Abstract
In brief
Traditionally viewed as enigmatic and elusive, adenomyosis is a fairly common gynecological disease but is under-recognized and under-researched. This review summarizes the latest development on the pathogenesis and pathophysiology of adenomyosis, which have important implications for imaging diagnosis of the disease and for the development of non-hormonal therapeutics.
Abstract
Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development in the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress in our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial–myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain are less understood but presumably involve increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, a new imaging technique can be used to diagnose adenomyosis more accurately and informatively and possibly help to choose the best treatment modality.
Introduction
First documented by German pathologist Carl von Rokitansky in 1860 (Benagiano & Brosens 2006), adenomyosis is defined as the presence of endometrial glands and stroma within the myometrium (Bird et al. 1972). It is a uterine disease that affects many women of reproductive age and is a contributing factor for dysmenorrhea, pelvic pain, abnormal uterine bleeding (AUB), and subfertility (Farquhar & Brosens 2006, Vercellini et al. 2014, Harada et al. 2016, Gordts et al. 2018).
In spite of its long history, adenomyosis is a under-researched disease (Wang et al. 2022b), but the seemingly neglect may be changing. In the last 10 years, there has been a growing interest in adenomyosis as seen by a swell of excellent reviews on the pathogenesis and pathophysiology of adenomyosis in recent years (Benagiano et al. 2012, Vannuccini et al. 2017, Garcia-Solares et al. 2018, Vannuccini & Petraglia 2019, Zhai et al. 2020, Bulun et al. 2021, Donnez et al. 2021, Stratopoulou et al. 2021b, Khan et al. 2022).
This manuscript intends to review some recent development in adenomyosis pathogenesis and pathophysiology. Given the vastly diverse areas in adenomyosis research spanning from epidemiology, pathogenesis, and pathophysiology to clinical management, it is perhaps more productive not to rehash what have been reviewed or just compile more published results. Fittingly or not, the state of adenomyosis research is often likened to the fable of ‘the elephant and the blind men’, in that researchers around the world are groping to untie the Gordian knot of adenomyosis pathogenesis/pathophysiology, with each reporting certain important and novel finding of their own. However, it is apparent that the whole and entire truth is still amiss. At the core of this state is the seeming lack of a big picture. For a good review, it is perhaps more profitable to have a clear framework and then piece together most, if not all, published results. Indeed, if the blind men in that fable were told that the creature they were trying to fathom is a mammal, perhaps they could have built on this, pieced together all their findings, and reached a much more revealing conclusion that was closer to the truth.
With this in mind, I shall provide an overview of new developments in the quest for the pathogenesis and pathophysiology of adenomyosis and then use the perspective that we gained from these findings to understand the pathophysiology of adenomyosis-associated heavy menstrual bleeding (HMB) and pain, and then mention, very briefly, how the new understanding of the natural history of adenomyotic lesions can help devise better imaging diagnostic and non-hormonal therapeutics. Due to space limitation, adenomyosis-associated infertility will not be reviewed here but can be found in a recent review (Khan et al. 2022). In particular, I shall capitalize on the intrinsic similarity that both adenomyosis and endometriosis share in common and extrapolate findings in endometriosis to adenomyosis. It is important to note that, because of the emphasis on a major framework, inevitably, this review has, by necessity, to pick and choose those data that are deemed to be relevant and not superfluous. By so doing, however, this may engender the risk of being biased in favor of the data generated from this author’s own lab, but by no means other published data would be slighted entirely. It just means that we have to comb through the vast sea of publications to get a firm grip of the nutshell of the matter.
Etiology and pathogenesis
The prevailing theories
There are currently two prevailing and competing theories: invagination and metaplasia (Garcia-Solares et al. 2018). The invagination theory was built primarily upon the tissue injury and repair (TIAR) hypothesis proposed by Leyendecker and his colleagues (Leyendecker et al. 2009, 2015, Leyendecker & Wildt 2011). The word ‘metaplasia’ was created following anatomical and histological observations of the unexpected appearance of foreign tissues in ectopic sites (Slack 1986) and is now commonly used to refer to the conversion from one type of differentiated cell to another (Slack & Tosh 2001).
In essence, the TIAR theory postulates that repeated and sustained myometrial overstretching due to hyperperistalsis of unknown origin would cause injury to the myocytes and fibroblasts in the junctional zone (JZ), an anatomic region originally defined by the MRI that overlaps with the endometrial–myometrial interface (EMI). This event, termed microtrauma, would focally activate the TIAR system with increased inflammation and local production of estrogens, which, in turn, induce more inflammation and more estrogen production, establishing a feed-forward loop that further induces uterine hyperperistalsis through ERα induction of the oxytocin (OT)/OT receptor (OTR) system (Leyendecker et al. 2009, Leyendecker & Wildt 2011). The chronic hyperperistalsis in the JZ facilitates repetitive autotraumatization, causing the disruption of the muscular fibers in the EMI, eventually leading to the invagination of endometrial basal layer into the myometrium, and thus adenomyosis. In fact, this theory is recently extended to encompass endometriosis as well, which is subsumed, along with adenomyosis, into the term ‘archimetrosis’ to indicate the common origin (Leyendecker et al. 2022).
The metaplasia theory posits that adenomyotic lesions may originate from metaplasia of displaced embryonic pluripotent Müllerian remnants (Ferenczy 1998). The underlying mechanisms are completely unclear. Alternatively, endometrial stem/progenitor cells or their niche cells may behave aberrantly for some unknown reason and their differentiating progeny cells move toward the myometrium, rather than functionalis, resulting in adenomyosis (Gargett 2007).
Despite the appeal, unfortunately, so far there have been no experimental data whatsoever to support or refute either of the theories or the TIAR hypothesis (Wang et al. 2022b). Of particular note is that neither theory seems to be backed by any epidemiological data. For the invagination theory, it is unclear as to why and how this injury – which amounts to primum movens – occurs. Indeed, uterine peristalsis occurs in all women of reproductive age, but why is there only a fraction of them develop adenomyosis? What are the risk factors, if any, for this hyperperistalsis/dysperistalsis? Is it possible to intervene or prevent it? What can be done to mitigate the risk of hyperperistalsis in the first place? It is also unclear why and how the stem cells are recruited and then turned into endometrial epithelial and stromal cells that respond to hormonal fluctuations and become adenomyotic lesions.
A good theory has to satisfy at least three basic requirements: falsifiability, explanatory power, and predictivity. While both theories could explain some phenomena, they have to be falsifiable and have predictive power. Hence, a better alternative would be to dramatically revamp the existing theories and start anew.
An emerging hypothesis
A large body of epidemiological data has shown, quite consistently, that iatrogenic uterine procedures, such as dilatation and curettage and induced abortion, increase the risk of developing adenomyosis later in life (Parazzini et al. 1997, Levgur et al. 2000, Taran et al. 2010). With this in mind, the hypothesis of endometrial–myometrial disruption (EMID) has been proposed (Guo 2020b). This hypothesis predicted that, first, the magnitude of risk of developing adenomyosis resulting from EMID depends on the severity and mode of disruption; and secondly, perioperative intervention may help reduce the risk of adenomyosis (Guo 2020b). This may explain why not all women who underwent iatrogenic uterine procedures develop adenomyosis, simply because different women may simply have experienced different modes or degrees of EMID. If EMID is extensive and severe enough, there should be an elevated risk of developing adenomyosis as opposed to minor or no EMID.
