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Uterine adenomyosis

Uterine adenomyosis
Literature review current through: Jan 2024.
This topic last updated: Nov 07, 2023.

INTRODUCTION — Uterine adenomyosis is a disorder in which endometrial glands and stroma are present within the myometrium (uterine musculature), resulting in hypertrophy of the surrounding myometrium. Patients with symptomatic adenomyosis will often present with uterine enlargement, abnormal uterine bleeding (AUB), and painful menses. Adenomyosis may also coexist with uterine leiomyoma and/or endometriosis.

Historically the diagnosis of adenomyosis was made retrospectively and based solely on histologic assessment of hysterectomy specimens. However, the diagnosis is now made by imaging-based criteria using transvaginal ultrasonography (TVUS) and/or magnetic resonance imaging (MRI) which has resulted in a greater understanding of the disease, its prevalence, effect on younger patients and patients with reproductive dysfunction, and treatment options.

The diagnosis and management of uterine adenomyosis will be reviewed here. Other topics related to uterine pathology and AUB are presented separately.

(See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

(See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

(See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

(See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

PATHOGENESIS — The pathogenesis of adenomyosis is not known. Four theories suggest that adenomyosis occurs from [1-5]:

Endomyometrial invagination of the endometrium.

De novo from müllerian remnants.

Microtrauma of the endometrial/myometrial interface (ie, junction zone [JZ]).

Disruption of the JZ may result in ultrastructural changes and differential growth factor (GF) expression that may result in migration of the endometrial cells into the myometrium [6-10].

Establishment of lesions from retrograde menstruation of endometrial cells.

The lack of basement membrane between the endometrium and myometrium likely influences these processes.

Estrogen and progesterone also contribute to adenomyosis pathophysiology, as in other gynecologic disorders; both estrogen and progesterone receptors appear to be upregulated in patients with adenomyosis. Studies suggest that estrogen is produced in, and appears to be a mitogen for, adenomyotic tissue [11]. In a murine model of adenomyosis, early exposure to estrogen modulators (in this experiment, tamoxifen) led to an increased risk of adenomyosis and abnormal myometrium, which also supports the invagination hypothesis [12]. In humans treated with tamoxifen (a selective estrogen receptor modulator [SERM] used in the treatment and prevention of some breast cancers), histopathologic uterine changes consistent with adenomyosis have been reported [13]. Similarly, treatments that inhibit estrogen production (eg, gonadotropin-releasing hormone [GnRH] agonists and antagonists, danazol) normalize aromatase expression in the endometrium of patients with adenomyosis [14,15]. (See 'Alternative hormone strategies' below.)

Other animal models suggest that pituitary protein hormones (eg, prolactin, follicle-stimulating hormone, oxytocin) may also have roles in the pathogenesis adenomyosis [2,11,16-23]. This hypothesis is strengthened by research showing that, in patients with adenomyosis, dopamine agonists (eg, bromocriptine; used for treatment of hyperprolactinemia) result in improvement in menstrual bleeding, pain, and quality of life [24,25]. However, this association may be a result of improved chronic pain or depression, rather than adenomyosis itself. Furthermore, the steroid and pituitary hormone pathways may be functionally linked. Progesterone appears to upregulate prolactin in adenomyosis cells, as it does in the endometrium [11,23]. Additionally, in normal myometrium and leiomyomas, prolactin can act as a smooth muscle cell mitogen [16].

Expression of other key molecules (eg, BCL2 gene expression, superoxide dismutase, granulocyte macrophage colony-stimulating factor, KRAS) in adenomyotic cells may also differ from eutopic endometrial glands [26-31]. Stem cells and immune and inflammatory mediators also appear to play a role [5].

EPIDEMIOLOGY — The epidemiology of adenomyosis is uncertain because data regarding adenomyosis has often relied on the assessment of the uterus following hysterectomy. Thus, what is reported here as the epidemiology of adenomyosis may, in fact, be reflecting the epidemiology of hysterectomy:

Studies report that adenomyosis is present in a wide range (eg, 9 to 62 percent) of individuals undergoing hysterectomy [10]. Variability is present not only with differing populations and reasons for hysterectomy (eg, adenomyosis is more common in patients with leiomyomas), but different diagnostic criteria used, and number of histologic sections examined.

In one retrospective study including 137 patients who underwent hysterectomy (at a mean age of 49 years) and in whom pathology reports were available, almost half (48 percent) had histologic-confirmed adenomyosis [32]. The authors of this study argued that adenomyosis is a normal variant and not a true disease.

