-sparing focal excision procedures may be considered in women who desire to preserve their fertility. Note that patients should be counselled regarding the uncertain impact on fertility, as well as the potential increased risk of uterine rupture in future pregnancies.

General principles

Treatment of symptomatic adenomyosis is dependent on the type and severity of symptoms, patient preference, and the need to preserve fertility. The presence of concurrent pathologies, such as leiomyoma (fibroids), endometriosis, or polyps, may result in overlapping symptoms.[16][86] Therefore, the management plan should be individualised to the patient, taking these factors into consideration.

Pain management is an important part of the care plan as chronic pelvic pain and dysmenorrhoea are common presenting symptoms. Many women will already have tried simple analgesia (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], paracetamol) and found it ineffective by the time they receive an image-confirmed diagnosis of adenomyosis. These drugs can be continued, as needed, alongside the treatment approaches outlined below.

Medical management can often provide effective symptom control for patients with adenomyosis and is an especially important option for women who have a desire to preserve their fertility.[2] No medical therapies are specifically approved for treating adenomyosis, but the condition can be managed by using drugs developed for contraception, or for symptoms of other gynaecological conditions such as leiomyoma or endometriosis (both of which commonly co-exist with adenomyosis).

Surgical or interventional options can be considered if pharmacological interventions have been ineffective, are contraindicated, or have been declined, or if surgery is the preferred first-line option for a woman with severe symptoms.[3]

Note that the evidence base underpinning the management of adenomyosis is limited by small study sizes and the common presence of co-existing endometriosis and/or other pathology. Additionally, there are currently no validated quality of life measurement tools for adenomyosis.

The recommendations provided in this topic for management of adenomyosis apply to adults only; consult a specialist for management options and medication dosages in adolescents with adenomyosis.

Hormonal treatments

Levonorgestrel IUD

Offer the levonorgestrel IUD as a first-line treatment for women with symptomatic adenomyosis.[2][3][87]

  • The levonorgestrel IUD has been shown in studies of patients with heavy menstrual bleeding from various causes to reduce menorrhagia and dysmenorrhoea, and improve quality of life.[87][88][89] One study noted that patient satisfaction 3 years after levonorgestrel IUD insertion for the treatment of adenomyosis was 72%.[90] Another retrospective study reported a success rate of 69% in avoiding hysterectomy through the continuous use of the levonorgestrel IUD in patients with symptomatic adenomyosis.[91]

The exact mechanism of action of the levonorgestrel IUD in adenomyosis remains unclear.

  • Levonorgestrel is a progestin. The improvement in heavy menstrual bleeding has been attributed to the reduction of prostaglandin I2, downregulation of oestrogen receptors, and the decidualisation and atrophy of the endometrium due to progestin.[92]

  • Additionally, the levonorgestrel IUD may relieve dysmenorrhoea by modulating neuropathological and non-neuropathological pain mediators, specifically by reducing the expression of nerve growth factor and its receptors.[93]

The levonorgestrel IUD has been suggested as an alternative to hysterectomy.

  • A prospective randomised clinical trial comparing the levonorgestrel IUD with hysterectomy in women with adenomyosis reported comparable effects on menorrhagia, with a significant improvement in haemoglobin levels after 1 year.[94] Additionally, although both treatment options improved quality of life, the levonorgestrel IUD showed slightly superior effects on psychological and social aspects of life as measured by quality of life scores.[94]

One randomised controlled trial demonstrated that the levonorgestrel IUD was superior to the combined oral contraceptive in reducing pain and bleeding frequency among 62 patients with adenomyosis. The study observed:[95]

  • An average decrease in pain scores (measured using a visual analogue scale) from 6.23 to 1.68 in the levonorgestrel IUD group, compared with 6.55 to 3.90 in the combined oral contraceptive group.

  • The mean number of bleeding days per month decreased from 9.81 to 2.63 in the levonorgestrel IUD group, compared with 9.97 to 5.52 in the combined oral contraceptive group.

Oral hormonal therapy

Consider the use of oral hormonal treatments for the management of dysmenorrhoea and heavy menstrual bleeding in women with adenomyosis who decline or are not suitable for management with a levonorgestrel IUD.[2][3] Options include a combined oral contraceptive, or an oral progestin such as norethisterone or dienogest.

