The pathophysiology of endometriosis and adenomyosis: tissue injury and repair

Abstract

Introduction: This study presents a unifying concept of the pathophysiology of endometriosis and adenomyosis. In particular, a physiological model is proposed that provides a comprehensive explanation of the local production of estrogen at the level of ectopic endometrial lesions and the endometrium of women affected with the disease.

Methods: In women suffering from endometriosis and adenomyosis and in normal controls, a critical analysis of uterine morphology and function was performed using immunohistochemistry, MRI, hysterosalpingoscintigraphy, videohysterosonography, molecular biology as well as clinical aspects. The relevant molecular biologic aspects were compared to those of tissue injury and repair (TIAR) mechanisms reported in literature.

Results and conclusions: Circumstantial evidence suggests that endometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of 'tissue injury and repair' (TIAR). This results in the local production of estrogen. With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues. In most cases of endometriosis/adenomyosis, a causal event early in the reproductive period of life must be postulated leading rapidly to uterine hyperperistalsis. In late premenopausal adenomyosis, such an event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life leads to the same extent of microtraumatization. With the activation of the TIAR mechanism followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principle the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of 'tissue injury and repair' (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary.

Fig. 1

Modified original drawing from Werth and Grusdew [9] showing the architecture of the subendometrial myometrium (archimyometrium) in a human fetal uterus. The specific orientation of the circular fibers of the archimyometrium results from the fusion of the two paramesonephric ducts forming a fundo-cornual raphe in the midline (dashed rectangle). The peristaltic pump of the uterus, which is continuously active during the menstrual cycle, is driven by coordinated contractions of these muscular fibers. Directed sperm transport into the dominant tube is made possible by differential activation of these fibers. The fundo-cornual raphe constitutes a region of increased mechanical strain and tissue injury followed by local estrogen production. By the time muscular distensions at the fundo-cornual raphe result in the formation of gaps that result in endometrial proliferation into these dehiscences

Fig. 2

Examples of uterine adenomyosis in six patients as presented by magnetic resonance imaging (MRI). Representative sagittal and coronary scans are shown. In the infertile, non-parous women (a–e) (30–32 years of age) pelvic endometriosis of grade I–IV was demonstrated by laparoscopy. In the parous woman (f) (40 years of age) no laparoscopy was performed. In all scans preponderance of the adenomyotic lesions (expanded junctional zone) in the midline close to the fundo-cornual raphe of the archimyometrium can be demonstrated. In the first three scans (a–c) the diagnosis of adenomyosis would not meet the established radiologic criteria for MRI. In a scientific context, however, the irregularities of the junctional zone are characteristic of beginning adenomyosis

Fig. 3

The basic aspects of the molecular biology of the physiological mechanism of ‘tissue injury and repair’ (TIAR) as demonstrated in mesenchymal tissue such as astrocytes, tendons, and cartilage

Fig. 4

Model of ‘tissue injury and repair’ (TIAR) on the level of the endometrial–myometrial interface at the fundo-cornual raphe. The mechanisms of first and second step injury are depicted. Persistent uterine peristaltic activity and hyperperistalsis are responsible for perpetuation of injury with permanently increased paracrine estrogen action

Fig. 5

Model of the pathophysiology of endometriosis and adenomyosis. Tissue injury in the depth of the endometrium and the activation of the TIAR system constitute the primum movens in the disease development. This pertains to spontaneously developing andometriosis/adenomyosis as well as to that induced by iatrogenic trauma. The dashed rectangle depicts the extra uterine sites of the disease process