Adenomyosis was previously described as a disease that developed between the ages of 40 and 50 years, which is also the age at which most hysterectomies are performed [10]. However, studies utilizing imaging diagnosis of adenomyosis suggest that adenomyosis can frequently be detected at younger ages (prevalence rates of 20 to 35 percent) [33-35], with one study reporting a mean age of 26 years for patients with an imaging diagnosis of adenomyosis [35].

Adenomyosis appears to be more common in parous than nulliparous patients [32,36,37]. However, this relationship is likely biased since nulliparous compared with parous patients are less likely to undergo hysterectomy. Interestingly, a greater number of pregnancies is not associated with a higher risk of the disease [38]. Other reproductive risk factors may include earlier age at menarche (≤10 years), shorter menstrual cycle duration (≤25 days), and use of menopausal hormone therapy [10].

Adenomyosis may occur more commonly in patients with prior uterine surgery [24,39]. However, patients with prior uterine surgery may also be more likely to undergo hysterectomy.

CLINICAL FEATURES

Clinical presentation — Presenting symptoms of adenomyosis include heavy menstrual bleeding, painful menses, and chronic pelvic pain. Some patients may present with infertility [40]. Historically, it was thought that approximately one-third of patients were asymptomatic [36]; however, this is likely an overestimate, and more recent studies report much lower rates (4.5 percent) of asymptomatic patients [41].

Heavy menstrual bleeding, also referred to as abnormal uterine bleeding-adenomyosis (AUB-A) in the International Federation of Gynecology and Obstetrics (FIGO), or PALM-COEIN, classification system (figure 1), occurs in approximately 50 to 60 percent of patients with adenomyosis [36,41]. AUB may be related to the increased surface of the enlarged uterus, an overexpression of inflammatory mediators in the adenomyotic tissue, or contractile dysfunction of the uterine smooth muscle as a result of the ectopic endometrium [42,43].

Painful menses occurs in approximately 25 to 80 percent of patients, depending on the population studied [36,41]. Pain may be due to bleeding and swelling of endometrial islands confined by myometrium.

Associated conditions — Adenomyosis often coexists with other uterine diseases, particularly uterine leiomyomas and endometriosis, which can obscure the diagnosis of adenomyosis and make delineation of a symptom profile specific to adenomyosis difficult.

Endometriosis — While both adenomyosis and endometriosis represent disorders of ectopic endometrium and can be a cause of pelvic pain, the two diseases are not thought to be otherwise related. Thus, in our practice, we avoid using the older term for adenomyosis, "endometriosis interna." (See 'Differential diagnosis' below and "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

Adenomyosis and endometriosis, however, coexist and in patients with persistence of pelvic pain following optimal endometriosis surgical therapy, the presence of adenomyosis should be more strongly considered [44,45]. In one prospective study including 227 patients with infertility, patients with endometriosis (70 percent of patients) versus without endometriosis had higher rates of concurrent adenomyosis (79 versus 28 percent); adenomyosis was diagnosed by MRI [46]. The prevalence was highest (90 percent) in patients <36 years with endometriosis and a partner with a normal sperm count.

Patient characteristics may differ between groups. In a longitudinal study recruiting females starting at age 22, patients with adenomyosis compared with endometriosis had increased parity, earlier menarche, and shorter menstrual cycles [37].

Leiomyoma — Adenomyosis also often coexists with leiomyoma. In the longitudinal study discussed above including patients with adenomyosis or endometriosis, over one-half of the patients in both groups had concomitant leiomyomas [37].

As with endometriosis, patient characteristics may differ between those with adenomyosis or leiomyomas. In a case-control study comparing patients undergoing hysterectomy with a pathologic diagnosis of adenomyosis alone (cases) versus leiomyomas alone (controls), those with adenomyosis were younger and more likely to have dysmenorrhea, pelvic pain, depression, and a history of prior uterine surgery [24]. In a multivariate analysis confined to patients with uteri weighing more than 150 grams, patients with adenomyosis were more likely to have depression and endometriosis compared with patients with only fibroids [24]. Similarly, while increased parity may be associated with increased rates of adenomyosis (see 'Epidemiology' above), the opposite is seen in patients with leiomyomas, in whom parity is associated with a decreased risk of disease. (See 'Differential diagnosis' below and "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history", section on 'Parity'.)

There is also evidence that adenomyosis and leiomyomas share elements of pathogenesis such as growth factor dysregulation and abnormalities of angiogenesis [29,47-52]. Thus, some therapies that are used for the treatment of leiomyomas may also be used for treatment of those with adenomyosis. (See 'Management of symptomatic patients' below.)

