Adenomyosis: Review of the Literature

Review Article

Adenomyosis: Review of the Literature Lydia Garcia, MD*, and Keith Isaacson, MD From the Center for Minimally Invasive Gynecologic Surgery, Newton-Wellesley Hospital, Newton, Massachusetts (both authors).

ABSTRACT Adenomyosis usually occurs in women in their reproductive years, predominantly in those with menorrhagia and dysmenorrhea. The etiology and pathophysiology remain unclear; however, recent advancements in diagnostic methods and new investigations of treatment options have changed how clinicians manage adenomyosis. A review was performed using PubMed and cross-references of reviews, case reports, and prospective and retrospective studies published from 1958 to 2010 to provide an overview of the etiology, diagnosis, prevalence, risk factors, clinical signs and symptoms, and treatments of adenomyosis. Journal of Minimally Invasive Gynecology (2011) 18, 428–437 Ó 2011 AAGL. All rights reserved. Keywords:

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Adenomyosis; Diagnosis; Dysmenorrhea; Menorrhagia; Pathogenesis; Treatment; Uterus

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The German pathologist Carl von Rokitansky first described adenomyosis in 1860 when he observed endometrial glands in the myometrium, calling it ‘‘cystosarcoma adenoid uterium’’ [1,2]. However, not until 1921 were these lesions recognized as originating from endometriotic implants, described as ‘‘epithelial invasions,’’ combining endometriosis and adenomyosis in the same category [1]. In the 1950s, Sampson’s hypothesis of retrograde menstruation helped to differentiate endometriosis from adenomyosis. However, not until 1972 was adenomyosis clearly defined by Bird et al [3] as ‘‘benign invasion of endometrium in the myometrium, producing a diffusely enlarged uterus, which microscopically exhibits ectopic, non-neoplastic, endometrial glands and stroma surround by hypertrophic and hyperplastic myometrium.’’ Since the work of these pioneers, several advancements in diagnostic methods and therapeutic options have evolved. Modern medicine includes no means for prevention of adenomyosis; however, hysterectomy is no longer necessary to diagnosis the condition. The diagnosis can now be made using less The authors have no commercial, proprietary, or financial interest in the products and companies described in this article. Corresponding author: Lydia Garcia, MD, Center for Minimally Invasive Gynecologic Surgery, Newton-Wellesley Hospital, 2014 Washington St., Newton, MA 02462. E-mail: [email protected] Submitted February 14, 2011. Accepted for publication April 19, 2011. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2011 AAGL. All rights reserved. doi:10.1016/j.jmig.2011.04.004

invasive techniques such as ultrasound and magnetic resonance imaging (MRI) and analysis of histologic specimens obtained at hysteroscopic biopsy. Although the diagnosis is usually made in women in their forties and fifties with symptoms, adenomyosis is being found incidentally in younger women undergoing infertility evaluations or who have signs and symptoms of dysmenorrhea and menorrhagia. Given that the diagnosis is being made in more younger women, new medical and surgical therapies are being investigated that would eliminate the need for hysterectomy, the criterion standard. Available medical treatments include administration of oral contraception, progestins, danazol, gonadotropinreleasing hormone (GnRH) agonists, and aromatase inhibitors. Minimally invasive surgical procedures enable conservative options including endometrial ablation and resection, laparoscopic excision of adenomyosis, and magnetic resonance– guided focused ultrasound. The objective of this review was to summarize the prevalence, etiology, risk factors, clinical features, and outcomes of medical and surgical treatment of adenomyosis. Etiology In adenomyosis, endometrial glands and stroma are present within the uterine musculature. Although the exact etiology is unknown, at least 4 theories have been proposed. The first and most popular hypothesis is that adenomyosis develops from invagination of endometrium into the

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Adenomyosis: Review of the Literature

