Comorbidities such as endometriosis can confound the picture in patients with adenomyosis, a condition that may lead to poor IVF outcomes.
Adenomyosis is a common gynecologic disorder, yet its etiology and association with infertility remains unclear. It is a benign disorder previously associated with multiparity. Recently, however, an association with infertility has emerged. Adenomyosis can be asymptomatic or present with menorrhagia, dysmenorrhea, and metrorrhagia with these symptoms usually occurring in patients aged 35 to 50.
Approximately 20% of cases of adenomyosis involve women younger than 40 and 80% are aged 40 to 50. On histological analysis, adenomyosis is defined by ectopic location of endometrial and stromal tissue distal to the endometrial-myometrial junction with associated myometrial smooth muscle hypertrophy.1 Histologic diagnostic criteria for adenomyosis have been debated and inconsistently applied, making studies unreliable and often incompatible.
The most accepted hypothesis for the etiology of adenomyosis stems from the invagination of the endometrial basalis layer into the myometrium.2,3 Adenomyosis can have a diffuse, haphazard distribution or more focal regions known as adenomyomas. Women with the condition, therefore, present with enlarged, boggy uteri.
How is adenomyosis diagnosed?
Traditionally, the diagnosis was made by means of histopathologic examination, usually on a hysterectomy specimen as the treatment of choice for the disease was hysterectomy.4 With the evolution of magnetic resonance imaging (MRI) and high-quality transvaginal ultrasound (TVS), today the diagnosis can be made with a level of accuracy of 80% to 90% without the need for excisional surgery (Figures 1a and 1b).5-7
Criteria used to define adenomyosis on ultrasound include focal areas with diffuse hyperechogeneity and loss of a normal endo-myometrial interface; increased or decreased areas of echogenicity; or cystic structures within myometrium with increased color Doppler flow. On MRI, assessment of the thickness of the junctional zone (the subendometrial myometrium) is the mainstay of diagnosis. The consensus for diagnosis of adenomyosis is when the junctional zone is greater than 12 mm but the disorder can be suspected when the thickness is between 8 and 12 mm.8 The advantage of MRI over TVS is that MRI has a greater specificity and can differentiate adenomyomata from leiomyoma.9 When noninvasive diagnosis with MRI and TVS imaging became available, the role of adenomyosis in infertility and early pregnancy was better recognized.10
How is the condition linked with infertility?
Most evidence that links adenomyosis to infertility is limited to case reports and small case series. There is also the potential for confounding in these studies as adenomyosis commonly coexists along with other pathologic processes linked to infertility, such as endometriosis, polyps, or leiomyoma.11 There is a significant association between pelvic endometriosis and adenomyosis, with estimates indicating that it occurs in 54% to 90% of cases.12,13 Because endometriosis is well-known to cause infertility, there is concern that findings of infertility were due to concurrent endometriosis rather than adenomyosis.14 However, a study in baboons showed a strong association between histological adenomyosis and lifelong infertility (20-fold increased odds) even in cases where coexisting endometriosis was excluded.15 In a study of women who received embryos created through oocyte donation rates of miscarriage were significantly higher in those who had adenomyosis alone versus those with co-existing endometriosis or controls.16
A recent meta-analysis concluded that adenomyosis has a detrimental effect on clinical outcomes of in vitro fertilization (IVF). In women undergoing IVF, rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live birth among women with adenomyosis were significantly lower than in those without adenomyosis.17 The miscarriage rate in women with adenomyosis was also higher than in those without adenomyosis.17One of the confounding variables in this study was age, given that women with adenomyosis were older; however, even after controlling for these confounders using regression analysis, the significant difference still existed.17
How does adenomyosis impact infertility?
Proposed mechanisms of infertility in patients with adenomyosis focus on derangements of three putative pathways: uterotubal transport, endometrial receptivity, and implantation.18In patients with adenomyosis, uterotubal transport is impaired due to intrauterine anatomical distortion that blocks the tubal ostia and potentially blocks sperm migration and embryo transport.19 Uterine hyperperistalsis has been seen on ultrasound in patients with adenomyosis due to destruction of normal myometrial architecture.20,21 These abnormal myometrial contraction waves lead to abnormal sperm transport through the uterine cavity and may also lead to increased intrauterine pressure.22
Endometrial receptivity and function becomes altered via increased production of estrogens from aromatization of androgens and altered estrogen receptor/progesterone receptor expression.23,24 The inflammatory response in women with adenomyosis has also been shown to be increased.25 Patients with severe adenomyosis in whom implantation failed were found to have higher density of macrophages.26 This increased macrophage density subsequently increases intrauterine inflammatory response and release of reactive oxygen species that are thought to be embryotoxic.27
Lastly, impaired implantation results from a lack of adequate expression of adhesion molecules, reduced expression of implantation markers, and altered function of the gene for embryonic development (HOXA10).28
In contrast to women with endometriosis, adenomyosis has not yet been shown to have an adverse influence on oocyte function or folliculogenesis.29 In patients with endometriosis, levels of activated macrophages, prostaglandins, interleukin (IL)-1Î², tumor necrosis factor (TNF)Î±, and proteases were increased in peritoneal fluid and their high concentrations may adversely affect oocyte function.30 As of yet, there no association has been found between adenomyosis and oocyte quality or function.
