Adenomyosis

Adenomyosis is a common benign uterine pathology that is char­acterized by the presence of ectopic endometrium within the myo­metrium. About two-thirds of affected women are symptomatic with dysmenorrhoea and menorrhagia.

Epidemiology

Adenomyosis typically affects multiparous premenopausal women over the age of 30 years (31), but it is also found in nulliparous women, where it may contribute to subfertility.

Pathogenesis

Adenomyosis is often associated with hormone-dependent pelvic lesions such as fibroids, endometrial hyperplasia, and endometri­osis. It has been postulated that these other lesions could be cases of ‘external’ adenomyosis, with connections to deep pelvic endometri­osis invading the myometrium from outside inwards. A particular correlation has been found between adenomyosis and lesions of the rectovaginal septum, and it is thought that both adenomyosis and endometriosis are governed by a single pathophysiological/genetic process (32-35). A number of factors appear to promote the devel­opment of adenomyosis including multiparity, spontaneous miscar­riage, surgical termination of pregnancy, curettage, hysteroscopic resection of the endometrium, myomectomy, caesarean section, and tamoxifen. A genetic predisposition for adenomyosis has also been proposed (36). Apart from high oestrogen levels, a correl­ation has also been made between adenomyosis and high levels of human leucocyte antigen 2-type immune response proteins interleukin-18 and leukaemia inhibitory factor, without necessarily implying that there is a causative relationship. Abnormal secretion of interleukin-6 from endometrial stromal cells and overexpression of cyclooxygenase-2 are additional factors implicated in the patho­genesis of adenomyosis.

Histology

Adenomyosis is characterized by the presence of ectopic endomet­rium within the myometrium (with the depth of invasion being at least 2.5 mm below the basal level of the endometrium) that leads to hypertrophy of the smooth muscle. The thickened myometrium is composed of haphazardly distributed hypertrophied muscular tra­beculae surrounding the ectopic endometrial tissue. Adenomyosis can be nodular with single or multiple foci scattered in the myome­trium or more diffuse with numerous foci affecting the whole of the myometrium. It is often asymmetric, most frequently affecting the posterior uterine corpus (36). There may be superficial lesions, not extending beyond the one-third of the depth of the myometrium, and deep lesions that invade deeper (36). Brownish old haemor­rhagic foci corresponding to blood and haemosiderin pigment de­posits may be contained within an area of adenomyosis.

Symptoms

One-third of women remain asymptomatic, and these women probably have superficial rather than deep adenomyosis. The re­maining two-thirds experience menorrhagia, dysmenorrhoea, and sometimes dyspareunia. On examination, the uterus feels globular and the woman often complains of pain on palpation of the uterus during vaginal examination (36).

What is the role of adenomyosis in infertility?

The association of adenomyosis with subfertility is not fully under­stood, but up to 14% of women with adenomyosis have been re­ported to have infertility (37). There are various theories proposed in the pathophysiology: one is that of hypermobility of the uterus which can prevent transfer of spermatozoa to the fallopian tubes, movement of the fertilized ovum, normal implantation of the em­bryo, and the ability of the trophoblast for effective penetration of the myometrium and thereby effective placentation, or there may be dysfunction of the junctional zone (JZ) (37).

Imaging features

Ultrasonography

The presence of adenomyosis is suggested by the presence of three or more of the following signs:

1.

2. There is a non-homogeneous appearance of the myome­trium with hyperechoic linear striations, tiny hyperechoic subendometrial nodules, pseudo-nodular hypoechoic zones with indistinct contours, and a thickened endometrial- myometrial junction. The heterogeneous appearance is due to the presence of heterotopic endometrial tissue and myometrial cell hypertrophy (36).

3. An enlarged uterus with smooth regular contours and asymmet­rical hypertrophy of the uterine walls, the posterior wall usually thicker than the anterior wall. This is known as the ‘pseudo­widening sign' (38).

4. Lack of visibility of the endometrial-myometrial (junctional) zone. This appearance can mimic endometrial hyperplasia. SIS can be useful in the differential diagnosis, demonstrating so- called pseudo-endometrial thickening (39).