myometrium. A second theory is that adenomyosis develops de novo from embryologic misplaced pleuripotent m€ ullerian remnants. A third theory suggests that invagination of the basalis proceeds along the intramyometrial lymphatic system, leading to adenomyosis. A recently proposed theory is that adenomyosis originates from bone marrow stem cells that are displaced through the vasculature. Herein, the literature pertinent to the most common theories is described in further detail. The most common opinion is that adenomyosis develops as a result of invagination of the basalis endometrium into the myometrium. Invagination may occur due to weakened myometrium from tissue trauma during previous pelvic surgery that enables the active endometrial tissue to grow into the injured lining [4]. Invagination may also occur from an aberrant immune phenomenon in the affected tissue. Immunochemistry demonstrates increased numbers of macrophages that can activate T and B cells to produce antibodies and stimulate cytokines that may disrupt the endomyometrial junction zone [5]. The exact trigger for invagination is unknown; however, it has been suggested that the influence of hormones may assist in cell-signaling pathways to stimulate the invasive and migratory properties of the basalis layer [2]. Steroidreceptor studies have yielded inconsistent results; however, some studies have demonstrated that adenomyotic tissue exhibits higher expression of estradiol receptors than does the eutopic endometrium [6]. The increased response to estrogen may facilitate the overall invagination and spreading of adenomyosis [4,6,7]. In addition, adenomyotic tissue also contains aromatase and estrogen sulphatase enzymes that locally produce estrogens to stimulate further growth and expansion of the abnormal endometriotic glands and stroma into the myometrium [4]. A second theory suggests a de novo origin of adenomyosis from m€ ullerian remnants. Extrauterine sites of adenomyosis such as those observed in the rectovaginal septum support this theory. In addition, studies of the proliferative and biological properties of ectopic and eutopic endometrium demonstrate distinct characteristics. Matsumoto et al [8] observed that the ectopic endometrium in adenomyosis did not respond to the same hormonal changes as the eutopic endometrium. Secretory changes were rare, even when the basal epithelium was in the secretory phase. Compared with eutopic tissue, the ectopic tissue also did not demonstrate cyclic properties of the induction of apoptosis regulatory proteins such as bcl-2 expression. These findings suggest constant proliferation of ectopic tissue within the myometrium, demonstrating different biological characteristics than those of eutopic tissue. Other studies have also compared various growth factors and cytokines such as angiogenic growth factors (e.g., basic fibroblast growth factor) that may contribute to the pathogenesis of abnormal uterine bleeding in adenomyosis [9]. Results demonstrated different expression of these factors in adenomyotic tissue than in eutopic endometrium, again supporting the theory that adenomyosis does not originate in the basal endometrium.

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The stem cell theory is supported by research that demonstrated that endometrial regeneration can be driven by bone marrow–derived stem cells. This finding has potential implications for the etiology of endometriosis and adenomyosis. Recent immunochemistry studies have revealed the presence of donor endometrium glands and stroma in 4 women who received single-antigen HLA mismatched bone marrow transplants. The data suggest that bone marrow–derived stem cells contributed to the repopulation of the new endometrium. Therefore, it is possible that these stem cells also could repopulate within the musculature of the uterus, causing adenomyosis with local proliferation of endometrial glands and stroma in the myometrium [10,11]. Diagnosis While the clinical findings of menorrhagia and dysmenorrhea with an enlarged uterus suggest adenomyosis, the diagnosis is made by histologic analysis. Because of the proliferative ectopic endometrial tissue in the myometrium, smooth muscle cell hyperplasia and hypertrophy occur, causing an enlarged globular uterus that can be observed macroscopically. Adenomyosis can also arise in focal forms of circumscribed nodular aggregates of smooth muscle, endometrial glands, and stroma, known as adenomyomas or present as a polypoid mass within the endometrial cavity [6,12]. At microscopy, adenomyosis demonstrates the presence of endometrial tissue within the myometrium (Fig. 1). Adenomyosis tends to be a diffuse process arising most frequently in the posterior wall, less frequently in the anterior wall, and rarely in the cornua or areas near the cervical os [13,14]. A smooth muscle hyperplastic reaction often occurs around the ectopic endometrial tissue [3]. A uniform diagnosis based on histologic criteria has not been developed. For example, adenomyosis has been defined as endometrial

Fig. 1 Histologic findings of adenomyosis with a foci of endometrial glands and stroma deep within the myometrium.

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glands within the myometrium greater than 1 low-power field from the basalis layer of the endometrium. Other definitions include foci located deeper than 25% of the myometrial thickness (the criterion most often used for the diagnosis in postmenopausal women) or glandular extension greater than 1 to 3 mm below the endometrial layer [4,6]. There is no universally agreed on minimal depth of invasion criteria; however, most studies use a cutoff of 2.5 mm below the basalis layer [15–17]. Because of the variation in definition for diagnosis, the prevalence of adenomyosis varies significantly between studies. The diagnosis of adenomyosis is made primarily on the basis of findings in hysterectomy tissue specimens. However, several studies have demonstrated that myometrial biopsy at hysteroscopy or laparoscopy can be performed to make a histologic diagnosis. Diagnostic hysteroscopy does not provide pathognomonic signs of adenomyosis, although some evidence suggests that irregular endometrium with pitting endometrial defects, altered vascularization, and cystic hemorrhagic lesions may be associated with the process (Fig. 2) [18,19]. Hysteroscopy does enable the ability to perform biopsies under direct visualization to obtain a histologic diagnosis. McCausland [20] performed hysteroscopy in 50 patients with normal-appearing cavities. Posterior wall myometrial biopsies were performed using a 5-mm loop electrode to remove specimens 1.5 to 3 cm long with depth of penetration up to 6 mm. Pathologic analysis of the specimen enabled diagnosis of adenomyosis in as many as 66% of patients with normal cavities and menorrhagia. Routine myometrial biopsy at operative hysteroscopy can be useful to assist in further treatment planning after the diagnosis is made. However, the diagnosis may be missed if adenomyosis is not superficial or if it is absent at the location of the random biopsy. Popp et al [21] performed myometrial biopsies with automatic cutting needles at laparoscopy in 34 patients. Bleeding was often noted at the bi-