Possible treatments for adenomyosis in infertility
Based on limited available evidence, patients with adenomyosis could be treated with medical and/or surgical therapies to improve pregnancy and live birth outcomes. Treatment with gonadotrophin-releasing hormone agonist (GnRH-a) serves to down-regulate the pituitary, exert an anti-proliferative effect, promote apoptosis, and reduce the anti-inflammatory and angiogenesis effect.31 Multiple case reports show conception and live birth in women with infertility and adenomyosis after pretreatment with GnRH-a for 3 to 5 months.32,33 In other retrospective studies, pretreatment with GnRH-a prior to fresh- or frozen-embryo transfer appears to increase pregnancy rates.34,35 Further prospective studies with larger sample size are needed to validate these findings.
In retrospective studies, conservative surgery or combination surgery with GnRH-a has shown to be more effective in controlling symptoms and also in increasing pregnancy and live birth rates when compared with GnRH-a alone in patients with extensive adenomyosis.36 In case reports and case series, multiple methods of fertility-sparing surgery for adenomyosis have been performed, with subsequent pregnancies. These techniques include classical adenomyomectomy, H-incision, triple-flap method, and laparoscopic cytoreductive surgery.37,38 No evidence as of yet points to superiority of one technique over another (Video). Surgical management of adenomyomas and adenomyosis can present an operative challenge, especially compared with myomectomy.39 Adenomyomas are less distinct given absence of well-defined borders and given protrusion into the myometrium. During dissection, the plane is identified mainly by recognizing healthy myometrium rather than simple enucleation as in myomectomies. This can lead to increased risk of intraoperative bleeding and weakening of the myometrium, which can increase risk of uterine rupture or abnormal placentation in future pregnancies. Uterine-preserving surgeries have shown benefit for women who have previously experienced IVF treatment failures, especially patients ≤ 39 years old.40
A large prospective study showed that combination conservative surgery and medical treatment with GnRH-a for patients with severe symptomatic adenomyoma lowers symptom relapse rates and yields a trend toward improved reproductive outcomes.36 Therefore, for patients with presumed severe adenomyosis who want to retain fertility, surgical cytoreduction and GnRH-a combined may be desirable.
Other methods of fertility-sparing treatment for adenomyosis have recently generated interest. High-intensity focused ultrasound ablation (HIFU) has been used for leiomyoma and is now being used for patients with adenomyosis who want fertility.41 HIFU is a noninvasive thermal ablation technique in which high-intensity ultrasound energy is focused on a small focal region to increase tissue temperature sufficient to cause irreparable cell damage in the target at a certain depth within the body.42 Selection criteria for using HIFU ablation for adenomyosis vary depending on the center, but very strict selection criteria are required to improve efficacy and decrease risk of thermal injury.43,44 Patients typically must be age 18 or older, premenopausal, have no history of pelvic inflammatory disease or severe pelvic endometriosis, and have symptomatic adenomyosis with junctional zone thickness > 3 cm for diffuse adenomyosis or a lesion diameter between 3 and 10 cm for focal adenomyosis.45A recent retrospective study showed high rates of conception and live birth in HIFU-treated patients with adenomyosis, suggesting that it is a promising noninvasive fertility-sparing treatment option.44 In another study, pregnancies after HIFU resulted in 2 miscarriages and delivery of 4 healthy babies. One delivery was complicated by a major placenta previa and hemorrhage.45
Although adenomyosis is a common gynecologic disorder, its role in infertility is unclear. It previously was believed to be a symptomatic disease in older women but it is now being seen in an asymptomatic and younger population undergoing evaluation for infertility. Limited studies have found an association between adenomyosis and poor reproductive outcomes. However, other coexisting pathologies, such as endometriosis, may be
Proposed mechanisms of adenomyosis and infertility point toward derangements in uterotubal transport, endometrial receptivity, and intrauterine inflammation impairing implantation. No association with oocyte function has yet to be identified. Women with severe adenomyosis and in whom IVF previously failed who want fertility can be treated with GnRH-a and/or surgical resection. The strategy has produced promising outcomes in pregnancy and live birth along with symptom improvement. While definitive treatment with hysterectomy was previously the gold standard for adenomyosis, emerging conservative surgical interventions are gaining momentum. Alternatively, HIFU thermal ablation has been presented as another potential noninvasive option for fertility preservation. Large prospective trials are needed to confirm the clinical efficacy of these new fertility-sparing treatment modalities and to better understand their risk and safety profiles.
The authors report no potential conflicts of interest with regard to this article.