Due to the scarcity of high-quality evidence on combined oral contraceptives for the treatment of adenomyosis, most data are extrapolated from studies using these agents to treat endometriosis or leiomyomas.[96][97] Numerous hormonal treatment options, including the combined oral contraceptive and progestins such as norethisterone and dienogest, have shown improvement in dysmenorrhoea and heavy menstrual bleeding.[96]

  • Oral hormonal treatments can result in a progestin-mediated inhibition of cellular proliferation and stimulation of apoptosis of adenomyotic cells.[98] Consistently elevated levels of steroids cause thinning of the endometrium and a decrease in the amount of endometrial shedding, leading to a reduction in menstrual bleeding.[96] Progestins have the potential to address the progesterone resistance observed in both ectopic and eutopic endometrium in adenomyosis and consequently reduce symptoms. However, this resistance may also limit their effectiveness.[99]

Combined oral contraceptives have been found to improve dysmenorrhoea and menstrual bleeding in patients with adenomyosis.[95] They are commonly used for cycle control and to suppress ovulation; if pain is strictly related to the menstrual cycle, continuous use of a combined oral contraceptive may be useful as women may become amenorrhoeic and therefore have less cyclical pain.[100] Adverse effects are generally mild and time-limited; however, the patient should be informed that continuous use of combined oral contraceptives is associated with breakthrough bleeding. Use is contraindicated in patients who are at high risk of arterial or venous thrombotic diseases; consult your local drug information source for a full list of contraindications before prescribing.

Norethisterone is an oral progestin approved for the treatment of endometriosis. It has been found to improve menstrual bleeding in adenomyosis patients.[101] When taken for 3 weeks followed by a 1-week break, it has also been found to improve patient-reported pain scores.[101]

Dienogest is an oral progestin approved for the treatment of endometriosis in many regions outside the US; however, it is currently only available in the US (and some other countries) in combination with estradiol. It has shown prolonged improvement in dysmenorrhoea in patients with adenomyosis after 8 weeks' use, with a sustained effect at up to 52 weeks of use.[102][103][104]

  • Prolonged use of dienogest exerts a hypo-oestrogenic effect without decreasing serum estradiol levels.[105]

  • Some patients report repeated bleeding and hot flushes after long-term use; these adverse effects are tolerable for most patients and make long-term use of dienogest a suitable alternative to avoid hysterectomy.[104]

Non-hormonal pharmacological treatment

Consider the use of NSAIDs or tranexamic acid as non-hormonal treatment options in patients with symptomatic adenomyosis who have abnormal uterine bleeding with or without dysmenorrhoea and who decline or are unsuitable for the levonorgestrel IUD.[3][106][107] These treatment options may be used on their own if symptoms are mild, but can also be used in addition to hormonal treatments if symptoms persist or recur.[108]

There is a lack of specific studies examining the use of NSAIDs and tranexamic acid in the context of adenomyosis.[2] NSAIDs have shown effectiveness in treating dysmenorrhoea and also provide analgesia.[107][108]

  • Although NSAIDs are effective for reduction of heavy menstrual bleeding, one meta-analysis of 19 randomised controlled trials found that NSAIDs were not as effective as tranexamic acid or the levonorgestrel IUD.[109] Note, however, that the cause of heavy menstrual bleeding in trial participants in this meta-analysis was not specified, and participants with pathological causes of heavy menstrual bleeding were excluded from the study.

Tranexamic acid is an antifibrinolytic agent commonly used for the management of heavy menstrual bleeding.[106] The role of tranexamic acid in conditions associated with heavy menstrual bleeding may be related to correlation of increased levels of plasminogen activators in the endometrium of women affected by heavy menstrual bleeding.[110]

  • A systematic review and meta-analysis of 85 studies covering 9950 participants concluded that tranexamic acid was the second most effective intervention (after levonorgestrel IUD) for reducing heavy menstrual blood loss.[87]

Gonadotrophin-releasing hormone (GnRH) agonists

Consider a GnRH agonist (e.g., goserelin, triptorelin, leuprorelin) as a second-line option for short-term treatment of dysmenorrhoea and heavy menstrual bleeding associated with adenomyosis.[2]

GnRH agonists have the potential to alleviate symptoms associated with adenomyosis through both systemic and local effects.[111][112]

  • Systemically, GnRH agonists induce a state of hypoestrogenaemia by downregulating pituitary GnRH receptors.

  • Locally, GnRH agonists exhibit anti-inflammatory and anti-angiogenic properties, along with a direct antiproliferative effect on adenomyotic tissue.

Several studies have demonstrated a reduction of menstrual bleeding, pelvic pain, and adenomyoma volume in women with adenomyosis.