Additionally, the EMID, as tissue trauma, would cause tissue injury, eliciting the release of substance P (Mantyh 1991) and PGE2 (Kirchhoff et al. 2009), and activate the hypothalamic–pituitary–adrenal (HPA)/sympathetic–adrenal–medullary (SAM) axes, resulting in increased release of catecholamines such as adrenaline/noradrenaline, which, in turn, may suppress cell-mediated immunity (Goldfarb et al. 2011), hampering the capability of immune cells to remove endometrial cells that invaded into the myometrium through breached EMI. Indeed, in mice that received the EMID procedure, the systemic levels of substance P, PGE2, adrenaline, and noradrenaline are all elevated as compared with those receiving a sham surgery (Wang et al. unpublished data). It has been reported that both adrenaline and noradrenaline suppress IL-12 production in a dose-dependent fashion and at physiological concentrations while dose-dependently increasing the production of IL-10, potentiating Th2-regulated responses (humoral immunity) (Elenkov et al. 1996). Yet, IL-12 is known to be a key inducer of differentiation of uncommitted T helper (Th) cells toward the Th1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits Th1 functions and potentiates Th2-regulated responses (i.e. humoral immunity). Both catecholamines also reduced NK cell cytotoxicity (Ben-Eliyahu et al. 2000).
In addition, PGE2 has been shown to reduce IL-12 production (Stolina et al. 2000) and CD4+ and CD8+ T cell numbers and CD4+ T cell cytotoxicity (Yang et al. 2003), increase IL-10 levels (Stolina et al. 2000), as well as regulatory T cell inhibitory capacity and numbers (Baratelli et al. 2005, Sharma et al. 2005).
The abundance of adrenergic nerve fibers in the uterus, especially in the EMI region (Alm & Lundberg 1988, Bae et al. 2001), seems to give credence to this view. This would indicate that perioperative intervention to counter either the action of the receptor for substance P, neurokinin receptor 1 (NK1R), or to contain the release of PGE2 by inhibiting COX-2 or the adrenaline receptors would reduce the risk of adenomyosis resulting from EMID (Hao et al. 2020). Indeed, perioperative administration of an NK1R inhibitor or a β-blocker plus a COX-2 inhibitor did reduce the risk of developing adenomyosis in mice (Hao et al. 2020).
Pursuit of this hypothesis, a mouse model mimicking iatrogenic uterine procedures has been established (Hao et al. 2020). Aside from being consistent with epidemiologic data and demonstrating the falsifiability of the EMID hypothesis, this model also demonstrates that indeed the risk of adenomyosis did depend precisely on the severity and mode of EMID, and, more importantly, perioperative intervention can significantly reduce the risk of developing adenomyosis (Hao et al. 2020). Hopefully, the insight gained from understanding of how EMID increases the risk of developing adenomyosis can help us unravel the adenomyosis pathogenesis due to other causes.
It should be noted that the EMID hypothesis has also been validated independently recently by Hiraoka et al. using multiple punctures onto the EMI in mouse (Hiraoka et al. 2022). Thus, as long as the EMID is severe enough, it will cause adenomyosis.
The EMID hypothesis and its experimental evidence provide a good explanation for primum movens. It should be noted that the nascent lesional focus, once formed, could still face possible removal by immune cells, and the successful establishment of an adenomyotic lesion would depend on whether it can resist the removal. However, once the lesion is securely established, and barring any extraneous factors or lifestyle/behavioral changes that either boost the immunity or decelerate the progression (such as caloric restriction or eustress (Yin et al. 2018, 2020)), the established lesion should progress mostly on cyclic bleeding (Guo 2018b). Conceivably, the lesional progression could, in fact, be facilitated by psychogenic stress (Long et al. 2016b, Guo et al. 2017), high-fat diet (Heard et al. 2016), lower dairy consumption (Nodler et al. 2020), surgery (Liu et al. 2016a, Long et al. 2016a), history of adverse early life events (Long et al. 2020), and perhaps other factors yet to be identified.
After an adenomyotic focus is successfully established, it would undergo cyclic bleeding similar to the eutopic endometrium (Brosens 1997) and, as such, effectively become a wound that undergoes repeated tissue injury and repair (ReTIAR) (Guo 2018b), progressing to fibrosis through epithelial–mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM) (Liu et al. 2016b, Shen et al. 2016). In other words, once the primum movens is effectively applied, everything else will be set in motion, more or less on its own, resulting in adenomyosis as we see it.
What is special about the EMI?
While EMID induction of adenomyosis has been experimentally demonstrated, one lingering issue is why and how. Of course, injury resulting from the EMID would lead to platelet aggregation, inflammation, and hypoxia, resulting in the release of copious inflammatory cytokines such as IL-1β and growth factors such as TGF-β1, as well as increased local estrogen production (Guo 2020b, Qi et al. 2020). The increased estrogen levels may promote EMT and enhance the invasiveness of endometrial epithelial cells, facilitating the invasion of these cells to cross the breached EMI and into the myometrium, establishing the adenomyotic lesion (Chen et al. 2010).
It should be noted that the EMI is more than just a demarcation area that separates endometrium from myometrium or a physical barrier that impedes or block the invasion of endometrial epithelial cells into the myometrium. In fact, it is the region where the endometrial stem cells reside (Cousins et al. 2018, Tempest et al. 2020). It is also the location from which uterine contraction is started (Brosens et al. 2010). More importantly, EMI, unlike endometrium or myometrium, is densely innervated with peripheral nerves (Krantz 1959, Quinn 2007, Barcena de Arellano et al. 2013b, Zhang et al. 2014), maintained by ensheathing Schwann cells (SCs) that are derived from neural crest (Jessen et al. 2015). SCs are the most important type of glial cells in the peripheral nerve system (PNS) and are distributed nearly ubiquitously in the human body (Alvarez-Suarez et al. 2020). Their abundance, coupled with their remarkable plasticity capable of dedifferentiating and re-differentiating following injury to the nerve, endows their important roles in repairing tissues and in promoting cancer progression (Jessen et al. 2015, Carr & Johnston 2017, Stierli et al. 2019, Sun et al. 2022).
Following injury, SCs rapidly dedifferentiate to an unmyelinated progenitor state that promotes axonal regeneration and repair (Carr & Johnston 2017). Of course, there are nuances when it comes to injured SCs (called bridge cells), intact region, and distal region (Clements et al. 2017). Elevated levels of TGF-β, which is aplenty in the wounded tissues due to activated platelets, also stimulate the targeted migration of SCs across the bridge, providing a conducive substrate for successful nerve regeneration and tissue repair (Clements et al. 2017). Dedifferentiated SCs (dSCs) overexpress genes encoding for secreted factors intimately associated with tissue repair, such as growth factors, TGF-β signaling, chemotaxis and inflammation, migration and adhesion, extracellular matrix (ECM) remodeling, and angiogenesis (Parfejevs et al. 2018). In particular, dSCs can release TGF-β3 that facilitates fibroblast proliferation and thus promotes wound healing (Ou et al. 2022). TGF-β signaling reprograms bridge SCs that are dedifferentiated to invasive mesenchymal-like cells (Clements et al. 2017). In the context of EMID, injury-induced dSCs can induce EMT in neighboring endometrial epithelial cells by releasing TGF-β1 (Wang et al. unpublished data).
Since EMID causes not only tissue injury but also nerve injury, naturally SCs should be viewed as a high-value suspect in causing adenomyosis. Indeed, when peripheral nerves are injured, SCs can dedifferentiate into immature SCs and acquire stemness (Lee & Wolfe 2000, Jessen et al. 2015, Jessen & Mirsky 2016). In addition, SCs can also transdifferentiate into endoneurial fibroblasts (Joseph et al. 2004), chromaffin cells (Kastriti et al. 2019), melanocytes (Adameyko et al. 2009), mesenchymal cells (Kaukua et al. 2014), and parasympathetic, sympathetic, enteric, GABAergic, glycinergic, serotoninergic, and cholinergic neurons (Dyachuk et al. 2014, Espinosa-Medina et al. 2014, Su et al. 2014, Wang et al. 2016, Milichko & Dyachuk 2020). In view of their pleiotropic roles after injury, there is reason to believe that EMID may cause injury to peripheral nerves residing in the EMI region, resulting in SC dedifferentiation. Inundated by inflammatory cytokines such as IL-1β (Shaw & Martin 2009), estrogens resulting from a hypoxia microenvironment (Qi et al. 2020), and growth factors such as TGF-β1 released copiously by activated platelets and other immune cells (Guo 2020b), it is conceivable the dedifferentiated SCs might be coaxed and differentiated into endometrial epithelial cells. Furthermore, these SC-turned endometrial epithelial and stromal cells (through EMT) may form the original focus of adenomyotic lesion. That is, SCs residing in the EMI, when injured, would become dedifferentiated and turn into endometrial epithelial and stromal cells, forming an original adenomyotic lesion in disrupted myometrium.