Other

Adverse pregnancy outcomes – Adenomyosis may be associated with poor pregnancy outcomes, including miscarriage, preterm birth, and small-for-gestational-age (SGA) infants [53-55].

In a meta-analysis of four studies and over 1100 patients, those with adenomyosis (13 percent) versus without adenomyosis had higher rates of preterm birth (odds ratio [OR] 3.09, 95% CI 1.88-5.09) and SGA (OR 3.23, 95% CI 1.71-6.09) [54]. A subsequent meta-analysis also showed an association between adenomyosis and miscarriage (OR 3.49, CI 1.41-8.65; six patients) [55]. These associations may be related to confounders or misdiagnosis of adenomyosis, and further studies are needed.

Infertility – Adenomyosis may be associated with infertility; however, there are many confounders with such an association (eg, hysterectomy was previously required for diagnosis, endometriosis commonly coexists) and most of the evidence comes from small case series [56,57].

In a meta-analysis of 11 cohort studies including 2054 patients undergoing in vitro fertilization (IVF), those with adenomyosis (25 percent) versus without adenomyosis had lower rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live birth [58]. These findings are supported by an earlier animal study which showed that baboons with infertility had a 20-fold increase of histologic adenomyosis even when concomitant endometriosis was excluded [59].

The type of adenomyosis (ie, focal or diffuse) may also impact fertility (see 'Histopathology' below). In a cross-sectional study including almost 248 patients with adenomyosis (mean age 32 years), the prevalence of infertility was 30 percent; after controlling for age and coexisting leiomyoma or endometriosis, focal adenomyosis was independently associated with primary infertility (adjusted OR 1.9; 95% CI 1.1-3.3) [60]. Diffuse adenomyosis did not appear to be associated with infertility.

Cancer – Adenomyosis may be associated with an increase in some cancers.

In a retrospective study including over 760 patients with adenomyosis, patients with adenomyosis compared with controls had higher rates of ovarian cancer (adjusted hazard ratio [aHR] 5.5, 1.95-15.5), endometrial cancer (aHR 5.13, 1.36-19.4) and colorectal cancer (aHR 13.04, 2.21-77.04) [61]. Similarly, in a subsequent population-based study including over 12,000 females with adenomyosis and age-matched controls, adenomyosis was associated with an increased risk of endometrial cancer (HR 2.2, 95% CI 1.5-3.2) and thyroid cancer (HR 1.7, 95% CI 1.3-2.2) [62]. Both studies relied on large administrative databases and did not control for clinical risk factors such as parity, anovulatory bleeding, and colorectal screening practices. Confirmation of these findings in appropriately controlled studies would likely impact screening for these diseases.

EVALUATION — Patients with suspected adenomyosis are evaluated with a medical history, pelvic examination, and pelvic imaging. Laboratory testing is not needed to diagnose adenomyosis.

History — A medical history is taken, including a full obstetric and gynecologic history. Patients should be asked about other conditions or medications that can cause abnormal uterine bleeding (AUB) or pelvic pain. This is discussed in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'History'.)

Pelvic examination — A pelvic examination is performed. Typical findings of adenomyosis include a mobile uterus that is diffusely enlarged (often referred to as "globular"), soft (often referred to as "boggy"), and tender. The uterus rarely exceeds the size of a pregnant uterus at 12 weeks of gestation [63]. While some patients have a symmetrical uterus, others have irregular masses (termed adenomyomas), which clinically resemble leiomyomas.

Adenomyosis does not result in a fixed uterus, but this may occur with endometriosis, which often coexists with adenomyosis. (See 'Endometriosis' above.)

Imaging

Modality

Transvaginal ultrasound and magnetic resonance imaging – Transvaginal ultrasound (TVUS) is the first-line imaging study for evaluation of an enlarged uterus, pelvic pain, and/or abnormal bleeding. The images should be reviewed by a radiologist or gynecologist experienced in evaluating adenomyosis. While there are clear consensus definitions for the diagnosis of adenomyosis with ultrasound [64], not all individuals performing or reading ultrasound systematically search for evidence of the disease.

MRI is typically reserved for patients in whom it is important to distinguish between diffuse and focal adenomyosis, focal adenomyosis and leiomyomas, and/or to help with treatment (eg, surgical, interventional) planning [65]. (See 'Uterus-sparing resection' below.)