5. Doppler sonography may show linear striations crossing the myometrium within the adenomyotic lesions (36).

6. The corpus uteri is flexed backwards, the fundus of the uterus faces the posterior compartment, and the cervix is directed frontally towards the bladder. This sign called the ‘question mark form of the uterus', and has high sensitivity and specificity for adenomyosis (40).

Three-dimensional ultrasound (and magnetic resonance imaging (MRI), see ‘MRI for diagnosis of adenomyosis') evaluates the coronal plane of the uterus, allowing visualization of modifications in the JZ. This appears as a hypoechoic halo around the endometrium, whose thickening and integrity can be assessed under 3D ultrasound. It has been reported that when the thickness of the JZ is greater than 8 mm or the difference between thicker and thinner parts is more than 4 mm, adenomyosis is likely (41).

Differential diagnosis on sonography

1. Multiple leiomyoma: localized forms of adenomyosis are more difficult to diagnose as these can mimic fibroids.

2. Cystic glandular hypertrophy, frequently caused by medica­tions such as tamoxifen, are more difficult to differentiate from the subendometrial cysts seen in adenomyosis. MRI may prove useful in such cases (36).

3. Endometrial thickening can mimic diffuse adenomyosis, in which case SIS might be useful. This technique uses saline infu­sion to opacify the subendometrial cysts. It demonstrates conti­nuity of the subendometrial cystic spaces with the endometrial cavity, with the superficial sites remaining in continuity and the deep sites losing continuity.

MRI for diagnosis of adenomyosis

MRI is believed to be the most accurate non-invasive technique for the diagnosis of adenomyosis (sensitivity 78-88%, specificity 67­93%) (42) although recent studies suggest equivalence with TVUS, particularly when 3D TVS is performed (41). TVS is frequently used to screen patients and select those who need to have MRI to confirm the diagnosis.

It is important to be aware that there are pitfalls in the use of MRI to diagnose adenomyosis, due to natural variation in JZ thickness (43). This especially so in the following circumstances:

• Day of the menstrual cycle (the JZ is thickest between day 8 and day 16, and variable during menstruation).

• Ageing and menopause: the JZ thickens up to the time of meno­pause and then thins and may disappear.

• Pregnancy: the JZ thins and frequently disappears by the third trimester.

• Use of the oral contraceptive pill or GnRH agonists can thin the JZ.

• Myometrial contractions can induce a pseudo-thickening of the JZ.

MRI should therefore be carried out at a time of the cycle when the patient is not menstruating.

Treatment of adenomyosis

Treatment depends on the symptoms and also if fertility is desired.

Medical treatment

Oral progestogens such as dydrogesterone can be used to treat pre­menopausal menometrorrhagia. It causes endometrial atrophy due to its antioestrogen effect and therefore relieves irregular bleeding, dysmenorrhoea, and pain. However, functional signs reappear in 50% of cases in 3-6 months (45).

LNG-IUS (Mirena IUS)

The Mirena IUS is a well-tolerated and effective treatment of menometrorrhagia and can reduce uterine enlargement, pain, and dysmenorrhoea. It might need to be replaced earlier than the 5-year recommended interval due to tachyphylaxis (46).

GnRH agonists

These induce hypo-oestrogenism which in turn leads to reduc­tions in uterine size, JZ thickness, and endometrial deposits that cause dysmenorrhoea. They can also be used for symptom relief for women who do not desire fertility immediately, but who want conservative treatment. They are generally administered for up to 6 months and rarely for up to a year, with add-back oestrogen/ges- tagen therapy to prevent menopausal symptoms (44). They are also used preoperatively to reduce uterine size prior to hysterectomy or to make resection of adenomyotic lesions easier (44).

Surgical treatment

The age of the patient and whether preservation of fertility is re­quired are the two factors that determine the type of surgery: radical or conservative.

Radical

Radical treatment involves hysterectomy, either total or subtotal, based principally on the condition of the cervix, pouch of Douglas, and rectovaginal septum (44). The decision to remove the adnexa will depend on the presence of endometrioma, deep peritoneal endometriosis, and the age of the patient.