To test the hypothesis that SCs are involved in inducing adenomyosis resulting from EMID, we treated mice perioperatively with either MEK/ERK or JNK inhibitors or vehicle 4 h before and 24, 48, and 72 h after the EMID procedure since Ras/Raf/ERK and c-Jun N-terminal kinase (JNK) are two important signaling pathways involved in the dedifferentiation of SCs (Jessen et al. 2015, Nocera & Jacob 2020) and inhibition of either pathway can prevent SCs from dedifferentiation (Harrisingh et al. 2004, Blom et al. 2014). We found that EMID resulted in progressive SCs dedifferentiation, concomitant with increased abundance of epithelial cells in the myometrium and subsequent EMT (Wang et al. 2022c). This EMID-induced change was abrogated significantly with perioperative administration of JNK or MEK/ERK inhibitors. Consistently, perioperative administration of a JNK or a MEK/ERK inhibitor reduced the incidence by nearly 33.5 and 14.3%, respectively, in conjunction with reduced myometrial infiltration of adenomyosis and alleviation of adenomyosis-associated hyperalgesia (Wang et al. 2022c). Both treatments significantly decelerated adenomyosis establishment and progression of EMT, FMT, and fibrogenesis in adenomyotic lesions. These data provide the first piece of evidence, strongly implicating the involvement of SCs in the pathogenesis of adenomyosis induced by EMID (Wang et al. 2022c).
It is also possible that terminal SCs residing in the EMI are also involved in uterine peristalsis. This is because the terminal SC area is known to play a role in neuromuscular junctions that are involved in muscle contraction (Alvarez-Suarez et al. 2020). In addition, SC-derived extracellular vesicles may also help to form the lesion by recruiting endometrial stem cells (Wang et al. 2022a). However, data on this area are very scanty, and further investigations are warranted.
Figure 1 provides a schematic illustration of possible mechanisms underlying EMID-induced adenomyosis. It should be emphasized that EMID is just one cause of adenomyosis. There are adenomyosis cases that are not caused by EMID.
Schematic illustration of the formation of adenomyotic lesions due to the endometrial–myometrial interface disruption (EMID). Iatrogenic procedures cause disruption at the endometrial–myometrial interface (EMI), resulting in tissue injury, including nerve injury. The tissue injury leads to platelet aggregation, inflammation, and the induction of HIF-1α, effectively causing tissue hypoxia. As a result, genes involved in estrogen production are upregulated, resulting in increased local production of estrogen and subsequent induction of both ERα and ERβ, which, in turn, leading to the induction of the OT/OTR signaling and increased uterine peristalsis. In addition, tissue hypoxia activates TGF-β1, VEGF, COX-2, and SDF-1 signaling pathways, leading to increased angiogenesis, vasculature, and recruitment of BMDSCs to the wounding site. The induction of COX-2 would also increase the production of PGH2 and TXA2, which also enhances uterine peristalsis. Moreover, the TGF-β1 signaling pathway induces EMT, leading to the invasion of endometrial epithelial cells to the EMI and further down to the myometrium. Tissue injury also would activate the HPA/SAM axes, leading to the release of catecholamines and PGE2, which collectively result in impaired cell-mediated immunity and, as such, enhances the survival of displaced and dispersed endometrial cells within the myometrium. Nerve injury results in the release of substance P and the induction of NK1R. It also leads to dedifferentiation of ensheathing Schwann cells, which are turned into endometrial epithelial cells under the influence of IL-1β and growth factors such as TGF-β1. These newly minted endometrial epithelial cells can also undergo EMT and differentiate into endometrial stromal cells. All these events ultimately lead to the formation of adenomyotic lesions in the myometrium. BMDSC, bone marrow-derived stem cells; COX-2, cyclooxygenase-2; E2, 17β-estradiol; EMI, endometrial–myometrial interface; EMT, epithelial–mesenchymal transition; ERα, estrogen receptor α; ERβ, estrogen receptor β; HIF-1α, hypoxia-inducible factor 1α; HPA, hypothalamic–pituitary–adrenal; OT, oxytocin; OTR, oxytocin receptor; P450 aromatase, aromatase; PGE2, prostaglandin E2; SAM, sympathetic–adrenal–medullary; SDF-1, stromal cell-derived factor 1; SF-1, steroidogenic factor-1; TGF-β1, transforming growth factor β1; TXA2, thromboxane A2; VEGF, vascular endothelial growth factor.
Citation: Reproduction 164, 5; 10.1530/REP-22-0224
Heterogeneity in pathogenesis
Growing evidence suggests that different subtypes of adenomyosis appear to have different symptomology and likely pathogenesis. Internal adenomyosis, that is, lesions proximal to the endometrium, has been shown to be more likely to be associated with HMB, while external adenomyosis distal to the endometrium but proximal to the uterine serosa is more closely linked with deep endometriosis (Kishi et al. 2012, Khan et al. 2019, Bourdon et al. 2021). It has been documented recently that there is a close link between external/extrinsic adenomyosis and deep endometriosis (Chapron et al. 2017, Marcellin et al. 2018, 2020, Khan et al. 2019, Bourdon et al. 2021), implying that the two disease entities may have a causal relationship or that the two entities may represent the same disease (Donnez et al. 2019). Equally likely, one disease entity could be simply caused by the other due to sheer physical proximity of each other and the invasiveness of ectopic endometrium (Gaetje et al. 1995). Of particular interest is that intrinsic/internal adenomyosis is found to contain almost tall columnar cell type with abundant stromal cells around glands reminiscent of the endometrial gland cells and stroma supporting their origin from endometrium, yet, in contrast, in extrinsic/external adenomyosis, the glandular epithelial cells are found to be mostly thin with scanty CD10-positive stromal cells that closely similar to their coexisting deep endometriotic lesions (Khan et al. 2019).
So far, preliminary mutation data seem to hint that deep endometriotic lesions adjacent to adenomyosis exhibited a higher KRAS mutation frequency than its neighboring adenomyotic lesions (Anglesio et al. 2017). Assuming a clonal relationship exists, this seems to suggest that external/extrinsic adenomyotic lesions may be colonized by their adjacent deep endometriotic lesions. At this moment, however, these data are too scarce to be conclusive.
The recent discovery of the three-dimensional histoarchitecture of the endometrium (Tempest et al. 2020, Yamaguchi et al. 2021) would lend support to the notion that EMID resulting from iatrogenic uterine procedures would likely cause intrinsic/internal, but less likely extrinsic/external, adenomyosis simply because of physical proximity. This seems to be supported by published data reporting that internal adenomyosis is associated with a history of uterine procedures (Kishi et al. 2012, Kobayashi et al. 2021).
One mouse experiment provides support for this notion. CD-1 mice neonatally fed with tamoxifen can develop adenomyosis (Parrott et al. 2001). As a selective estrogen receptor modulator, the action of tamoxifen is mediated through ERα and ERβ (Jordan 2006), as well as non-genomic mechanisms, such as through the G-protein coupled receptor 30 (GPR30) signaling pathway (Ignatov et al. 2010, Mo et al. 2013, Rouhimoghadam et al. 2018, Liu et al. 2021). In a manner identical to the tamoxifen induction of adenomyosis, mice neonatally fed with tamoxifen and diarylpropionitrile (DPN, an ERβ agonist) yielded adenomyosis in 100 and 50% of ICR mice, respectively (Cao et al. 2022), while those fed with propylpyrazoletriol (PPT, an ERα agonist) or G-1 (a GPR30 agonist) did not develop adenomyosis. Of particular note, adenomyotic lesions in the DPN group were found to be restricted to the serosal layer reminiscent of extrinsic/external adenomyosis in humans (Kishi et al. 2012, Bazot & Darai 2018) and were quite different from those induced by tamoxifen. These findings not only demonstrate that neonatal feeding of tamoxifen does not induce adenomyosis through a single ER but also seem to suggest that the pathogenesis of extrinsic/external adenomyosis may be different from other subtypes of adenomyosis.