Both TVUS and MRI have a high sensitivity and specificity for diagnosing adenomyosis. In a meta-analysis including over 3300 patients with adenomyosis confirmed on hysterectomy specimen, TVUS had a sensitivity and specificity for diagnosing adenomyosis of 81 and 87 percent, respectively [66]. The sensitivity and specificity with MRI were 71 and 91 percent, respectively.

Hysterosalpingogram – Hysterosalpingogram (HSG), primarily used to determine tubal patency in patients with infertility, may show multiple small outpourings of endometrium extending into the myometrium. (See "Hysterosalpingography", section on 'Uterine contour abnormalities'.)

Computed tomography (CT) has no role in the assessment of adenomyosis [67].

Findings – Findings of adenomyosis on TVUS or MRI vary and include (figure 2) [64]:

An enlarged uterus.

Asymmetric thickening of the myometrium (with the posterior myometrial typically thicker) (image 1).

Myometrial cysts (image 2). Typically, these cysts are small (eg, 2 to 5 mm), and for histologic diagnosis, the cysts must be separated from the endometrium by at least 2 low-power fields. (See 'Histopathology' below.)

In the past, the term "cystic" was used to describe adenomyomas ≥1 cm in diameter on imaging studies. The entity "juvenile cystic adenomyoma" has been used to describe a syndrome in which females 30 years or younger with severe dysmenorrhea have myometrial cysts ≥1 cm [68]. However, cystic adenomyosis has been reported in females of a variety of reproductive ages [69].

Hyperechoic islands in the myometrium.

Linear striations radiating out from the endometrium (image 3). This can also be described as fan-shaped shadowing and appears as alternating bands of shadowing and hyperechogenicity on ultrasound. These are thought to be caused by the small cysts in the myometrium allowing for increased through transmission and shadowing caused by the surrounding compact myometrium.

Increased lesional vascularity in adenomyomas. By contrast, peripheral vascularity is seen in leiomyomas.

Increased myometrial heterogeneity.

Thickening, interruption, or irregularities of the junctional zone (JZ) on MRI (endomyometrial border). Some quantitation of the thickening of the JZ is possible (termed "junctional zone hyperplasia"), with >12 mm generally considered diagnostic of the disease [70].

Echogenic subendometrial lines or buds extending from the JZ.

Features of adenomyosis can also change with the menstrual cycle. For example, cysts may become larger and echogenic masses within the myometrium may change in echogenicity during the menstrual cycle.

Limited role of other tests — There are no laboratory tests that diagnose adenomyosis [71]. The following tests may be utilized in addition to imaging for selected patients to evaluate other conditions:

Urine or serum hCG – A urine or serum human chorionic gonadotropin (hCG) should be measured to exclude pregnancy in reproductive-age patients with uterine enlargement, AUB, or pelvic pain.

Hemoglobin or hematocrit – A hemoglobin/hematocrit may be ordered for patients with AUB or when anemia is suspected.

Chlamydia and/or gonorrhea – If pelvic pain is present, tests to exclude infection may be sent, if appropriate.

Endometrial biopsy – Endometrial biopsy is not informative in the diagnosis of adenomyosis since it is a myometrial disease. However, it is often required in patients with adenomyosis since they have AUB, and endometrial hyperplasia or carcinoma must be excluded. In addition, thickening of the junctional zone on ultrasound can sometimes be misinterpreted as endometrial thickening, which may lead to additional endometrial evaluation (eg, endometrial biopsy, dilation and curettage with hysteroscopy) in some patients. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Transvaginal ultrasound'.)

Needle biopsy – Needle biopsy of the myometrium is not common practice and is reserved for clinical situations in which a malignancy needs to be excluded. Sensitivity of needle biopsy depends on several factors, including the extent of disease, number of biopsy specimens obtained, sampling site, needle gauge, and operator experience [63].

DIAGNOSIS — A definitive diagnosis of adenomyosis is made based on the finding of endometrial tissue within the myometrium during pathology evaluation of the uterus after hysterectomy. (See 'Histopathology' below.)

A presumptive diagnosis of adenomyosis can be made in patients with characteristic clinical manifestations (eg, heavy menstrual bleeding and dysmenorrhea in a patient with an enlarged uterus) and imaging findings consistent with adenomyosis. (See 'Clinical presentation' above and 'Imaging' above.)

HISTOPATHOLOGY — There are three forms of adenomyosis: diffuse, focal and junctional zone disease.

Diffuse adenomyosis – On gross inspection, the uterus with diffuse adenomyosis is uniformly enlarged and boggy. The average uterine weight is usually between 80 and 200 grams, unless coexisting leiomyomas are present.

