Adenomyosis and infertility: is there a causal link?

KEYWORDS:

• Adenomyosis
• infertility
• miscarriage
• pregnancy
• myometrium

1. Introduction

Adenomyosis is a benign uterine disease defined by the presence of endometrial glands and stroma within the myometrium [1,2]. Although about 35% of affected women may be asymptomatic at the time of diagnosis [3], the remaining women suffer from invalidating symptoms such as abnormal uterine bleeding (AUB), dysmenorrhea, dyspareunia, chronic pelvic pain, infertility, and miscarriage [4].

For many decades, the diagnosis of adenomyosis has required pathological examination of hysterectomy specimens. Therefore, the disease was typically diagnosed in multiparous women in their fourth and fifth decade of life [5–7]. More recently, the introduction in clinical practice of transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) has made possible a noninvasive diagnosis of adenomyosis. At TVUS, ectopic endometrial glands appear as echogenic nodules, striations radiating from the endometrium into the myometrium or myometrial cysts, whereas muscular hyperplasia and hypertrophy are seen as focal or diffuse myometrial thickening or asymmetric globular uterine enlargement. MRI is particularly useful in detecting the thickening, hyperplasia, or disruption of the uterine junctional zone (JZ) located between the endometrium and the internal myometrium [8,9]. It has been shown that the accuracies of two-dimensional TVUS, MRI, and histology are comparable in diagnosing adenomyosis [8].

Diagnostic imaging has improved the understanding of adenomyosis in women of all ages and has allowed to investigate the relationship between adenomyosis and infertility [9].

The relevance of addressing this issue is emphasized in present times, when more and more women are delaying childbearing until their late thirties/early forties due to social reasons, with a possibly increased risk of developing adenomyosis-related infertility [5].

2. Pathophysiology of adenomyosis-associated infertility

The more widely accepted theory about the pathogenesis of adenomyosis proposes that basal endometrial glands and stroma invade the underlying myometrium, giving rise to intrinsic adenomyosis, i.e. adenomyosis affecting the JZ as well as the internal myometrium. A different theory, i.e. the invasion of the uterus by a deep endometriotic nodule of the pouch of Douglas, has been proposed for explaining the extrinsic type of adenomyosis, affecting the outer myometrium [10]. Other pathogenetic theories for adenomyosis include embryologically displaced pluripotent Mullerian remnant, invagination of the endometrium through the basalis along the intramyometrial lymphatics, and displaced bone marrow stem cells [11].

Since the presence of adenomyosis involves alterations of the myometrium and may also affect the JZ, which are critical areas for successful reproduction, it seems reasonable to hypothesize the existence of a causal link between adenomyosis and subfertility [12]. The biological basis for a negative impact of adenomyosis on fertility may include the following [13]:

• Adenomyosis-induced local inflammation [14].

• Impairment of the utero-tubal system of sperm transport [15]. This is mainly due to the subversion of the JZ, from which the peristaltic activity originates [16].

• Altered endometrial function and receptivity that occurs through abnormal levels of free radicals due to oxidative stress, leading to an unfavorable environment for the development of the embryo [17]; and impaired endometrial vascularization [18].

• Dysregulation of the local hormonal metabolism leading to a hyperestrogenic hormonal mileau [19]. According to this pathogenetic mechanism, adenomyosis and infertility would be two manifestations of one underlying condition (i.e. hyperestrogenism) rather than having a cause–effect relationship [20].

3. Adenomyosis and infertility: evidences from clinical studies

Most studies investigating adenomyosis as a possible cause of infertility have focused on the comparison of outcomes of in vitro fertilization (IVF) or intracytoplasmatic sperm injection (ICSI) between affected and non-affected infertile women. The rationale for this approach is that it allows to evaluate the influence of adenomyosis on embryo implantation [21]. Two systematic literature review and meta-analysis have summarized the available evidence. Vercellini et al. in 2014 reported a clinical pregnancy rate after IVF/ICSI of 40.5% in women with adenomyosis versus 49.8% in women without adenomyosis (RR = 0.72; 95% CI, 0.55–0.95) [14]. The authors concluded that adenomyosis appears to impact negatively on IVF/ICSI outcome, because it is associated with a 28% reduction in the likelihood of clinical pregnancy and with more than a doubled risk of miscarriage [14]. As a consequence, the screening for adenomyosis before embarking on medically assisted reproductive procedures should be encouraged [14]. Data from Younes et al. in 2017 are consistent with these findings [22]. According to their review, in fact, adenomyosis has a detrimental effect on IVF clinical outcomes, being associated with reduced rates of implantation (OR = 0.66; 95% CI, 0.49–0.88) and pregnancy (OR = 0.75; 95% CI, 0.61–0.93), increased risk of miscarriage, and, consequently, a decrease in live birth rate [22]. In addition, this latter review analyzed the effects of surgical and medical treatment of adenomyosis and concluded that pre-IVF treatment with long-term Gonadotrophin-releasing hormone agonists (GnRHa) or long protocol could be beneficial [22]. A few limitations of this meta-analysis have to be pointed out. First, they were both based mostly on the same data, with the second meta-analysis adding only a few more recent studies to the first one, and therefore similar conclusions were expected. Second, the populations of the different studies were heterogenous for several important characteristics such as prevalence of adenomyosis, age of the enrolled women, diagnostic criteria for adenomyosis, concomitant presence of endometriosis, and use of GnRH agonist down regulation protocols.