Pathophysiology
Adenomyosis can cause HMB, dysmenorrhea and other pelvic pains, and infertility. From the perspective of healthcare providers, it suffices to understand the pathophysiology for the purpose of management. As of now, the pathophysiology underlying adenomyosis-induced symptomology is still poorly understood. To understand pathophysiology, the crux is, first and foremost, to understand the natural history of adenomyotic lesions, at least in broad strokes, since these lesions conceivably serve as the root causes for all the symptoms manifested.
The natural history of adenomyotic lesions
In the last 6–7 years, the natural history of adenomyotic lesions, at least in silhouette form, has emerged. In a nutshell, as adenomyotic lesions experience cyclic bleeding just as eutopic endometrium, they are fundamentally wounds undergoing ReTIAR (Guo 2018b). Similar to endometriotic lesions, they undergo EMT, FMT, and SMM and progress ultimately to fibrosis (Liu et al. 2016b, Shen et al. 2016, Zhang et al. 2016). Due to FMT and SMM, stromal cells within lesions eventually are turned into smooth muscle cells (SMCs) (Liu et al. 2016b, Shen et al. 2016, Zhang et al. 2016), which are fused into existing myometrium, causing enlarged uterus in women with adenomyosis.
Of course, myometrial SMCs from women with adenomyosis also exhibit cellular hypertrophy (Mehasseb et al. 2010), most likely due to the activation of the MAPK/ERK and the PI3K/mTOR/AKT pathways (Streuli et al. 2015) and, curiously, the upregulation of cannabinoid receptor CB1 (Wang et al. 2021a). Irrespective of the sources, the enlarged uterus is likely to result in increased magnitude of uterine contraction, especially when oxytocin receptor (OTR) is overexpressed (Guo et al. 2013). In addition, due to the fusion of newly turned SMCs into the myometrium, the uterine contraction is likely to be out of synchronization, resulting in dysperistalsis (Mao et al. 2011).
Aside from ectopic endometrial cells, many other cells within lesions and the uterus also participate in the progression of adenomyosis. Platelets, for example, can induce EMT, FMT, and SMM in ectopic endometrium, facilitating fibrogenesis (Liu et al. 2016b, Shen et al. 2016, Zhang et al. 2016). Vascular endothelial cells, stimulated by activated platelets, can be turned into myofibroblasts within lesions through endothelial–mesenchymal transition (Yan et al. 2020b). Activated platelets can also promote mesothelial–mesenchymal transition in peritoneal mesothelial cells (Yan et al. 2020a), causing adhesion and immobility of the uterus in women with adenomyosis. In addition, alternatively activated macrophages and regulatory T cells (Tregs) within lesions could promote lesional fibrogenesis through type II immunity (Bacci et al. 2009, Duan et al. 2018, Xiao et al. 2020).
Among all the molecular/cellular events involved in adenomyosis development, EMT appears to be the most documented. Many factors/molecules have been reported to be involved in EMT in the context of adenomyosis: estrogen (Chen et al. 2010), β-catenin (Oh et al. 2013), HGF (Khan et al. 2015), Notch1 (Qi et al. 2015), platelet-derived TGF-β1 (Liu et al. 2016b, Shen et al. 2016), macrophages (An et al. 2017a,b), ILK (Zhou et al. 2018), eIF3e (Cai et al. 2019), FAK (Zheng et al. 2018), and Talin1 (Wang et al. 2021b), among others. However, it is well-known that, aside from its involvement in development and cancer metastasis, EMT is known to be vital in wound healing, where it is rapidly activated and results in wound closure through re-epithelialization (Savagner 2015). Along the same vein, FMT or myofibroblast activation also is critical in tissue repair, as it leads to tissue contraction, restoring tissue integrity and reducing the wound size (Hinz 2016). Thus, from the ReTIAR perspective, the involvement of EMT in adenomyosis should be considred as obligatory.
Ectopic endometrial stromal cells can secrete neurotrophic factors, such as NGF, NT-3, TrkB, TXA2, and GDNF (Barcena de Arellano et al. 2011, 2013a, Greaves et al. 2015, Yan et al. 2017a), and axon guidance molecules such as Semaphorin 3E and SLIT/ROBO (Greaves et al. 2014, Asally et al. 2019), resulting in increased nerve fiber density and hyperinnervation in lesions (Wang et al. 2009a,b, Zhang et al. 2010). Moreover, eutopic endometrium from women with endometriosis, and possibly with adenomyosis as well, can promote neuroangiogenesis through exosome release (Sun et al. 2019).
As a consequence of hyperinnervation in endometrium and myometrium from women with adenomyosis (Zhang et al. 2009, 2010, Lertvikool et al. 2014, Choi et al. 2015), any minute or seemingly innoxious nociceptive stimulation, or elevation in pain mediators, or hyperperistalsis/dysperistalsis would be transduced, through the ascending transmission from primary afferent terminals to dorsal root ganglia and then to the central nervous system (CNS), resulting in the perception of pain. This, coupled with loss of GABAergic inhibition that inhibits the transfer of nociceptive signals from primary afferent fibers to the CNS in adenomyosis (Chen et al. 2014), would exacerbate the pain sensation.
Conversely, with the increase in nerve fibers, especially elevated density of sensory nerve fibers, there would be an increase in the secretion of neuropeptides. Yet, several neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), can facilitate EMT, FMT, and SMM in ectopic endometrium (Liu et al. 2019, Yan et al. 2019), accelerating lesional fibrosis. In other words, adenomyotic lesions and their surrounding nerves are partners in crime that cause pain in women with adenomyosis (Yan et al. 2017b).
Pain is a potent stressor, and HMB and/or infertility also would cause anxiety, discomfort, depression, and stress of various degrees. Yet, chronic or persistent stress would inevitably activate the HPA/SAM axes, yielding the release of catecholamines. Adrenaline and noradrenaline would activate the adrenergic β2 (ADRB2) and cAMP-responsive element-binding protein (CREB) on ectopic endometrium, accelerating the lesional progression (Long et al. 2016b, Guo et al. 2017). Chronic stress can also suppress dopamine receptor D2 (DRD2) expression in ectopic endometrium (Guo et al. 2017). In contrast, eustress, or the opposite of stress, increases the lesional expression of DRD2 and retards lesional progression (Yin et al. 2020). This seems to echo the reports that dopamine or DRD2 agonists could block stress-facilitated angiogenesis and proliferation in cancers (Moreno-Smith et al. 2011, 2013). Thus, a vicious cycle of adenomyosis–pain–stress–lesional progression–more pain could be established.
Aside from platelets, immune cells, endothelial cells, and sensory nerves, dSCs may also participate in facilitating lesional progression. This is because that SCs can become dedifferentiated not only because of injury but also due to other pathological stimuli, such as hypoxia (Demir et al. 2016) and STAT3 activation (Benito et al. 2017), which have been reported to be involved in adenomyosis (Goteri et al. 2009, Guo et al. 2021, Hiraoka et al. 2022). Indeed, dSCs release many secreted factors that are actively involved in tissue repair and promote myofibroblast differentiation by paracrine modulation of TGF-β signaling (Parfejevs et al. 2018), likely facilitating progression and fibrogenesis adenomyotic lesions. Research in this area has been ongoing, and the precise role of SCs in adenomyosis will be hopefully clarified.