Upon sectioning the uterus, the myometrial wall appears thickened and small hemorrhagic or chocolate-colored areas (representing islands of endometrial bleeding) without well-demarcated borders are dispersed throughout the myometrium (picture 1).

Focal adenomyosis (also called adenomyoma) – On gross inspection, focal adenomyosis can resemble a leiomyoma but without its characteristic pseudocapsule which allows for easy enucleation during surgical resection.

Upon sectioning the uterus, circumscribed, nodular aggregates of hemorrhagic or chocolate-colored areas are visualized in only one part of the myometrium.

Junctional zone disease – The junctional zone (JZ) is the border between the endometrium and myometrium; the presence of endometrial tissue within the myometrium at a distance of at least two low-power fields (though proposed cut-off values are variable) from the JZ is pathognomonic of adenomyosis (picture 1) [72]. The distance requirement is to preclude mistaking the normal endometrium between muscle fibers at the mucosa for adenomyosis when the specimen is transected for slide preparation. The ectopic endometrium usually has an immature proliferative pattern.

While thickening, discontinuity, and interruption of the JZ can be clearly visible on MRI (see 'Imaging' above), its use as a histologic marker of adenomyosis is limited. In addition, a prior history of endometrial ablation can confound the diagnosis of adenomyosis as the procedure distorts or destroys the JZ.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of adenomyosis includes other conditions that cause uterine enlargement, abnormal uterine bleeding (AUB) (table 1 and table 2), and/or dysmenorrhea (table 3). Negative pregnancy testing excludes conditions associated with bleeding during pregnancy.

Most commonly, adenomyosis must be differentiated from uterine leiomyomas and endometriosis.

Uterine leiomyomas may cause uterine enlargement and heavy menstrual bleeding. While leiomyomas tend to cause noncyclic pelvic pain or pressure, they may also be associated with dysmenorrhea. Pelvic imaging can usually differentiate the two conditions, but fibroids may also coexist with adenomyosis, and if a patient has both, it can be difficult to know which is the cause of the patient's symptoms. (See 'Leiomyoma' above and "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

Endometriosis classically present with dysmenorrhea, dyspareunia, and infertility. Endometriosis usually requires surgery for diagnosis, but some patients may have characteristic findings (eg, ovarian endometrioma, extrauterine endometrial implants) on imaging. Patients with persistent pain following adequate treatment for endometriosis may have adenomyosis as an underlying diagnosis [45]. (See 'Endometriosis' above and "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact" and "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Findings'.)

Less common conditions that need to be differentiated from adenomyosis include:

Chronic endometritis can cause AUB and dysmenorrhea. While the uterus is often tender, it is typically normal in size (unless coexisting adenomyosis or leiomyomas are present). An endometrial biopsy demonstrating plasma cells in the endometrial stroma is diagnostic of chronic endometritis. (See "Endometritis unrelated to pregnancy", section on 'Chronic endometritis' and "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Pelvic inflammatory disease (PID) may present with acute or subacute pelvic pain. Cervical motion, uterine, and adnexal tenderness on bimanual pelvic examination are the defining characteristics of acute symptomatic PID, and purulent endocervical discharge and/or vaginal discharge is also common. While AUB can occur, it is less common than with adenomyosis. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Patients with AUB should also be evaluated for endometrial carcinoma, as appropriate. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)

MANAGEMENT OF SYMPTOMATIC PATIENTS — Management of patients with symptomatic adenomyosis is described here (algorithm 1). Patients with adenomyosis but no symptoms do not require treatment.

First line therapies

NSAIDs — If not already initiated, first line therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, naproxen, mefenamic acid), which are effective for the treatment of heavy menstrual bleeding and dysmenorrhea. These are discussed in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Nonhormonal therapies' and "Dysmenorrhea in adult females: Treatment", section on 'First-tier'.)

52 mg levonorgestrel IUD — In our practice, first line therapy also includes the 52 mg levonorgestrel-releasing intrauterine device (LNG 52), given its direct action on the uterus, low systemic levels of steroid hormones, and long-acting user-independent administration.