opsy site, and required injections of ornipression solution for bleeding control. Overall sensitivity was low, ranging from 8.0% to 18.7%. Random biopsies performed on adenomyotic uteri in vitro also confirmed the low sensitivity of myometrial needle biopsy. Brosens and Barker [22] performed 8 random serosal needle biopsies in 27 hysterectomy specimens, resulting in calculated sensitivity ranging from 2.3% to 56.0%. Overall sensitivity depended on the number of biopsies and the depth of penetration of adenomyosis [22]. More studies with larger numbers of patients are needed for further evaluation of the role of myometrial biopsy in diagnosis of adenomyosis. Although the diagnosis of adenomyosis is made histologically, several imaging techniques have been useful in assisting in the differential diagnosis including ultrasound and MRI. Both transvaginal ultrasound (TVUS) and transabdominal sonography characterize adenomyosis by identifying myometrial cysts (1- to 7-mm round anechoic areas), distorted and heterogeneous myometrial echotexture, and poorly defined foci of abnormal myometrial echotexture (Fig. 3) [23–25]. The most predictive ultrasound finding of adenomyosis is the presence of ill-defined myometrial heterogeneity [26]. Findings at MRI include a large asymmetric uterus without leiomyomas, thickening of the junctional zone from 8 to 12 mm, or an abnormal ratio of junctional zone to myometrial thickness greater than 40% (Fig. 4) [23–25]. The junctional zone is the innermost myometrial layer, which is distinct at light optic microscopy but lacks histologic distinction. Thickening of the junctional zone on MRI is the consequence of inordinate inner myocyte proliferation, a process that has been referred to as ‘‘junctional zone hyperplasia.’’ It does not reflect detection of endometrial glands and stroma in the muscles but suggests adenomyosis based on the theory that

Fig. 2 Hysteroscopic image of adenomyosis with pathognomonic signs of pitting endometrial defects and cystic hemorrhagic lesions.

Fig. 3 Sagittal transvaginal ultrasound shows an asymmetric uterus with thickened posterior myometrial wall. Arrow shows findings of decreased echogenicity and heterogeneity consistent with diffuse adenomyosis in the posterior wall of the uterus.

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Adenomyosis: Review of the Literature

Fig. 4 Sagittal T2-weighted magnetic resonance images demonstrate illdefined 6.0 ! 6.8-cm heterogeneous hyperintense foci extending from the junctional zone anteriorly and measuring 21.94 mm (.12 mm), suggestive of adenomyosis. Posterior junctional zone is normal at less than 8 mm. The maximum junctional zone–total myometrium ratio is greater than 40%, which also suggests adenomyosis. Myometrial cysts can be observed anteriorly.

disruption of the junctional zone precedes and predisposes the myometrium to development of adenomyosis [27,28]. Cyclic changes alter junctional zone thickening due to hormone influences, which is why MRI diagnosis in postmenopausal women often is based on the criterion of a 40% ratio of junctional zone to myometrial wall thickness rather than junctional zone thickness alone [28]. Bazot et al [23] compared the accuracy of imaging methods for the diagnosis of adenomyosis and correlated the findings with histologic diagnosis after hysterectomy. Their study demonstrated lower accuracy with transabdominal ultrasound in comparison with TVUS. Similar accuracy rates were noted between TVUS and MRI when no additional uterine lesions were present. When leiomyomas were present, both MRI and sonography demonstrated lower diagnostic accuracy; however, MRI exhibited higher sensitivity and specificity than did ultrasound techniques. Overall review of the literature demonstrates that TVUS exhibits sensitivity of 53% to 89% and specificity of 50% to 99% for the diagnosis of adenomyosis when no myomas are present [23–30]. Sensitivity decreases to as low as 33% when myomas are present, in particular when the volume of the myoma is greater than 300 mL [29]. In cases with coexistent adenomyosis and myomas, MRI demonstrated sensitivity of 67% and specificity of 82% compared with sensitivity of 87% and specificity of 100% when myomas were absent. In summary, TVUS is an excellent first-choice imaging method for use by experienced sonographers; however, MRI can be used as an adjunct in cases with coexisting uterine abnormalities. The combination of both techniques offers the highest sensitivity for preoperative diagnosis [29,30].