Adenomyosis is widely regarded to exhibit progesterone resistance (Vannuccini et al. 2017), manifesting as progesterone unresponsiveness in ectopic endometrium and possibly in eutopic endometrium as well. Overexpression of ERβ, coupled with reduced expression of ERα, may play a role in decreased progesterone receptor (PR) expression and thus is responsible for progesterone resistance (Bulun et al. 2019). One proximate cause is the promoter hypermethylation of PR-B and thus its silence (Jichan et al. 2010), which might be caused by chronic and prolonged exposure to inflammatory cytokines such as TNF-α (Wu et al. 2008). KRAS mutation, likely a result of lesional progression (Guo 2018a, 2020a), also has been reported to be linked with progesterone resistance in adenomyosis (Inoue et al. 2019).
Aside from these possible causes, progressive fibrogenesis would lead to reduced vascular density and PR expression (Liu et al. 2018b) and, as such, may also contribute to progesterone resistance. In addition, increasing lesional fibrosis may yield epigenetic aberrations (Liu et al. 2018b). These epigenetic aberrations (Liu & Guo 2012, Liu et al. 2012) can be refractory to medical treatment or rectification and reduced lesional vascularity would pose a great challenge to deliver therapeutic agents to the target tissues. These aberrations, in conjunction with KRAS mutation, reduced PR-B expression or even silencing and other epigenetic aberrations would explain why adenomyosis is typically resistant to medical treatment, in general, and to progesterone/progestins, in particular.
Figure 2 is a schematic sketch of known and possible mechanisms underlying the natural history of adenomyosis. Note that the natural history is similar to that of endometriotic lesions but not identical, simply due to the different lesional microenvironments and also to the closer proximity to myometrium (which may be easier to cause dysperistalsis) and to endometrium (which may be more likely to impact on endometrial repair).
Schematic illustration of the natural history of ectopic endometrium. The arrows indicate the crosstalk between adenomyotic lesions and other cells in the lesional microenvironment. Pain, HMB, and/or infertility would constitute psychological stress, activating the HPA/SAM axes, resulting in the release of adrenaline/noradrenaline, which, when reaching adenomyotic lesions, downregulate DRD2 but upregulate ADRB2 in adenomyotic lesions, promoting the progression of adenomyosis. Many cells in the lesional microenvironment interact with adenomyotic lesions, and cytokines/chemokines, growth factors, and neuropeptides released by these cells, such as platelets (anuclear), immune cells (such as macrophages and lymphocytes), sensory nerve fibers, and Schwann cells can facilitate the development of adenomyotic lesions. Type 2 immunity also promotes fibrogenesis of adenomyotic lesions. ADRB2, adrenoceptor β2; DRD2, dopamine receptor D2; EMT, epithelial–mesenchymal transition; EndoMT, endothelial–mesenchymal transition; FMT, fibroblast-to-myofibroblast transdifferentiation; HMB, heavy menstrual bleeding; MMT, mesothelial–mesenchymal transition; PR, progesterone receptor; SMM, smooth muscle metaplasia.
Citation: Reproduction 164, 5; 10.1530/REP-22-0224
Redefine adenomyosis
Despite the first description dating back over 160 years ago, the definition of adenomyosis is still the one made by Bird et al. half a century ago, that is, ‘the benign invasion of endometrium into the myometrium, producing a diffusely enlarged uterus which microscopically exhibits ectopic, nonneoplastic, endometrial glands, and stroma surrounded by hypertrophic-hyperplastic musculature’ (Bird et al. 1972). Obviously, this definition was made before the advent of imaging techniques and was based entirely on post-hysterectomy samples. With the increasing popularity of imaging diagnostics, the increased thickness (>12 mm) of the JZ progressively became pathognomonic of adenomyosis and, for a number of years, represented a sort of a golden standard for non-invasive identification of the disease (see, for example, Novellas et al. 2011).
However, using the JZ thickness in defining adenomyosis can be fraught with many problems. First, the JZ is defined on MRI and is not really an anatomically definable area. Secondly, in about 20% of premenopausal women, the JZ is simply undefinable on MRI (Harada et al. 2016). As such, the importance of JZ thickness has been downplayed and a ‘sole criterion’-based diagnosis has been called into question, with a broader approach being proposed (Bazot & Darai 2018). Finally, how the JZ thickness relates to adenomyosis itself is poorly understood.
Moreover, as the natural history of adenomyotic lesions is unveiled, perhaps we could define adenomyosis as a condition that started with the deposition of endometrial stroma and epithelium within the myometrium, which undergoes cyclic bleeding and thus repeated tissue injury and repair, resulting in gradual and progressive smooth muscle metaplasia and fibrogenesis (Guo 2018b ). One advantage of this definition is that it seems to capture the essence of the natural history of the disease and highlights the dynamic and progressive nature of adenomyotic lesions.
Heavy menstrual bleeding
Per the FIGO AUB classification ‘PALM-COEIN’, adenomyosis is known to be a structural cause of AUB, which includes the symptom of HMB (Munro et al. 2011). HMB is defined as excessive menstrual blood loss (MBL) that disrupts physical, social, emotional, and/or material quality of life ((NICE) 2018). HMB has been objectively defined as MBL greater than 80 mL (Hallberg et al. 1966, Higham & Shaw 1999). Unfortunately, the mechanisms underlying adenomyosis-induced HMB are poorly understood (Critchley et al. 2020).
In the absence of pregnancy, endometrial cyclooxygenase-2 (COX-2) is upregulated following the progesterone withdrawal in the late secretory phase, resulting in subsequent increased levels of prostaglandins (PGs), namely, PGE2 and PGF2 α. This signifies a pivotal event for subsequent menstrual induction (Critchley et al. 1999, Sugino et al. 2004). Increased endometrial PGE2 signaling, coupled with endometrial generation of PGF2 α, a vasoconstrictor, leads to local hypoxia in the upper functional layer of the endometrium and the activation of hypoxia-inducible factor 1α (HIF-1α), the master regulator of cellular hypoxia. This defining event establishes an endometrial microenvironment that is conducive to tissue repair and angiogenesis (Critchley et al. 2006, Maybin et al. 2011, 2018). It is well documented that the disruption of the hypoxia signaling or the PGE2 signaling in endometrium would impair endometrial repair, causing HMB (Maybin et al. 2018, Critchley et al. 2020).
In many fibrotic diseases, PGE2 is known to be anti-fibrotic (Huang et al. 2007, 2009, Penke et al. 2014, Wettlaufer et al. 2016). With the progression of adenomyosis and fibrogenesis (Liu et al. 2016b , Shen et al. 2016, Hao et al. 2020, Yang et al. 2021), the lesional stiffness or rigidity has been observed to increase (Liu et al. 2018a ), which would result in the downregulation of COX-2 expression and consequent decrease in PGE2 production and signaling (Liu et al. 2010a ). Indeed, it has been shown recently that endometriotic stromal cells cultured in stiffer substrates demonstrate the downregulation of COX-2 and E-series receptor type 2 (EP2) and EP4 (Huang et al. 2022b ). Since adenomyotic and endometriotic lesions, as ectopic endometrium, share the same and defining hallmark of cyclic bleeding (Brosens 1997), they also share similarities but are not necessarily identical due to different microenvironments and molecular processes that underpin lesional progression (Guo 2018b ). Consequently, this raises the possibility that, as adenomyotic lesions become progressively fibrotic and thus increasingly stiffened, the behavior of neighboring eutopic endometrial cells may likely change.
Given the natural history of adenomyotic lesions as outlined above and in light of the documented mechanisms underlying HMB as well as the disrupted PGE2 signaling in fibrosis, it is conceivable that women with adenomyosis who complain of HMB may have a greater extent of lesional fibrosis and thus greater stiffness, as well as reduced PGE2 signaling. This can be manifested by reduced immunostaining of HIF-1α, COX-2, EP2, and EP4 in adenomyotic lesions and their neighboring JZ and eutopic endometrium. This may lead to attenuation of local PG signaling with reduced expression of COX-2, EP2, and EP4 and thus reduced PGE2, which, in turn, may result in suppression of HIF-1α and subsequent impaired endometrial repair and, finally, HMB.