Observational studies suggest that the LNG 52 improves both adenomyosis-associated heavy menstrual bleeding and dysmenorrhea [73-76]. In one observational study including 29 patients with MRI-diagnosed adenomyosis, treatment with the LNG 52 for six months was associated with a 24 percent reduction in the thickness of the junctional zone on MRI as well as a reduction in pain and abnormal bleeding in most patients [76]. In a subsequent observational study including 94 patients with transvaginal ultrasound-diagnosed adenomyosis, treatment with the LNG 52 was associated with a reduction in dysmenorrhea and uterine volume during the 29 month (mean) follow-up period; IUD expulsion (16 percent) or premature removal (18 percent) occurred in over one-third of patients [75].

While other LNG IUDs (ie, LNG 19.5, LNG 13.5) are available, the data on adenomyosis treatment were generated based on the 52 mg system. Thus, for the purposes of adenomyosis treatment, this formulation is preferred. (See "Intrauterine contraception: Background and device types", section on 'Devices and characteristics'.)

Alternative hormone strategies — For patients who prefer not to, or cannot use, the LNG 52, other hormonal strategies may be used; data on efficacy are limited:

Oral contraceptive pills – While data on the efficacy of estrogen-progestin contraceptives for the treatment of adenomyosis are limited, these contraceptives are effective as primary treatments for heavy menstrual bleeding and dysmenorrhea; thus, a trial of estrogen-progestin contraceptives is reasonable.

In a randomized trial including 57 patients with ultrasound-diagnosed adenomyosis in whom six-month follow-up data was available, treatment with oral contraceptives or LNG 52 IUD both reduced reducing pain and bleeding, but larger reductions were demonstrated in the LNG 52 IUD group [77]. Other contraceptive pill options, including progesterone only pills (eg, norethindrone acetate) and dienogest (available outside the United States as a single agent), have also been described [78].

GnRH agonists and antagonists – Gonadotropin-releasing hormone (GnRH) analog combinations (elagolix plus estradiol and norethindrone, relugolix plus estradiol and norethindrone), approved for the treatment of heavy menstrual bleeding in patients with uterine fibroids, may also be used for patients with concomitant adenomyosis [79-84]. However, the use of these agents with isolated adenomyosis has not been studied.

In an analysis of two identical phase III trials including 126 patients with fibroid-related heavy menstrual bleeding and concurrent adenomyosis diagnosed on imaging, more patients treated with elagolix plus hormonal add-back therapy (elagolix 300 mg twice a day with daily estradiol 1 mg and norethindrone acetate 0.5 mg) compared with placebo met the primary endpoint of menstrual blood loss of <80 mL during the final month of treatment and at least a 50 percent reduction in menstrual blood loss from baseline to the final month (range 77 versus 12 percent) [85]. Side effects were modest, including hot flushes (18 percent), nausea (11 percent), and night sweats (8 percent).

Other – Use of other hormonal options including aromatase inhibitors, oxytocin antagonists, and progesterone receptor modulators have been described [78,86], but data are limited and we do not use these routinely in our practice.

In one randomized trial including 134 premenopausal patients with MRI- or ultrasound-diagnosed adenomyosis, those receiving mifepristone (10 mg orally daily) compared with placebo had a greater improvement of dysmenorrhea (92 versus 23 percent), blood loss (mean increase in hemoglobin: 2.1 versus 0.48 g/dL), and uterine volume (mean change: -29.3 versus -18.4 cm3) after twelve weeks of treatment [86]. Further studies are needed to determine the long-term efficacy of mifepristone in such patients.

When hormonal medications are discontinued (eg, when a patient wants to conceive) recurrence of symptoms and enlargement of the uterus in those with treatment associated volume reduction are usually documented within six months.

Later line: Surgical procedures

Patients who have completed childbearing

Hysterectomy — For patients who have completed childbearing and in whom first-line therapies were ineffective or contraindicated, hysterectomy is the definitive treatment option. Hysterectomy is also the only way to remove diffuse adenomyosis and is generally preferred to the removal of adenomyomas with uterine conservation, except where future pregnancy is desired. (See 'Patients who desire future childbearing' below.)

However, patients with adenomyosis in whom pain is the primary or sole symptom should be carefully counseled that they may continue to have pain following hysterectomy as neural pathways of pain may still be active.

The procedure for hysterectomy is the same as for other benign indications and may be performed via laparotomy, transvaginal, laparoscopy, or robotic surgery. Since disease is confined to the uterine corpus, the ovaries may be conserved. (See "Hysterectomy (benign indications): Selection of surgical route" and "Hysterectomy: Abdominal (open) route" and "Hysterectomy: Laparoscopic" and "Hysterectomy: Vaginal".)