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Epidemiology Because the diagnosis of adenomyosis is made by histologic analysis, the exact incidence has not been accurately determined. In various studies, the prevalence has been reported to range from 5% to 70%. The discrepancy may be due to many factors including the various diagnostic classifications, differences in the number of tissue samples reviewed, and possible pathologist bias because of awareness of the patient’s history [3,12,15]. Overall, the mean frequency of adenomyosis at hysterectomy is approximately 20% to 30% [12,31,32]. Clinical series have demonstrated an increased frequency of adenomyosis in multiparous patients [15,31–34]. Pregnancy may be a risk factor because of the invasive nature of the trophoblasts into the myometrium at implantation. In addition, given that, compared with eutopic tissue, adenomyotic tissue may have a higher ratio of estrogen receptors, the increased hormone profile in pregnancy may also stimulate development of adenomyosis. Vercellini et al [32] observed that the frequency of adenomyosis was directly associated with the number of pregnancies [32]. In addition, Levgur et al [33] reported that patients who had undergone pregnancy termination via dilation and curettage demonstrated higher rates of adenomyosis than women without pregnancy terminations [33]. The study offers clinical evidence of the effect of previous pregnancy on the pathogenesis of disease but does not provide data on the importance of the actual procedure or the number of abortions performed. Some studies have suggested that trauma from pelvic surgery may trigger invagination of adenomyotic tissue. Parazzini et al [31] also observed higher rates of adenomyosis in patients who had undergone dilation and curettage. However, the higher rates of the disease with dilation and curettage in that study may have been influenced in that women who required the procedure had confounding factors of endometrial disease such as hyperplasia due to hyperestrogen states, which can also contribute to adenomyosis. Other studies have observed no statistical association between adenomyosis and previous transcervical or transmural surgery [15] or cesarean section [34,35]. Therefore, it remains unclear whether previous uterine surgery is a significant risk factor for adenomyosis. Seventy percent to 80% of adenomyosis cases are reported in women in the fourth and fifth decades of life [12]. Because the diagnosis of adenomyosis is established by histologic analysis, the higher prevalence in older women may be due to the higher rate of hysterectomy as women age. However, it may also be due to exposure to hormones over a longer time as women age, enabling development of symptoms. Five percent to 25% of adenomyosis cases are observed in patients younger than 39 years, and only 5% to 10% occur in women older than 60 years [13]. While the reported incidence of adenomyosis is low in postmenopausal women, there may be a higher incidence

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in those who receive tamoxifen to treat breast cancer. Tamoxifen is a synthetic weak estrogen that binds to selective estrogen receptors and can act as an estrogen agonist on the receptors of endometrial cells. Because ectopic extrauterine endometrial tissue is subject to hormonal stimulation, adenomyosis and endometriosis can develop or be reactivated. Cohen et al [36] reported eight postmenopausal women with breast cancer who were receiving tamoxifen and underwent hysterectomy with the postoperative diagnosis of adenomyosis, demonstrating a higher incidence in postmenopausal women who received treatment in this small study population.

Infertility seems to be less common in patients with adenomyosis because it is usually diagnosed in the fourth and fifth decades, with a higher incidence in multiparous patients. However, as more women are delaying childbearing, adenomyosis is being diagnosed in younger asymptomatic women during infertility evaluation [41]. It is unclear whether adenomyosis actually has a role in infertility or whether it is diagnosed more frequently because of improved ability to diagnosis adenomyosis using radiologic studies. In a prospective study of 26 patients with infertility and symptoms of dysmenorrhea and menorrhagia, MRI enabled detection of adenomyosis in 53.8% of patients [42]. While it is unclear whether adenomyosis affects fertility, several theories exist as to how it may interfere with reproductive outcomes. Investigators have hypothesized that the abnormal interface between endometrium and myometrium with adenomyotic foci may disrupt implantation. Disruption of the junctional zone may also produce abnormal contractility, affecting implantation [43]. However, patients with a diagnosis of adenomyosis at sonography who are undergoing in vitro fertilization demonstrate no difference in implantation rates [44]. Another theory is that adenomyosis activates a series of immune responses that include changes in both cellular and humoral immunity that can impede sperm function and embryonic development [5]. In addition, it is unclear whether other concurrent gynecologic disease, not the adenomyosis, is affecting fertility. Endometriosis is observed in 6% to 22% of patients with adenomyosis, and myomas are concurrently observed in 35% to 55% of patients [4]. No treatments have been proved to help infertile patients with adenomyosis; however, several authors have published case reports of successful pregnancies after treatment with GnRH agonists for temporary relief of symptoms of menorrhagia and dysmenorrhea [45–49].