  • In one small study evaluating the use of goserelin for 12 weeks, 92.8% of women self-reported improvement in chronic pelvic pain and 100% reported improvement in dysmenorrhoea and menorrhagia.[113]

  • One study comparing triptorelin with dienogest demonstrated improvement in dyspareunia and chronic pelvic pain, with no significant difference between the two groups.[102] However, triptorelin was found to be superior to dienogest in relieving dysmenorrhoea after 16 weeks.[102] The study also noted 100% improvement in irregular bleeding among patients who received triptorelin, with amenorrhoea occurring in 94.4% of patients.[102] In the very small number of women who do not become amenorrhoeic, an NSAID or tranexamic acid is sometimes used as needed for symptomatic relief; however, this is rarely necessary.

Long-term treatment with a GnRH agonist beyond 6 months is typically not feasible due to the adverse effects associated with anti-oestrogen therapy, such as vasomotor syndrome, mood instability, reduced bone mineral density, and genital atrophy.[114] As a result, the use of 'add-back' hormone replacement therapy may be considered when GnRH agonists are used for longer than 6 months.[2]

  • There is currently no specific guidance for when and which type of add-back therapy should be used, particularly in cases involving severe vasomotor symptoms or to prevent bone loss.[115]

  • In practice, add-back therapy options such as low-dose norethisterone or conjugated oestrogens/medroxyprogesterone may be used. Non-hormonal treatments such as selective serotonin-reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs) may also be considered for vasomotor symptoms.

GnRH agonists have also shown promise when used in combination with surgical resection of adenomyosis lesions for patients with adenomyosis who are trying to conceive; however, the available data on this topic are limited to a few case reports or small series.[116][117][118]

Studies investigating the administration of GnRH agonists before IVF cycles have found conflicting results.

  • One systematic review concluded that treatment with GnRH agonists could be beneficial in improving the clinical pregnancy rate in both symptomatic and asymptomatic patients with adenomyosis.[119] However, another systematic review confirmed the detrimental effects of adenomyosis on infertility and did not show significant benefits of using GnRH agonists to improve IVF outcomes.[120]

  • It is challenging to separate confounding factors, such as advanced maternal age and co-existence of endometriosis, which is frequently associated with adenomyosis. Further studies are needed to differentiate focal from diffuse adenomyosis and to design more standardised IVF protocols, reducing bias and evaluating the potential benefits of GnRH agonists in IVF treatment.

Surgical and interventional treatment

Refer a patient with adenomyosis for consideration of surgical or interventional management options if pharmacological interventions have been unsuccessful, are contraindicated, or have been declined.[3] In addition, patients with severe symptoms of adenomyosis at presentation may be referred to a specialist for consideration of surgical intervention as a first-line option if this is their preference.[2][3]

The type of surgical or interventional treatment that may be considered should be individualised to the patient, and may be influenced by numerous factors including the severity of disease, the patient's desire to preserve or improve fertility, and the patient's comorbidities and suitability for major surgery. In more complex cases, the most appropriate technique is best decided via a multidisciplinary team discussion that includes a gynaecologist and an interventional radiologist.

Patient does not wish to preserve fertility

Hysterectomy

Consider referral for hysterectomy as a definitive treatment option in patients with abnormal uterine bleeding, dysmenorrhoea, or bulk symptoms secondary to adenomyosis who do not desire future fertility or uterine preservation.[2][106] Hysterectomy may be considered in women who:

  • decline or have contraindications to medical management

  • have failed to adequately respond to medical management

  • are unsuitable for endometrial ablation

  • have severe symptoms and a preference for hysterectomy as a first-line treatment option.

While hysterectomy is highly effective for the treatment of benign uterine diseases such as adenomyosis, patients should be counselled regarding both benefits and risks of the procedure.[2][3] This should include discussion of emerging data suggestive of potential long-term health risks associated with hysterectomy, even with conservation of both ovaries.[121]

For non-cancerous uterine conditions such as adenomyosis, minimally invasive surgical approaches (vaginal or laparoscopic) are recommended in preference to open abdominal hysterectomy, if feasible.[122]

  • Vaginal hysterectomy is the preferred minimally invasive intervention due to faster recovery rates and lower rates of ureteral injury.[122]

Endometriosis is a common co-existing condition in women with adenomyosis who undergo hysterectomy. One study of 76 such women found that 26% had a history of endometriosis.[123]

  • In such cases, total laparoscopic hysterectomy, diagnostic laparoscopy followed by vaginal hysterectomy, or natural orifice transluminal endoscopy (vNOTES) may be considered; these options allow visualisation of the peritoneal cavity and treatment of concomitant endometriosis through complete excision during the surgery.[124]

Endometrial ablation

Consider second-generation endometrial ablation as an alternative to hysterectomy in women with heavy menstrual bleeding caused by adenomyosis who wish to preserve their uterus.[3] Endometrial ablation may also be an option for women who are a high-risk group for major surgery and therefore not candidates for hysterectomy (e.g., because of cardiac or pulmonary dysfunction).