Uterine artery embolization, as an alternative — For patients who have failed hormonal treatment and decline, or have contraindications to, a hysterectomy, uterine artery embolization (UAE) may be used to reduce symptoms related to adenomyosis (image 4). UAE is not intended for use in patients who desire to optimize future childbearing as adverse pregnancy outcomes can occur. (See "Uterine fibroids (leiomyomas): Treatment with uterine artery embolization", section on 'Reproductive outcomes'.)

Studies on UAE for adenomyosis show a 25 percent reduction in uterine volume and clinical improvement in abnormal bleeding and overall symptom reduction [87-91]. In a meta-analysis of observational studies including patients with adenomyosis undergoing uterine-sparing procedures, those undergoing UAE had recurrence and reintervention rates of 29.5 and 12.8 percent (16 studies); follow-up ranged from six months to seven years (table 4) [92]. In one cohort study included in this meta-analysis, adverse outcomes occurring within 12 months of UAE included failed embolization (1.5 percent; 4 of 264 patients), premature ovarian insufficiency diagnosed within three months of the procedure (3 percent; 7 of 264), and there was one periprocedural death due to a pulmonary embolus [93]. From one to five years, an additional 57 patients were lost to follow-up, nine had hysterectomies, and three died of other causes. Among the 195 patients who completed five years of follow-up, approximately 70 percent of patients had improvement in painful and heavy menses and that improvement was greatest in patients with hypervascular lesions as determined by digital subtraction angiography at the time of treatment.

Patients who desire future childbearing

Uterus-sparing resection — Uterus-sparing resection of focal adenomyosis may be performed in patients who desire future childbearing and in whom first-line therapies were ineffective or contraindicated [94-96]. Unlike uterine leiomyomas, which can be readily shelled out from the surrounding myometrium, adenomyomas are not easily excised, a surgical plane often cannot be easily developed, and sharp dissection is required. Furthermore, the consistency of the adenomyotic uterus is described as "woody," and suturing is difficult in this environment. Surgical resection of diffuse adenomyosis is considered investigational [97]. Such surgical techniques include wedge resection of the uterine wall, transverse H-incision on the uterine fundus with resection of the adenomyosis, and Osada triple-flap method.

A preoperative MRI is obtained for such patients to evaluate the location and extent of the adenomyosis, determine if uterus-sparing surgery is feasible, and help the surgeon plan the procedure (see 'Imaging' above). Both laparoscopic and laparotomy techniques can be utilized.

The disadvantage of uterus-sparing resection is that even when performed by expert surgeons, the rate of uterine rupture in a future pregnancy is reported to be 4 percent and occurs between 12 and 35 weeks of gestation [97]. This rate exceeds the uterine rupture rate after myomectomy or classical cesarean birth (estimated risk of rupture with labor after classical cesarean: 2 percent [98]). Other pregnancy complications, such as abnormal placental attachment, have also been reported.

After uterine-sparing resection is performed, in vitro fertilization is often utilized to optimize the chance of conception prior to disease recurrence. If pregnancy needs to be delayed, hormonal agents (eg, GnRH agonists, the LNG IUD) may be used to prevent recurrence and for symptom control [99,100]. (See 'Alternative hormone strategies' above and '52 mg levonorgestrel IUD' above.)

During pregnancy, patients are managed even more conservatively than patients who have had other transmyometrial surgery and are candidates for prelabor cesarean birth. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Scheduling' and "Repeat cesarean birth", section on 'Timing'.)

Outcomes after uterine-sparing resection have been reported. In a meta-analysis of 12 studies including patients with adenomyosis undergoing uterus-sparing surgery, partial and complete excision of adenomyosis were associated with improvement of pain and menorrhagia and reduction in uterine volume [101]. Of the 364 patients who attempted to conceive, 35 percent were successful, and, of those, 18 percent miscarried, 7 percent delivered preterm, and 74 percent had a full-term birth. One uterine rupture occurred (1/126 or 0.8 percent). In the subsequent meta-analysis of observational studies discussed above (see 'Uterine artery embolization, as an alternative' above), those undergoing adenomyomectomy had recurrence and reintervention rates of 12.6 and 2.6 percent (14 studies); follow-up ranged from 13 months to seven years (table 4) [92].