Clinical and Pathophysiologic Findings Eighty percent of women with adenomyosis are middleaged. Fifty percent of women with symptoms have menorrhagia, 30% have dysmenorrhea, and 20% have metrorrhagia [4,6]. Only 18.7% of patients have both menorrhagia and significant dysmenorrhea [3]. Less common symptoms include dyspareunia and chronic pelvic pain. Because as many as 80% of women with adenomyosis have coexisting pelvic disease, it is often difficult to determine which symptoms are caused only by adenomyosis. In addition, as many as 35% of adenomyosis cases are discovered incidentally in women who have none of these symptoms [13]. The exact mechanism for development of clinical symptoms of adenomyosis is unclear; however, there are several theories. At least three pathologic changes within the myometrium in patients with adenomyosis can contribute to menorrhagia. Adenomyotic foci can interfere with the normal musculature of the uterus, and, therefore, it is unable to contract properly during menses, enabling a greater amount of blood loss. Inner myometrial distortion at the junctional zone may also affect myometrial contraction, orientation, amplitude, and frequency, contributing to menorrhagia because the subendometrial myometrium is involved in modulation of uterine contractions throughout the menstrual cycle [37,38]. In addition, adenomyosis can cause an enlarged uterus, with a greater endometrial surface area, and may contribute to increased blood flow. Furthermore, ectopic adenomyotic tissue contains cytokines such as angiogenic growth factors (basic fibroblast growth factor), which may contribute to the pathogenesis of the symptoms of menorrhagia [9]. Menorrhagia can cause uterine irritability or dysmenorrhea from stimulation and edema of the endometrial tissue within the myometrium [6,12]. Nishida [39] examined the relationship between histologic findings of adenomyosis and onset of dysmenorrhea, and determined that the number of islands, the depth of invasion, and the relative rate of invasion correlated with the severity of dysmenorrhea. In addition, it is thought that adenomyotic tissue may have the same characteristics of endometriosis, in which the ectopic endometrium exhibits high expression of cyclooxygenase-2. Higher expression leads to increased prostaglandin formation, resulting in severe dysmenorrhea and chronic pelvic pain [40].

Treatment of Adenomyosis The standard of treatment of adenomyosis is hysterectomy. However, the challenge comes in treating symptomatic women with conservative medical or surgical options to maintain fertility or women who cannot undergo major surgery because of risk factors for surgical complications. There is no medical therapy to treat symptoms of adenomyosis while allowing patients to conceive. Medical treatments using suppressive hormonal treatments such as continuous use of oral contraceptive pills, high-dose progestins, the levonorgestrel-releasing intrauterine device (LNG-IUD), danazol, and GnRH agonists can temporarily induce regression of adenomyosis. These treatments as well as more conservative surgical options are described in further detail. Oral Contraception and Progestins Although no randomized controlled trials have evaluated continuous oral contraception in patients with adenomyosis, patients with dysmenorrhea and menorrhagia may benefit

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from induction of amenorrhea, which may provide relief of symptoms. Use of high-dose progestins such as continuous oral norethindrone acetate or subcutaneous depot medroxyprogesterone has not been studied for treatment of adenomyosis; however, but their role as suppressive hormonal agents can also help temporarily to induce regression of adenomyosis. Levonorgestrel Intrauterine Device The LNG-IUD (Mirena) releases 20 mg of levonorgestrel per day and has is an effective treatment for adenomyosis. The use of LNG-IUD is associated with decidualization of the endometrium to decrease bleeding and is also thought to act directly on adenomyotic deposits by downregulating the estrogen receptors. This in turn reduces the size of foci, improves contractility of the uterus to decrease blood loss, and improves dysmenorrhea by reducing prostaglandin production within the endometrium and by inducing amenorrhea [50,51]. Studies have demonstrated that use of the LNG-IUD results in improvement in symptoms of menorrhagia and dysmenorrhea, and radiologic changes in adenomyotic uteri [52–54]. However, none of these studies were randomized controlled trials, and patients were not followed up after removal of the IUD. Therapy with the LNG-IUD may be beneficial in women who desire to conceive after treatment. Sheng et al [52] evaluated the efficacy of the LNG-IUD after use for 36 months in 94 women with moderate to severe dysmenorrhea associated with adenomyosis diagnosed using TVUS. The rate of pain measured using a visual analog scale decreased from a mean (SD) baseline score of 77.9 (14.7) to 11.8 (11.8), with 25% of patients reporting amenorrhea. Uterine volume decreased significantly, from 115.8 (46) mL to 94.5 (40.1) mL), as did CA-125 concentration. The overall satisfaction rate with the treatment was 72.5%. Bragheto et al [53] evaluated 29 women with menorrhagia with adenomyosis diagnosed with MRI who received treatment using the Mirena IUD for 3 to 6 months. After 6 months of treatment, a significant reduction of 24.2% was observed in junctional zone thickness, but no change in uterine volume. Twenty-three of the women demonstrated a decrease in the visual analog scale pain score, and all 29 reported decreased bleeding, with 27% reporting amenorrhea. Fedele et al [54] evaluated 25 women with menorrhagia with adenomyosis diagnosed at TVUS who received treatment using the Mirena IUD for 1 year. Follow-up of 23 women demonstrated reduced uterine volume, from 948 (171) mL to 914 (139) mL; decrease in blood loss; and significant increases in concentrations of hemoglobin, from 10.1 (1.3) to 12.5 (1.2) g/dL, and serum ferritin, from 27 (23) to 82 (19). At 1-year follow-up, all patients demonstrated decreased bleeding, with only 2 women reporting amenorrhea. One expulsion of the IUD was noted, and 1 patient requested removal of the device after 4 months because of persistent irregular bleeding. Adverse effects included