Table 1 summarizes available data on the effect of adenomyosis on clinical pregnancy rate and miscarriage rate. Data were derived from 10 observational cohort studies, 4 of which prospective and 7 retrospective, including a total of 2042 women, 561 with and 1481 without adenomyosis. As shown, adenomyosis was associated with a lower pregnancy rate in 3 out of 10 studies and with a higher miscarriage rate in 4 out of 9 studies that evaluated these issues, respectively.

Table 1. The effect of adenomyosis on the rates of implantation/clinical pregnancy and on the rates of miscarriage in published cohort studies on IVF/ICSI outcomes.

Authors	Study design	No. of women withadenomyosis/withoutadenomyosis	Implantation/Clinicalpregnancy rates	Miscarriage rate
Chiang et al. [28]	Prospective	19/144	No effect	Higher
Mijatovic et al. [23]	Retrospective	20/54	No effect	No effect
Maubon et al. [29]	Prospective	39/113	Lower	Not evaluated
Martinez-Conejero et al. [27]	Retrospective	152/147	No effect	Higher
Youm et al. [30]	Retrospective	111/302	Lower	Higher
Costello et al. [24]	Retrospective	37/164	No effect	No effect
Salim et al. [25]	Prospective	19/256	No effect	Higher
Thalluri et al. [31]	Retrospective	38/175	Lower	No effect
Yan et al. [26]	Retrospective	77/77	No effect	No effect
Benaglia et al. [21]	Prospective	49/49	No effect	No effect

4. Conclusions and future perspectives

According to the meta-analysis of available data, adenomyosis is associated with reduced pregnancy rates and increased miscarriage rates in women undergoing IVF. These findings seem to support the hypothesis that adenomyosis interferes with embryo implantation due to a compromised uterine peristalsis and a reduced endometrial receptivity. Moreover, an unfavorable ‘adenomyotic’ uterine environment might persist after embryo implantation, leading to an increased risk of miscarriage. Consistently, Martınez-Conejero et al. evaluating women with adenomyosis receiving donated oocytes, thus at low risk of miscarriage due to poor oocyte quality, observed a double risk of miscarriage that was apparently related only to reduced uterine receptivity [27].

However, available data cannot be considered conclusive for establishing a causal relationship between adenomyosis and infertility. In fact, although many studies suggest a causal relationship between these two conditions [27–31], a definitive demonstration is still lacking [14]. Similarly, although available evidence suggests that treatment with GnRH analogues improves pregnancy rates in infertile women with adenomyosis, more studies are needed to confirm the potentially beneficial effect of deep hypo-estrogenism in these women [22].

Unfortunately, there are several factors that make it difficult to investigate the relationship between adenomyosis and infertility. First, the incidence of adenomyosis is not known; in fact, a great variability in the incidence of adenomyosis has been observed [32]. Second, universally accepted diagnostic criteria for adenomyosis are still lacking and there is no agreement on what TVUS or MRI parameters are the most useful to identify the disease and grade its severity. As an example, different studies might define adenomyosis on the bases of different cutoff values for the thickness of the JZ, thus including nonhomogeneous populations of women, which make the comparison of results unreliable. Third, up to 80% of women with adenomyosis have other concomitant pelvic disease that often prevent the possibility to attributing specific symptoms exclusively to adenomyosis [11]. In particular, adenomyosis often coexists with endometriosis and uterine fibroids, the first condition being potentially responsible for dysmenorrhea, dyspareunia, pelvic pain, and infertility, the latter condition being potentially responsible for AUB, infertility, and miscarriage.

Unfortunately, available studies on the correlation between adenomyosis and infertility show discrepant results due the inclusion of clinically heterogeneous populations, different inclusion criteria, different quality of imaging evaluation, confounding factors such as the coexistence of endometriosis or uterine fibroids, and biases in studies’ design. There is the need for adequately designed prospective studies addressing the correlations between adenomyosis and infertility in order to improving our knowledge of this polymorphic disease and consequently establish more effective treatment strategies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.