Indeed, it has been recently demonstrated that, in women with adenomyosis who complained of excessive MBL, the lesional stiffness, as measured by transvaginal ultrasonic elastography, is significantly higher than in those who complained of moderate–heavy MBL (Huang et al. 2022a). Consistent with the increased lesional stiffness, the extent of lesional fibrosis and the extent of tissue fibrosis in neighboring EMI and eutopic endometrium are also significantly higher. In addition, in adenomyotic lesions and their neighboring EMI and eutopic endometrial tissues, the expression of HIF-1α, COX-2, EP2, and EP4 is significantly reduced, concomitant with increased tissue fibrosis (Huang et al. 2022a ).
These findings strongly indicate reduced hypoxia and reduced PGE2 production and signaling in adenomyosis lesions, as well as in their neighboring EMI and endometrial tissues, as lesions become highly fibrotic. This reduced hypoxia and PGE2 signaling appears to be first initiated presumably in adenomyosis lesions and then propagates to their neighboring EMI and then eutopic endometrium. Given the recent report that adenomyosis lesions are directly connected with their neighboring endometrial glands (Yamaguchi et al. 2021), this propagation could conceivably be conducted through cellular communications in a paracrine or autocrine manner. There is an apparent gradient in the extent of tissue fibrosis, with the adenomyosis lesion having the highest fibrotic content, followed by EMI and then endometrium, suggesting that the progression of adenomyotic lesions impacted the same signaling pathways in both EMI and eutopic endometrium (Huang et al. 2022a). In light of the well-documented role of PGE2 and hypoxia signaling pathways in endometrial repair and HMB (Critchley et al. 2006, Maybin et al. 2011, 2018), these data strongly suggest that the increased lesional fibrosis may contribute to disturbed PGE2 signaling in eutopic endometrium and thus possibly reduced hypoxia necessary for endometrial repair, leading to HMB in women with adenomyosis.
Recent investigations further reveal that glycolysis plays an important role in endometrial repair, and decreased glycolysis at menstruation impairs endometrial repair, causing HMB (Mao et al. 2022). This is not surprising, considering that a complete endometrial repair would require, by necessity, increased (but transitory) inflammation, followed by cellular proliferation and angiogenesis (Critchley et al. 2020) – all of which require obligatorily more nutrients and energy expenditure (Vinaik et al. 2020), with the goal of a full repair to prepare for endometrial differentiation and decidualization that set the stage for possible pregnancy. Somehow, endometrium would modulate their cellular bioenergetics in response to increased demands and shift to glycolysis-based metabolism. Glycolysis has several distinct advantages over more traditional metabolism through oxidative phosphorylation (OXPHOS): first, it produces the energy currency ATP faster in a given time span despite lower efficiency in one cycle, as well as macromolecules necessary for fast dividing cells and, simultaneously, reduced oxidative stress. The anabolic pathways branching out from the glycolytic sequence produce the intermediate products necessary for cellular proliferation, including amino acids and lipid precursors (Levine & Puzio-Kuter 2010, Cairns et al. 2011). Consequently, fast proliferating endometrial cells can increase the availability of macromolecules for growth needs through glycolysis by facilitating glucose uptake and slowing the entry of pyruvate into mitochondria (Vander Heiden et al. 2009). Secondly, glycolysis can offer much needed protection against oxidative stress (Cairns et al. 2011) by reducing reactive oxygen species (ROS) – common byproducts of OXPHOS and through re-channeling glycolytic intermediates into the pentose phosphate pathway (PPP) that generates essential nucleotide precursors and at the same time reduces nicotinamide adenine dinucleotide phosphate hydride that is necessary for the activity of antioxidant enzymes. Excessive ROS and/or impaired ROS detoxification cause oxidative damage and are thus detrimental to cells and thus to tissue repair (Cano Sanchez et al. 2018) and conceivably can compromise or impair normal endometrial repair.
Since HIF-1α can regulate its target genes involved in glycolysis, including genes encoding for key enzymes in the glycolysis such as glucose transporter 1 (GLUT1), pyruvate kinase isoform M2 (PKM2), lactate dehydrogenase A (LDHA), hexokinase 2 (HK2), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) (Semenza 2013, Xie et al. 2019, Zhang et al. 2019, Wu et al. 2020), the reduced hypoxia signaling in endometrium resulting from fibrotic adenomyotic lesions (Huang et al. 2022a) conceivably can impair glycolysis and, as such, impair endometrial repair and cause adenomyosis-induced HMB (Mao et al. 2022).
The possible mechanisms underlying adenomyosis-associated HMB are depicted in Fig. 3. Note that since tissue factor is overexpressed in adenomyosis (Liu et al. 2011), patients may also exhibit hypercoagulability as in endometriosis (Wu et al. 2015, Ding et al. 2018), causing HMB.
Diagram depicting possible mechanisms of adenomyosis-associated heavy menstrual bleeding (HMB). Increasing lesional fibrosis would propagate to neighboring endometrial–myometrial interface and then eutopic endometrium, attenuating the PGE2 and hypoxia signaling by downregulation of COX-2, EP2, 4, and HIF-1α. As a result, glycolysis, which is vital for normal endometrial repair, is impaired, resulting in reduced supply of energy and macromolecules and reduced inflammation necessary for endometrial repair. Collectively, reduced PGE2 and hypoxia signaling, in conjunction with diminished supply of energy and macromolecules and attenuated inflammation, results in impaired endometrial repair and, as such, HMB. The upward arrows indicate upregulation/overexpression or increase. The directional arrows mean ‘lead to’ or ‘result in’.
Citation: Reproduction 164, 5; 10.1530/REP-22-0224
These findings provide a good explanation as to why different subtypes of adenomyosis have different symptoms. Indeed, one early study reported that shallower penetration of adenomyosis lesions into the myometrium was associated with higher incidence of HMB (Bird et al. 1972). This is because adenomyosis lesions that are closer to the endometrium are more likely than those more distant ones to cause HMB as lesions progress, simply because of the ease of propagation due to physical proximity. They also explain why internal adenomyosis is more likely to be associated with HMB while external adenomyosis is more often associated with deep endometriosis (and thus pain) (Bourdon et al. 2021).
It is also possible that HMB could further exacerbate endometrial repair impairment as bleeding may cause local iron overload, which may attenuate the proliferation of endometrial stromal cells by inducing autophagy (Zhou et al. 2022) and thus exacerbating impaired endometrial repair. Of course, whether this is true would await further investigation.
Pain
Among all complaints from women with adenomyosis, dysmenorrhea and other types of pain top the list of complaints and are the most debilitating that substantially and significantly reduced the quality of life in affected women. According to the recently revised definition by the International Association for the Study of Pain, pain is ‘an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage’ (Raja et al. 2020). As such, pain is always a personal experience, influenced, to varying degrees, by not only biological but also a myriad of psychological and social factors (Vader et al. 2021). In addition, pain, which is always subjective, and nociception, which could be quantitated, are different phenomena, and the former cannot be inferred exclusively from activity in sensory neurons (Vader et al. 2021).
With this understanding, it is then easy to understand why there is no direct correlation between the disease stage and severity of pelvic symptoms in women with endometriosis (Vercellini et al. 2007), and likely in women with adenomyosis as well. Indeed, with a kaleidoscopic variation in subtype (internal, external, intramural, or unclassified, or focal vs diffuse), size, depth of infiltration, presence or absence of adhesion, and co-occurrence with or without endometriosis, uterine fibroids or other co-morbidity, on top of age, phase of menstrual cycle, gravidity, parity, hormonal status, and previous history of uterine surgery, along with different developmental trajectories including, but not limited to, in utero and early childhood development that may shape one’s neuronal wiring and pain threshold, variation in symptomology and severity is something to be expected. This is especially true that adenomyosis-associated pain may be accompanied by histological changes in the CNS, as shown in endometriosis (As-Sanie et al. 2012, 2016).