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breakthrough bleeding, headache, breast tenderness, acne, and weight gain. Danazol Danazol, a 19-nortestosterone androgen derivative with progestinlike effects induces direct inhibition of ovarian enzymes responsible for estrogen production and pituitary gonadotropin secretion. Experience with use of systemic therapy in patients with adenomyosis is limited. This is likely due to the adverse effect profile of the drug, which includes weight gain, muscle cramps, reduced breast size, acne, hirsutism, oily skin, decreased high-density lipoprotein levels, increased liver enzyme concentrations, hot flashes, mood changes, depression, and deepening of the voice. After systemic treatment with danazol, estrogen receptors are decreased, which may contribute to reduced uterine size and improvement of symptoms [55]. New techniques of local delivery of hormones have enabled danazol to be used as a more favorable optional treatment with fewer adverse effects through intracervical injections and the IUD [56,57]. Igarashi [56] evaluated 14 women who received a danazol-loaded IUD containing 300 to 400 mg danazol. In these women, adenomyosis was diagnosed at TVUS or MRI, and they exhibited clinical symptoms of dysmenorrhea, menorrhagia, or infertility. Thirteen of the women experienced improvement of dysmenorrhea, and 12 reported decreased bleeding. Only 2 devices were expelled. Serum concentration of danazol remained below the limit of detection, and no systemic adverse effects were noted. Uterine measurements were not obtained in this study. After removal of the danazol IUD, 3 of 4 infertile patients were able to conceive. Cervical injections of danazol have also been successful. Takebayashi et al [57] injected 10 mg danazol into the cervix in 22 patients at 2-week intervals for 12 weeks. There was 60% improvement in subjective symptoms of bleeding, pain, and dyspareunia, and a mean (SD) decrease in uterine size, from 334.6 (211.9) cm3 to 243.1 (11.9 cm3). No adverse effects were noted as a result of local administration of the hormone. GnRH Agonists GnRH agonists bind to GnRH receptors in the pituitary gland, which results in downregulation of GnRH activity. The result is a reversible state of medical menopause. The therapy is not active in oral form, and is administered via intramuscular or subcutaneous injection or as a twice-daily nasal spray. It is typically used for limited periods of 3 to 6 months because of adverse effects including hot flashes and decreased bone mineral density. The first reported case of biopsy-proved adenomyosis treated using a GnRH analogue was reported in 1991. Results demonstrated a reduction in uterine volume from 440 to 150 cm3 and amenorrhea and relief of severe dysmenorrhea [58]. However, on discontinuation of therapy, symptoms recurred

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and uterine volume was 420 cm3. Subsequently, a small numbers of case reports all demonstrated similar results, with reduction in uterine size, induction of amenorrhea, and resolution of pelvic pain during therapy for 3 to 6 months. In addition, several case series reported that infertile patients with adenomyosis who had received short-term treatment with GnRH agonists were able to conceive within 6 months of cessation of therapy [45–49].

progesterone therapy. Patients with deep adenomyosis greater than 2 mm experienced poor results and ultimately required hysterectomy. With deep adenomyosis, the ectopic deep endometrial glands can persist under the scar and eventually proliferate though the area of ablation or resection to cause recurrent bleeding. Repeat resection is usually unsuccessful in deep adenomyosis, and these patients rarely respond to continuous progesterone therapy. Global endometrial ablation has also proved successful in treatment of excessive bleeding in women with adenomyosis. However, a retrospective review of women with adenomyosis diagnosed at ultrasonography who underwent thermal balloon and radiofrequency ablation demonstrated a 1.5-fold increased risk of failure requiring subsequent hysterectomy or repeat ablation [68].

