Adenomyosis and its impact on women fertility

Abstract

Adenomyosis is a widespread disease affecting the reproductive period of women's life. In the last ten years, different pathogenetic hypotheses have been proposed to explain the initiation and development of the disease. This article aims to present and discuss the most important pathophysiologic mechanisms underlying adenomyosis development in order to clarify the relationship between adenomyosis and infertility. A PubMed search was undertaken for English language literature using the MeSH terms 'adenomyosis', 'infertility', 'treatment', and 'pathogenesis'. Although the exact etiology of adenomyosis is unknown, many theories have been proposed. We analysed the most important pathogenic theories expressed and evaluated the potential consequences on women fertility. A better comprehension of the adenomyosis pathogenesis has allowed realizing that adenomyosis may affect young women and may have a great impact on their fertility through different mechanisms. The understanding of these mechanisms helps to clarify the potential usefulness of current therapies.

Keywords: Adenomyosis; Hyperestrogenism; Infertility; Pathogenesis; Treatment.

Figure 1

First step: micro-traumatization. The uterus is constantly active thereby subjected to mechanical strain. Molecular mechanisms associated with mechanical strain, injury, and repair displays a pattern which involves the expression of the P450 aromatase and the local production of estrogen. It was suggested that this uterine dysfunction in women with endometriosis and adenomyosis is a result of archimetral hyperestrogenism which leads to increased uterine peristaltic activity of the subendometrial myometrium. Deviations from the normal cyclic endocrine pattern with increases or prolongations of E₂ stimulation of uterine peristalsis could impose supraphysiological mechanical strain on the cells near the fundo-cornual raphe activating the TIAR system focally with increased local production of E₂

Figure 2

TIAR system: The mechanism of tissue traumatization and healing is associated with a specific physiological process that involves the local production of Interleukin-1-(IL-1). IL-1-induced activation of the cyclooxygenase-2 enzyme (COX-2) results in the production of prostaglandin E₂ (PGE2), which in turn activates STAR (steroidogenic acute regulatory protein) and the P450 aromatase. Thus, testosterone can be formed and aromatized into E₂ that exerts its proliferative and healing effects via the ER2. Hyperperistalsis would constitute a mechanical trauma resulting in an increased desquamation of fragments of basal endometrium and, in combination with an increased retrograde uterine transport capacity, in enhanced transtubal dissemination of these fragments. Hyperperistalsis and increased intrauterine pressure would with time, result in myometrial dehiscences that are infiltrated by basal endometrium with the secondary development of peristromal muscular tissue

Figure 3

Hyperestrogenism and infertility (A): the TIAR system causes an over-production of PGE2 with an increase in local estrogen concentrations. This may explain the high comorbidity between adenomyosis and endometrial polyps, myomas, endometrial hyperplasia and endometriosis, that in their turn is a cause of female infertility too

Figure 4

Hyperestrogenism and infertility (B): The increase in PGE-2 and estrogens may lead also to uterine hyper-peristalsis, which has two consequences: an alteration in tubal sperm transportation and an alteration of embryonic implantation. The increase in PGE2 production could also explain the increase risk of preterm delivery in patients with adenomyosis