However, since adenomyosis is known to be associated with dysmenorrhea and other types of pain, it must have certain attributes that induce these pain behaviors. In addition, the disease stage or lesion type may not fully capture the essence of an adenomyotic lesion. For example, if we quantitate the extent of lesional fibrosis, then we can find its correlation with the severity of dysmenorrhea (Nie et al. 2022), albeit imperfect correlation.
There are several attributes that are known to contribute to dysmenorrhea and other types of pain in women with adenomyosis. First, the myometrium of women with adenomyosis exhibits elevated expression of OTR, which can result in increased frequency and magnitude of uterine contractions (Nie et al. 2010, Guo et al. 2013). As eluded to above, the newly formed SMCs, differentiated from FMT and SMM, would be fused into existing myometrium, and this is likely to cause irregular contractions (Guo et al. 2013), possibly akin to spams. Of course, adenomyotic lesions may also secrete certain molecules that facilitate the proliferation of myometrial SMCs (Huang et al. 2021a,b, Wang et al. 2021c). Irrespective of sources, there is a net increase in myometrial SMCs, leading to uterine enlargement. This, coupled with hyperinnervation in endometrium and myometrium (Wang et al. 2009a,b, Zhang et al. 2010, Choi et al. 2015) as well as reduced suppression of the transfer of nociceptive signals to the CNS in adenomyosis (Chen et al. 2014), would easily entail patients to perceive dysmenorrhea.
Secondly, adenomyotic lesions may secrete neurotrophic factors that promote hyperinnervation. These factors include neurotrophins such as NGF and its receptor TrkA, brain-derived neurotrophic factor (BDNF) and its receptor TrkB, neurotrophin-3 (NT-3) which binds to TrkC, and neurotrophin-4/5 (NT-4) which also binds to TrkB. All these neurotrophins can bind to p75. These factors support and direct neuritogenesis.
Mouse models of adenomyosis show elevated expression of NGF and its high-affinity receptor p75 and low-affinity receptor TrkA in lesions, eutopic endometrium, and myometrium (Green et al. 2003, Li et al. 2011, Barcena de Arellano et al. 2012, Carrarelli et al. 2017). In particular, adenomyotic stromal cells secrete NGF (Li et al. 2015). TrkA expression is also found to be elevated in dorsal root ganglia from mice with induced adenomyosis (Li et al. 2011). However, there is also a study reporting no difference in the expression of NGF, NT-3, and p75 in eutopic endometrium and myometrium (Barcena de Arellano et al. 2012).
Ectopic endometrial stromal cells are known to secrete thromboxane A2 (TXA2) that induces neurite outgrowth (Yan et al. 2017a). In patients with adenomyosis who were treated with levonorgestrel-releasing intrauterine system (LNG-IUS), the expression of NGF and its cognate receptors p75 and TrkA in endometrium and myometrium was significantly decreased as compared to those of hormonally untreated patients (Choi et al. 2010).
Lastly, it is likely that women with adenomyosis may exhibit central sensitization as in those with endometriosis (He et al. 2010). Thus, once there is central sensitization, any stimulus, be it noxious or innocuous, would easily elicit the perception of pain.
Overall, however, our understanding on the mechanisms underlying adenomyosis-associated pain is still fragmentary. For example, transient receptor potential vanilloid type 1 (TRPV1), a pain signal integrator, is reported to be highly expressed in adenomyotic lesions (Nie et al. 2010). But what kind of role TRPV1 plays in adenomyosis-associated pain is largely unknown since TRPV1 is typically expressed in primary nociceptive nerves such as Aδ- and C-fibers, serving as a sensor of noxious stimuli. In addition, whether nerves and adenomyotic lesions form a partnership in facilitating lesional progression, as in endometriosis (Yan et al. 2017b), has not been fully elucidated. We recently reported that certain neuropeptide receptors, such as NK1R (receptor for substance P), receptor activity modifying protein 1 (RAMP-1) and calcitonin receptor-like receptor (CRLR), the two receptors for CGRP, and neurotransmitter receptor ADRB2 are all elevated in adenomyotic lesions (Xu et al. 2021). In contrast, the expression of α7 nicotinic acetylcholine receptor (α7nAChR) is reduced (Xu et al. 2021). Given the report that women with endometriosis have reduced vagal tone (Hao et al. 2021) and α7nAChR activation appears to be therapeutic (Hao et al. 2022), it seems that a great deal of work is still needed to unravel the mystery of adenomyosis-associated pain.
Clinical significance
Imaging diagnosis
In the last three decades, MRI and ultrasound have gradually become the mainstay for the diagnosis of adenomyosis, completely replacing histological evaluation following hysterectomy as the main diagnostic tool. In particular, overall, transvaginal ultrasound (TVUS) and MRI have similar diagnostic sensitivity and specificity (Chapron et al. 2020), although the latter is less operator-dependent, more subjective, and relies less on the capacity of the observer to diagnose. However, TVUS remains to be the first-line technique in gynecological work-up because it is widely available, easier than MRI to operate but less expensive than MRI, and also allows a dynamic examination to explore organ mobility and site-specific tenderness.
Thus, both TVUS and MRI are excellent imaging modalities for diagnosing adenomyosis. However, there is still ample room for improvement in terms of diagnostic accuracy. In addition, neither of the two imaging modalities produces features that directly correlate with the severity of symptoms and the response to hormonal treatment or prognosis (Chapron et al. 2020, Habiba et al. 2020) and neither of them is helpful in predicting the response to hormonal treatment. Moreover, no universally accepted classification system exists (Gordts et al. 2008, 2018, Habiba et al. 2020).
As alluded to above, fibrosis is one important pathognomonic feature of adenomyosis, as in endometriosis (Guo 2018b, Vigano et al. 2018). Incidentally, uterine fibroids also have excessive ECM deposition (Stewart 2015). The extent of fibrosis in either adenomyosis or fibroids can conceivably determine the lesional stiffness or rigidity, which could be evaluated by palpation through tissue deformation. Hence, lesional stiffness contains information inherently embedded within adenomyotic lesions, revealing just how advanced the lesion is. Unfortunately, neither TVUS nor MRI can directly measure the lesional stiffness.
Elastography is an emergent imaging technology that recently becomes commercially available. It generates images of tissue stiffness, by ultrasound elastography (UE) (Cui et al. 2022) or magnetic resonance elastography (MRE) (Mariappan et al. 2010). Thus, it is akin to the traditional palpation in clinical examination but it is less subjective, requires little experience, and provides better spatial localization information (Shiina et al. 2015). As of now, the application of MRE in gynecology has been scanty, but UE has been gaining tracks in gynecology. Perhaps, the greatest advantage of elastography is that it has a much wider dynamic range than CT, ultrasound, and MRI (Mariappan et al. 2010).
UE has been shown to be used to diagnose adenomyosis (Liu et al. 2018a) and deep endometriosis (Ding et al. 2020). Remarkably, the average lesional stiffness in adenomyosis is significantly higher than that of uterine fibroids, which, in turn, is higher than normal myometrium (Liu et al. 2018a). More importantly, lesional stiffness as measured by UE correlated positively with the extent of lesional fibrosis and negatively with lesional staining levels of PR and vascularity (Liu et al. 2018a, Ding et al. 2020). Thus, once lesional stiffness is quantitated by UE, the possible lesional response to hormonal treatment can be determined, since lower PR expression is associated with poor response to progesterone treatment (Flores et al. 2018). Preliminary data show that women with ‘soft’ lesions are more likely to respond to dienogest treatment (Ding et al. unpublished data). Therefore, UE can not only improve diagnostic accuracy but, more importantly, help physicians to decide on the best treatment modality.