Aromatase Inhibitors Aromatase cytochrome P-450 expression has been observed in endometriosis implants [59,60]. This enzyme converts androgens to estrogens. In multiple case reports and a randomized trial, aromatase inhibitors have been used in the treatment of severe endometriosis, with resultant decrease in pain [61]. However, no studies have examined its role as a treatment option for adenomyosis. Hysterectomy Hysterectomy has been the primary diagnostic and treatment option for adenomyosis. Vaginal hysterectomy has been preferred over abdominal hysterectomy because of lower morbidity and faster recovery. However, in a retrospective review of 1246 vaginal hysterectomies, 14 women with adenomyosis exhibited higher rates of bladder injury. The authors concluded that the reason for such injury was unknown; however, it was hypothesized that there may be greater difficulty in identifying the supravaginal septum and the vesicovaginal or vesicocervical planes [62]. Laparoscopic hysterectomy may facilitate dissection of these planes to prevent injury. Compared with vaginal hysterectomy, the trend is toward lower rates of bladder injury with the laparoscopic approach but slightly higher rates of ureteral injury [63]. Laparoscopic hysterectomy may also be more beneficial than vaginal hysterectomy because of less postoperative pain [64,65]. Endometrial Ablation and Resection Endometrial ablation has been used to treat menorrhagia, including in patients with adenomyosis who have completed childbearing. It can be performed using an yttrium aluminum garnet laser, rollerball resection, or global ablation techniques. One of the largest studies to evaluate the outcomes of rollerball resection in adenomyosis demonstrated that the depth of foci correlated with the success of the resection. McCausland et al [66] performed rollerball resection with penetration of 2 to 3 mm into the myometrium. Deeper resection is not usually performed because of the risk of bleeding from the arteries situated approximately 5 mm into the myometrial surface [67]. In that study, in patients with superficial adenomyosis with penetration less than 2 mm the procedure was successful or they experienced postablation light cyclic periods that resolved with continuous

Uterine Artery Embolization The effectiveness of uterine artery embolization (UAE) in the management of symptomatic adenomyosis is controversial. Short-term studies have demonstrated various success rates, which may be due to the different embolic agents used and the role of concomitant myomas. Myomas tend to have larger arteries, which may require more vigorous embolization and larger primary embolic agents in comparison with the smaller arteries in adenomyosis, in which smaller embolic agents are preferred [69]. Thus, studies have demonstrated higher failure rates in patients with concomitant myomas [70,71]. However, successful outcomes have been reported with UAE with the diagnosis of adenomyosis alone. Kim et al [69] published one of the largest longterm retrospective studies, which observed 54 women with an MRI diagnosis of adenomyosis without myomas who underwent UAE. Fifty-seven percent of patients reported decreased bleeding and pain after 4.9 years. In 4 patients, treatment failure was immediate, and 19 patients experienced relapse within 5 years, with 5 patients requiring hysterectomy for further treatment. Median (range) time to relapse was 17.3 (4–48) months. Overall rate of patient satisfaction was 70%. Myometrium or Adenomyoma Excision Focal excision of adenomyosis may be performed if the location of foci can be determined. Unlike with myomectomy, it may be difficult to expose lesions, define margins, and determine extent of disease. Given these challenges, it is likely that a portion of the adenomyosis can be left behind, and the disease can remain symptomatic or relapse. For this reason, the efficacy of excision remains low at 50% [67]. The addition of postoperative treatment with GnRH agonists for 6 months after excision decreases relapse rates by 20% within 2 years [72]. In women who wish to maintain fertility, excision can be performed if sufficient myometrium is left and if scar formation does not interfere with uterine expansion. The rate of

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spontaneous abortion (38.8%) is higher than in the general population after the excisional procedure. This is likely due to uterine scar tissue formation, which can affect the gestation capability of the uterus [73]. However, a small study demonstrated that conservative treatment with adenomyoma excision (mean size, 55 mm) resulted in a 70% pregnancy rate (49 of 71 patients), with relief of symptoms of menorrhagia and dysmenorrhea [72]. Myometrial Electrocoagulation Laparoscopic myometrial electrocoagulation can be performed using unipolar or bipolar needles inserted into the affected myometrium in both diffuse and focal adenomyosis. The procedure is less accurate than surgical excision because electrical conduction in abnormal tissue may be incomplete and the foci may be difficult to discern at surgery. The procedure is not recommended in women who wish to conceive because it can decrease the strength of the myometrium by replacing the adenomyotic foci with scar tissue, and, therefore, there is increased risk of uterine rupture [74]. It can be performed at the same time as endometrial ablation or resection, or concurrent with hormone therapy. Review of the literature reveals small study numbers (n 5 3 to n 5 11), with rates of symptom improvement ranging from 55% to 70% and better outcomes in patients who underwent concurrent endometrial resection [67,74–76]. Myometrial Reduction Myometrial reduction to treat diffuse adenomyosis has been performed in a limited number of cases. A large portion of the myometrium is removed with a wedge resection, followed by metroplasty via laparoscopy or laparotomy. A classic incision is made with dissection of the uterus longitudinally in the midline, with resection of the anterior and posterior portions of the myometrium. A new approach using a transverse H incision enables easy removal of a considerable amount of tissue with good exposure. In a small study that compared the H incision (n 5 6) with the classic incision (n 5 5), relief of symptoms was more apparent with the modified technique, and 2 women were able to conceive spontaneously, compared with no pregnancies in the group in which the classic incision was used [77]. Overall, myometrial reduction has resulted in low postoperative pregnancy rates, likely as a result of reduced uterine capacity and compromised fertility [67,78]. Regardless of the type of incision or approach, demarcation of the adenomyosis may be difficult, leading to recurrence from tissue left behind. Magnetic Resonance–Guided Focused Ultrasound Surgery Magnetic resonance–guided focused ultrasound surgery is a new noninvasive technique for ablation of soft tissue that has been successfully used to treat myomas and experimentally to treat adenomyosis. In 2004, the procedure was approved by the US Food and Drug Administration for treatment of myo-