Conservative

This involves local excision of an adenomyotic lesion. This is difficult in terms ofpreserving fertility because ofthe ill- defined endometrial- myometrial boundaries (47). Surgery often results in fibrotic scars and suture material in surrounding healthy tissue, which can affect future fertility adversely.

More recently, endomyometrial ablation, laparoscopic myometrial electrocoagulation, and excision have been tried as an alterna­tive treatment options for patients with localized adenomyosis. Transcervical endometrial ablation or resection is only possible for patients with submucous or superficial localized adenomyosis (48). However, symptoms may be persistent after use of this approach when the depth of the lesion is greater than 2.5 mm, indicating that there are limitations in treating deep lesions. Although laparoscopic electrosurgical excision can significantly relieve pain, with low rates of complications, a second procedure is often required (49).

Uterine artery embolization

This involves selective embolization of the uterine artery on each side with microarticulate non-calibrated polyvinyl alcohol or cali­brated trisacryl alcohol with or without gelatin sponge. On the basis of limited evidence, there seems to be short-term clinical resolution of symptoms particularly menorrhagia, but not pain (50). There seems to be a frequent recurrence of symptoms after 2-3 years and repeat treatment in the form of hysterectomy may be required (51). MRI shows post-treatment changes including reduction in uterine size, decreased JZ thickness, and full or partial infarction of the lesions with non-vascularized areas of low signal intensity on T2- weighted images.

High-intensity focused ultrasound ablation

High-intensity focused ultrasound (HIFU) ablation has been used to treat patients with a variety of malignancies, and can be delivered by ultrasound, magnetic resonance guidance, or more recently and experimentally, by ultrasound. HIFU uses thermal energy to ablate tumours at depth through intact tissue. The fundamental differ­ence to other ablation techniques using coagulation necrosis such as radiofrequency, laser microwave, and cryotherapy is that it does not require the use of applicators to deliver the energy. The advan­tages are an absence of bleeding or risk of seeding metastasis, and the ability to treat poorly perfused tumours, large volume, or irregular tumours. There are two mechanisms by which HIFU may act on adenomyosis, by coagulation necrosis of the adenomyotic cells or by affecting the blood supply by causing necrosis and emboliza­tion in the feeding blood vessels. There have been several case re­ports using magnetic resonance-guided focused ultrasound surgery (MRgFUS) for the treatment of focal adenomyosis, with satisfactory results (52). However, the high energy levels used may affect tissues in the path of the beam, potentially resulting in inadvertent ablation of the endometrium or the endometrial blood vessels. As the endo­metrium and the JZ are embryologically a single unit, transient loss of perfusion in the endometrium is inevitable. Compared with other endometrial ablation approaches, which extend several millimetres into the myometrial wall, MRgFUS is less invasive and can safely ablate adenomyosis close to the endometrium or serosal surface. It reduces the uterine volume and width of the myometrial zone and JZ. Patients report amelioration of pain with minimal side effects.

Ultrasound-guided HIFU and more recently the laparoscopic HIFU approach have also been safely and effectively used in the treatment of adenomyosis (53). As a non-invasive approach, HIFU may offer complete ablation of adenomyoma, at a low cost, with less complications, less trauma, and shorter hospital stay. However, high-quality randomized trials are necessary before its introduction into clinical practice.

Conclusion

Adenomyosis is a common benign condition that can cause menor­rhagia, dysmenorrhoea, and dyspareunia. Its role in infertility is not fully understood but hypermobility of the uterus and dysfunction of the JZ are thought to play a role. There are two main modalities of diagnosis: TVUS and MRI. With ultrasound it can be difficult to dif­ferentiate a leiomyoma from adenomyosis. Medical treatment using progestogens is effective in controlling menorrhagia and pain but symptoms reappear in at least half of the women upon cessation of medication, although the Mirena IUS appears to be more effective. Conservative therapies such as local resection and high-energy abla­tion are promising, but require further rigorous evaluation. For now, hysterectomy is the only definitive solution.