Endometrial ablation is not an appropriate option for women who have a desire for future child-bearing.[3][125]

  • Advise women to use effective contraception to avoid subsequent pregnancy after endometrial ablation.[3]

  • A desire for future child-bearing is an absolute contraindication for first-generation ablation techniques.[125] Data on fertility outcomes and pregnancy complications (including the risk of uterine rupture) remain scarce with regard to second-generation techniques; hence, great caution is required.[2]

Various techniques may be performed to ablate the endometrial lining, with an aim to hinder regeneration and reduce abnormal bleeding. The available evidence suggests that second-generation endometrial ablation techniques are associated with greater satisfaction with treatment and a reduction in blood loss compared with first-generation techniques; therefore, second-generation options are usually preferred.[3]

  • Second-generation minimally invasive approaches involve non-resectoscopic thermal endometrial ablation, which utilises a disposable device inserted into the uterine cavity to deliver energy to uniformly eliminate the endometrial lining. Such methods include bipolar radiofrequency, hot liquid-filled balloon, cryotherapy, circulating hot water, and microwave techniques.[126] First-generation techniques entail endometrial resection or ablation via hysteroscopy, utilising electrosurgical instruments such as a rollerball, wire loop, vaporising electrode, or laser.[126]

Radiofrequency (RF) thermal ablation is a minimally invasive thermal ablation technique that has received Food and Drug Administration (FDA) approval for the treatment of leiomyomata (uterine fibroids) in the US, using either a laparoscopic or a transcervical ultrasound-guided system. RF thermal ablation results in volumetric tissue reduction and destruction, which provides the observed symptomatic relief.[125]

  • A meta-analysis of thermal ablation for treatment of adenomyosis reported a reduction in uterine volume after RF ablation of 44.0% (95% CI 36.0% to 52.0%; two studies), and adenomyosis volume reduction of 61.3% (95% CI 52.5% to 70.2%; three studies).[127] The results from two further studies indicate a significant decrease (71% to 72%) in dysmenorrhoea measured using a visual analogue scale (VAS).[128][129] In one study of 87 women with symptomatic adenomyosis, symptom severity scores were reported to decrease by 73% at 12 months after treatment. However, most cases of diffuse adenomyosis showed no improvement and required additional treatments, with the majority of these cases proceeding to hysterectomy.[129]

Microwave ablation involves the percutaneous insertion under ultrasound guidance of a 15-gauge needle antenna with an exposed tip, generating 40 to 60 W of energy into the lesion.[130] Several studies have reported a significant reduction in uterine volume and an improvement in adenomyosis symptoms, including dysmenorrhoea and bleeding.[130][131][132]

  • One study of microwave ablation in 107 patients with focal and non-focal adenomyosis found no significant difference between focal and non-focal ablation over a 12-month follow-up, with uterine volume decreased by 61.1% (±13.6%) versus 59.4% (±10.2%), respectively.[131] Dysmenorrhoea and heavy bleeding showed significant or complete remission at 12 months with no significant difference between focal and non-focal ablation (77.7% vs. 81.1%, respectively).[131]

Uterine artery embolisation

Consider uterine artery embolisation (UAE) for management of pain and heavy bleeding associated with adenomyosis in women who do not wish to have future pregnancies but wish to retain their uterus.[2][125][133] It may also be an option for women who are a high-risk group for major surgery and therefore not candidates for hysterectomy (e.g., because of cardiac or pulmonary dysfunction).

