Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

Abstract

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

Establishment of Adenomyosis Organoids as a Preclinical Model to Study Infertility

“…Adenomyosis is a benign uterine disease affecting 35% of women of reproductive age [1], characterized by invagination of endometrial glands and stroma into the myometrium [2]. Many mechanisms have been postulated to be involved in adenomyosis' development and its associated symptoms, such as altered sex steroid signaling, excessive proliferation and invasiveness of the endometrium, and an abnormal immune response [3]. To date, the exact trigger of the disease is not known but there are two main hypotheses that attempt to explain adenomyosis origin [4,5].…”

“…Local inflammation [24], oxidative stress [25], impaired vascularization [26], hyperestrogenism [27], and epithelial-mesenchymal transition (EMT) [28] may be mechanisms involved in adenomyosis pathogenesis. Steroid hormones disruption, particularly hyperestrogenism, which ultimately results in progesterone resistance, are known to play a key role in its pathogenesis [3,27]. Since many of the mechanisms involved in the pathogenesis of adenomyosis are driven by estrogen upregulation, adenomyosis is widely known as an estrogen-dependent disease [27].…”

Conservative Management of Uterine Adenomyosis: Medical vs. Surgical Approach

“…While not yet registered for clinical use against symptomatic adenomyosis, oral GnRH antagonists constitute an attractive option, increasingly gaining the interest of the medical community and yielding promising results in preliminary studies [ 49 , 50 ]. These molecules antagonize GnRH binding to its receptors, leading to dose-dependent suppression of FSH and LH and a subsequent decline in ovarian steroids [ 15 , 41 ].…”

Linzagolix: First Approval

“…Estradiol, which is recognised to have proinflammatory and antiapoptotic effects on ectopic endometrial cells, is required for proliferation of endometriotic deposits [ 5 ]. Consequently, lowering levels of circulating estrogens is an effective medical approach [ 6 , 7 ]. Although the pathogenesis of uterine adenomyosis is not fully understood [ 8 ], estrogens are thought to have an important role in its development.…”