Development of novel therapeutics
While hysterectomy is a definitive treatment for adenomyosis, whether or not to undergo this procedure can be an agonizing and difficult decision to make for women who wish to preserve their fertility or hold the view that uterus is an iconic symbol of womanhood. Total hysterectomy is also reported to increase the risk of cardiovascular disease, depression, and dementia (Madueke-Laveaux et al. 2021). Traditionally, progestins, oral contraceptives, LNG-IUS, and GnRH agonists, along with uterine artery embolization (UAE) and conservative surgery involving endomyometrial ablation, laparoscopic myometrial electrocoagulation or excision were the mainstay therapeutics (Wood 2001). Fortunately, the arsenals for combating adenomyosis have been expanded greatly during the last decade. There are several excellent reviews on this topic already (Vannuccini et al. 2018, Cope et al. 2020, Stratopoulou et al. 2021a).
While hormonal drugs are the mainstay of current therapeutics, a recent survey of 1420 patients with endometriosis in Austria, Germany, and Switzerland found that an overwhelming proportion of them hold a negative attitude toward hormonal drugs, and the majority of them disliked the side effects of these drugs, especially amongst young, city-dwelling, educated women (Burla et al. 2021). Remarkably, 95.3% of the surveyees expressed preference for plant-based products, preferably in oral form (Burla et al. 2021). This demand contrasts sharply with resounding failure in clinical trials on non-hormonal drugs in endometriosis and adenomyosis (Guo & Evers 2013, Guo 2014) and highlights the medical need that has not been fulfilled.
As of writing, 83 clinical trials on adenomyosis have been registered at ClinicalTrials.gov (accessed on June 23, 2022). With only two exceptions (NCT01821001 and NCT03749109), all trial drugs are hormonal. Trial NCT01821001 is on the use of vaginal ring containing bromocriptine, a DRD2 agonist. A pilot study found that this therapy is effective in improving HMB and dysmenorrhea in women with adenomyosis (Andersson et al. 2019). A recent study on 18 patients with diffuse adenomyosis who complained of HMB also reports that treatment with vaginal bromocriptine for 6 months resulted in a significant decrease in JZmax and a reduced number of women with asymmetric myometrial wall thickness as evaluated by ultrasound (Andersson et al. 2020). Another trial (NCT03749109) on the use of vaginal ring containing Quinagolide, also a DRD2 agonist, to treat adenomyosis is recently completed (www.ClinicalTrials.gov, accessed on September 9, 2022) but not yet published as of writing.
While the mechanism of action for bromocriptine has been thought to suppress prolactin (Cope et al. 2020), there could be some other possible mechanisms. Chronic stress can activate the HPA/SAM axes, causing the release of adrenaline and noradrenaline, which, in turn, can activate the expression of ADRB2 and suppress DRD2 expression in endometriosis (Guo et al. 2017), and possibly in adenomyosis as well. Dopamine or DRD2 agonists could block the stress-facilitated angiogenesis and proliferation of adenomyotic cells, as in cancer (Moreno-Smith et al. 2011, 2013). Alternatively, DRD2 agonists may be anti-fibrotic (Jiang et al. 2014, Han et al. 2015) and thus can stall lesional fibrogenesis. Indeed, DRD2 can act as a negative regulator of inflammation (Zhang et al. 2012, Jiang et al. 2014). Incidentally, increased local prolactin production is also seen in uterine fibroids, which may stimulate transdifferentiation of myometrial cells to myofibroblasts, which, in turn, promotes fibrogenesis in fibroids (DiMauro et al. 2022). Taken together, the mechanisms of action for DRD2 agonists seem to be in need of further elucidation.
Given the role of platelets in the development of adenomyosis (Liu et al. 2016b, Shen et al. 2016, Zhang et al. 2016), anti-platelet therapy has been proposed and shown to be promising in mouse with induced adenomyosis (Zhu et al. 2016). In addition, since andrographolide is known to be anti-platelet (Lu et al. 2011), it has been proposed as a potential therapeutics (Li et al. 2013), and its clinical use appears to be very encouraging (Liu et al. 2015). Moreover, many compounds that are extracted from traditional Chinese medicine herbs, such as resveratrol, scutellarin, tanshinone IIA, quercetin, leonurine, and tetramethylpyrazine, all share the commonality of being anti-platelet or anti-thrombotic, and they have demonstrated promising potential in mouse models of endometriosis and adenomyosis (Zhu et al. 2015, Nie & Liu 2017a,b, Nie et al. 2018, Ding et al. 2019, Luo et al. 2020, Huang et al. 2022c).
Similar to endometriosis, adenomyosis has many epigenetic aberrations (Liu & Guo 2012, Liu et al. 2012). Based on the desirable effect of histone deacetylase inhibitors in ectopic endometrium (Wu & Guo 2006, 2007, Wu et al. 2007, Liu & Guo 2011, Mao et al. 2011), a pilot clinical study reported on the use of valproic acid (VPA) to treat adenomyosis (Liu & Guo 2008). An expanded case series also provided encouraging results (Liu et al. 2010b). Unfortunately, since clinical trials typically demand a great deal of resources, further research in this direction has not been continued. Incidentally or not, VPA also possesses anti-platelet and anti-fibrotic capabilities (Larsson et al. 2016, Costalonga et al. 2017).
In endometriosis area, many drug trials fail simply because of safety concerns (e.g. ulipristal and AKR1C3 inhibitor) (Guo 2014, Saunders & Horne 2021). Yet, many anti-platelet compounds extracted from herbs, such as tanshinone IIA, quercetin, and tetramethylpyrazine, are known to have excellent safety profiles. For example, both tanshinone IIA and tetramethylpyrazine are officially listed in the Chinese Pharmacopoeia for the treatment of menstrual disorders and blood circulation diseases and prevention of inflammation (Kuang et al. 2005). It may be desirable to select those compounds that are, first, known to be safe and target known molecular pathways in the development of adenomyosis.
Conclusions
Adenomyosis has been traditionally viewed as an enigmatic disease and, as such, defying effective management. Fortunately, research published in the last decade has helped us to unveil some pathogenesis and pathophysiology of the disease. We now know that EMID can increase the risk of adenomyosis, and Schwann cells within the EMI may play an important role. In addition, the pathogenesis of adenomyosis is surely multifactorial, and EMID is just one such cause.
We also have a fairly good grip on the natural history of adenomyotic lesions by now through the identification of several underlying key molecular processes such as EMT, FMT, SMM, and fibrogenesis. This knowledge also led to our better understanding of adenomyosis-associated HMB. Along the way, we have learned several important lessons from this investigation: (1) lesional progress is a dynamic process; (2) cell identity within lesions is not immutable; and (3) lesional microenvironment is also important for lesional progression – many cells within the microenvironment also participate in lesional progression. Of course, there are still many t’s that need to be crossed and many i’s need to be dotted. Nonetheless, this skeletal knowledge has helped us to piece together many observations that are seemingly unrelated and to capitalize on emerging imaging technology such as elastography for better diagnosis of the disease. The addition of elastographic information on adenomyosis and on co-existent pathology should help to enhance the future classification system for adenomyosis. The development of novel therapeutics would take time, but the grip of the natural history of ectopic endometrium has already helped us understand why clinical trials on endometriosis/adenomyosis fail (Guo & Groothuis 2018).
Of course, there is still a long way to go before the day when a precision medicine approach can effectively alleviate adenomyosis-associated symptoms and when a safe preoperative or perioperative intervention can be instituted to mitigate or even eliminate the risk of adenomyosis. Until then, effects on molecular, genetic/epigenetic, clinical, and epidemiologic investigation on adenomyosis need to be doubled down.
Declaration of interest
S W G provided consultancy advice for MSD R&D, Chugai Pharmaceutical Co., and BioHaven Pharmaceuticals, but these activities had no bearing on this work.
Funding
This study was funded in part by grant 82071623 from the National Natural Science Foundation of China, an Excellence in Centers of Clinical Medicine grant (2017ZZ01016) from the Science and Technology Commission of Shanghai Municipality, and Clinical Research Plan grant SHDC2020CR2062B from Shanghai Shenkang Center for Hospital Development.
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