Although data are conflicting, outcomes of UAE in patients with adenomyosis may vary according to specific characteristics. Patients with hypervascular, focal adenomyotic lesions seem to respond better to treatment.[2] Patients should be made aware that symptoms may not resolve following the procedure, or may recur.[133]

There is a paucity of high-quality evidence regarding the use of UAE for the treatment of adenomyosis.[58] Pelvic pain, nausea, and fever caused by ischaemic necrosis are among the adverse effects of UAE frequently reported after treatment.[134]

  • Studies have demonstrated a reduction of uterine volume following UAE of approximately 25%, correlating to improvement of adenomyosis symptoms.[135][136] Several investigations have demonstrated marked improvement in abnormal or heavy menstrual bleeding following UAE, with 88% and 70% of patients reporting significant improvement after 6 and 12 months, respectively.[137][138]

  • UAE appears to have a positive impact on dysmenorrhoea and pelvic pain in patients with adenomyosis; one study found that 74% of patients reported improvement in dysmenorrhoea at 12 months and 70.4% at 5 years.[138] However, after 5 years, 47.2% of women experienced recurrence of at least one symptom.[138] The vascularity pattern of the adenomyotic lesion on MRI was identified as a predictor of UAE outcomes, with highly vascularised, focal lesions being associated with better short- and long-term pain relief than diffuse disease.[138]

  • The rate of long-term recurrence of symptoms was 36% in one study and 35% in another study, with a time to recurrence ranging from 4 to 48 months.[135][139]

Rates of subsequent hysterectomy following initial UAE range from 10% to 18%.[135][139]

Patient desires to preserve fertility

Uterine-sparing focal excision surgery

Uterine-sparing excision procedures (adenomyomectomy) may be considered in patients with focal adenomyotic disease who desire preservation of fertility, who have been counselled about risks during subsequent pregnancy, and in whom medical management has failed to resolve symptoms.[2] The aim is to resect diseased tissue to decrease uterine size while preserving fertility and improving symptoms.[125]

Adenomyomectomy is a challenging surgical procedure due to unclear surgical planes between healthy myometrium and adenomyotic tissue.[140] There are significant perioperative risks, and the procedure must be performed by an experienced surgeon.[2] Several different resection techniques are available for surgical excision of adenomyosis, such as the H-incision, double-flap, and triple-flap adenomyomectomy.[140][141][142][143]

  • Laparoscopic focal excision has been shown to be non-inferior to the abdominal approach in one study; however, strong evidence regarding perioperative and long-term outcomes of each method is lacking.[144]

  • Data regarding outcomes related to quality of life, dysmenorrhoea, and abnormal bleeding are limited, and while these data suggest an improvement, regardless of approach, they are too heterogeneous to recommend one surgical approach over another.[125]

Improvement of heavy bleeding has been reported up to 6 years after surgery, irrespective of the approach used, with a low rate of persistent abnormal bleeding (8% to 10% of patients).[144][145][146][147]

  • In one study, 94% of women who had dysmenorrhoea as a primary symptom reported complete pain resolution at 6 months following excisional procedures; the remaining 6% experienced partial improvement.[147]

Careful counselling is needed about the uncertain impact of adenomyomectomy on fertility and pregnancy outcomes as well as the increased risk of serious pregnancy-related complications including uterine rupture.[2][148] Many experts recommend pre-labour caesarean delivery because of this risk.[125]

  • There are insufficient strong data to support performing surgery for the express purpose of enhancing fertility as evidence is mixed.[2] One study of 40 patients with adenomyosis that compared the effect on fertility outcomes of GnRH agonist therapy alone versus combined GnRH agonist therapy plus conservative surgical excision found that at 3-year follow-up the cumulative pregnancy rate was higher in the combined therapy group (44.4%) than in the GnRH agonist alone group (13.6%).[149] However, another study of 165 women who were treated with either adenomyomectomy alone or a combination of surgical and medical treatment (adenomyomectomy followed by a 6-month course of a GnRH agonist) found that there were no significant differences in the clinical pregnancy rate (CPR) and live birth rate (LBR) between the two groups (surgery only CPR of 79.5% and LBR of 72.7%, vs. 74.1% and 63.0%, respectively, for the combined surgery-medical group) at 2-year follow-up.[150]

  • Several small studies have highlighted adverse pregnancy outcomes associated with uterine-sparing surgeries for adenomyosis. Significant risks may include placenta accreta spectrum and uterine rupture, which are thought to occur due to adenomyosis-induced changes in myometrial strength and perfusion, further aggravated by surgical trauma that potentially hampers uterine healing.[142][148][151][152] In one large series, a 4% rate of uterine rupture was reported.[148] However, a meta-analysis of 12 studies involving 364 women who had partial or complete excision of adenomyosis reported that 35% successfully conceived and, of that group, 74% delivered at full term with a uterine rupture rate of 0.8%.[152]

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