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mas. Sequential ultrasound beams are precisely focused to locally heat tissue, causing thermal coagulation and subsequent necrosis in a precisely defined area [79]. High focused ultrasound surgery can be used alone; however, imprecision has led to variable outcomes and concern for patient safety because of inability to precisely focus the wave on a specific target. Magnetic resonance–guided focused ultrasound surgery has helped to overcome these concerns because of the excellent anatomic resolution and high thermal imaging sensitivity of MRI [80]. The procedure has been used successfully to treat myomas, with reported improvement of clinical symptoms in 75% of 108 patients [81]. Review of the literature reveals low complication rates in small study populations, including a 5% risk of skin burns, 0.9% risk of postoperative nausea and vomiting requiring hospitalization, and 2 reports of sciatic nerve palsy due to absorption of energy by the bone that transferred to the nerve [82–84]. There has been only 1 report of severe skin burn requiring hospitalization [82–84]. This noninvasive procedure is now beginning to be used in patients with adenomyosis. Treatment of diffuse and generalized adenomyosis may be difficult; however, a case report demonstrated a successful outcome in focal disease, with marked reduction in bleeding, and followed by an uncomplicated pregnancy and delivery [85]. Summary In the literature, the prevalence of adenomyosis ranges from 5% to 70% in symptomatic women, with a mean frequency of 20% to 30% at hysterectomy. The wide range of prevalence may be due to a variety of diagnostic classifications, as well as the number of tissue samples reviewed per surgical procedure and the possible bias at the time of diagnosis. Confirmatory diagnosis can be made only from histologic analysis of uterine specimens. However, both MRI and ultrasound have been proved accurate in determining the presence of adenomyosis. Review of the literature reveals that TVUS has sensitivity of 53% to 89% and specificity of 50% to 99%, compared with MRI with sensitivity of 88% to 93% and specificity of 67% to 99%. Both imaging techniques have lower accuracy rates for the diagnosis of adenomyosis when myomas are present; however, MRI has proved better as a diagnostic method with coexistent myomas. While MRI and ultrasound have evolved as effective tools for diagnosis of adenomyosis, further studies are needed to examine their clinical effect and cost-effectiveness. Several theories exist as to the etiology of adenomyosis; however, the most common opinion is that it is a result of invagination of the basalis endometrium into the myometrium. Several clinical series have shown an increased frequency of adenomyosis in multiparous women that may be due to the invasive nature of trophoblasts into the myometrium contributing to invagination and migratory properties of the basalis layer. Other risk factors such as previous uterine surgery may also help support the invagination theory because of tissue trauma weakening the lining.

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Journal of Minimally Invasive Gynecology, Vol 18, No 4, July/August 2011

The most common symptoms of adenomyosis are menorrhagia and dysmenorrhea. This may be due to disruption of the normal musculature of the uterus by adenomyotic foci causing dysynergia or inability of the uterus to contract properly. Treatment of these symptoms usually depends on the patient’s desire to maintain fertility. Several medical treatment options exist; however, most have been studied only for short term use in small study populations. The efficacy of long-term treatment is unknown. The most promising medical therapy based on the literature is the LNG-IUD because of its ability to provide hormone suppression to improve symptoms, with a low profile of adverse effects, while enabling women to maintain future fertility. The LNG-IUD has proved to decrease or eliminate symptoms of dysmenorrhea and to decrease menorrhagia, increasing the hematocrit concentration after just 3 months of treatment. In women who have completed childbearing, less invasive surgical procedures such as endometrial ablation and resection have been demonstrated to improve symptoms of menorrhagia, with a mean failure rate of 20%. Higher failure rates are noted if adenomyosis has penetrated more than 2.5 mm from the basalis layer. Other conservative surgical treatments such as adenomyotic muscle excision, reduction, and electrocoagulation can be performed but are usually not so effective as hysterectomy because of the difficulty in completely excising or coagulating the foci. The outcomes of these procedures have demonstrated low pregnancy rates because of reduction in uterine volume and scarring. Newer techniques such as magnetic resonance–guided focused ultrasound surgery and UAE need further study. Currently, hysterectomy remains the criterion standard treatment for adenomyosis.

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