Other treatments — Other uterine-sparing interventions, more commonly used for uterine fibroids, show some efficacy for treatment of adenomyosis. Case series of both ultrasound- or MRI-guided focused ultrasound surgery show both symptom improvement and uterine volume reduction with 6 to 12 months of follow-up [102-105]. Reports of laparoscopic radiofrequency ablation and transcervical radiofrequency ablation of uterine adenomyosis also suggest some efficacy in terms of short-term symptom improvement and volume reduction [106,107]. In the meta-analysis described above (see 'Uterine artery embolization, as an alternative' above), patients undergoing thermal ablation had recurrence and reintervention rates of 10 and 8.2 percent (12 studies); follow-up ranged from 12 months to five years (table 4) [92]. (See "Overview of endometrial ablation", section on 'Factors associated with treatment failure'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Uterine adenomyosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Uterine adenomyosis is a disorder in which endometrial glands and stroma are present within the myometrium (uterine musculature). The ectopic endometrial tissue appears to induce hypertrophy and hyperplasia of the surrounding myometrium, which results in a diffusely enlarged uterus (often termed "globular" enlargement). (See 'Introduction' above.)

Epidemiology – The epidemiology of adenomyosis is uncertain because data regarding adenomyosis has often relied on the assessment of the uterus following hysterectomy. (See 'Epidemiology' above.)

Clinical features

Clinical presentation – Common presenting symptoms of adenomyosis include heavy menstrual bleeding, painful menses, and chronic pelvic pain; patients may also be asymptomatic. (See 'Clinical presentation' above.)

Associated conditions – Adenomyosis often coexists with other uterine diseases, particularly uterine leiomyomas and endometriosis, which can obscure the diagnosis of adenomyosis and make delineation of a symptom profile specific to adenomyosis difficult. (See 'Associated conditions' above.)

Evaluation – Patients with suspected adenomyosis are evaluated with a medical history, pelvic examination, and pelvic imaging. There are no laboratory tests that diagnose adenomyosis.

Examination – On bimanual examination, the uterus is typically mobile, diffusely enlarged, soft (often referred to as "boggy"), and tender. (See 'Pelvic examination' above.)

Imaging – Transvaginal ultrasound is the first-line imaging choice for evaluation of an enlarged uterus, pelvic pain, and/or abnormal bleeding. Magnetic resonance imaging is typically reserved for patients in whom it is important to distinguish between diffuse and focal adenomyosis and/or to help with treatment planning. (See 'Imaging' above.)

Diagnosis – A definitive diagnosis of adenomyosis is made based on the finding of endometrial tissue within the myometrium during pathology evaluation of the uterus after hysterectomy (picture 1). A presumptive diagnosis of adenomyosis can be made in patients with characteristic clinical manifestations (eg, heavy menstrual bleeding, painful menses) in a patient with an enlarged uterus and imaging findings consistent with adenomyosis (figure 2). (See 'Diagnosis' above.)

Management of symptomatic patients (algorithm 1)

First-line therapies

-NSAIDs – If not already initiated, nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, naproxen, mefenamic acid) are often prescribed as a first line treatment as they are effective treatment options for heavy and painful menses, as discussed separately. (See 'NSAIDs' above and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Nonhormonal therapies' and "Dysmenorrhea in adult females: Treatment", section on 'First-tier'.)

-LNG 52 – For most patients with symptomatic adenomyosis, we also suggest treatment with the 52 mg levonorgestrel-releasing intrauterine device (LNG 52) (Grade 2C). The LNG 52 provides direct action on the uterus, low systemic levels of steroid hormones, and long-acting user-independent administration. (See 'First line therapies' above.)

Alternative hormone strategies – For patients who prefer not to, or cannot use, the LNG 52, other hormonal strategies (eg, oral contraceptive pills, gonadotropin-releasing hormone [GnRH] agonists and antagonists) may be used; data on efficacy are limited. (See 'Alternative hormone strategies' above.)

Later-line therapies

-Patients who have completed childbearing For patients who have completed childbearing and in whom first-line therapies were ineffective or contraindicated, we suggest hysterectomy (Grade 2C). Hysterectomy is the definitive treatment option for adenomyosis. For patients who have failed hormonal treatment and decline, or have contraindications to hysterectomy, uterine artery embolization (UAE) may be used to reduce symptoms related to adenomyosis (image 4). (See 'Patients who have completed childbearing' above.)

-Patients who desire future childbearing – For Patients with focal adenomyosis who desire future childbearing and in whom first-line therapies were ineffective or contraindicated, uterus-sparing resection can be performed. Surgical resection of diffuse adenomyosis is considered investigational. Other uterine-sparing interventions (eg, ultrasound- or MRI-guided focused ultrasound surgery, laparoscopic or transcervical radiofrequency ablation) have been described. (See 'Patients who desire future childbearing' above.)

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Topic 5489 Version 40.0

References

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