Expression profiles of E/P receptors and fibrosis in GnRHa-treated and -untreated women with different uterine leiomyomas

Abstract

Differential expressions of estrogen/progesterone receptors (ER/PR) and individual component of extracellular matrices derived from fibroid are reported. Information on the pattern of change in ER/PR expression and amount of tissue fibrosis after hormonal treatment is unclear. We investigated pattern of change in ER/PR expression and percentage of tissue fibrosis in different uterine leiomyomas after gonadotropin-releasing hormone agonist (GnRHa) treatment. Biopsy specimens from fibroids and adjacent myometria were collected after surgery from women with submucosal myoma (SMM, n = 18), intramural myoma (IMM, n = 16) and subserosal myoma (SSM, n = 17). A proportion of women in each group of fibroid underwent treatment with GnRHa for a variable period of 3–6 months. Tissue expression of ER and PR was analyzed by immunohistochemistry. In vitro cell proliferation effect of GnRHa on human umbilical vein endothelial cells (HUVECs) was examined. Distribution of tissue fibrosis was examined by Masson’s trichrome staining with computer-captured image analysis of fibrosis derived from different types of fibroid. PR content was significantly higher than ER in tissues derived from GnRHa-untreated women with SMM and SSM (p = 0.04 for both). Comparing to untreated group, GnRHa-treatment significantly decreased either ER or PR expression in different fibroids. Exogenous treatment with GnRHa dose-dependently decreased proliferation of HUVECs. No significant difference was observed in the percentage of fibrosis in tissues collected from GnRHa-treated and -untreated women with fibroids. The distribution of fibrosis in myoma/myometria and occurrence of fibrosis in perivascular area showed an increasing trend with higher age of the women and with larger size of fibroids. Our findings suggest that despite estrogen dependency, higher PR content in GnRHa-untreated group may indicate a potential role of progesterone in leiomyoma growth. Although GnRHa therapy may shrink fibroids and reduce risk of bleeding during surgery, the occurrence of diffuse tissue fibrosis may impair effective reduction of fibroid size after hormonal treatment.

Markers of Cellular Proliferation, Apoptosis, Estrogen/Progesterone Receptor Expression and Fibrosis in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids

“…Some studies demonstrate increased numbers of ERs in leiomyomas [ 17 , 18 ], while other argue against it [ 19 , 20 , 21 ]. In their most recent study, Khan et al observed that in the tissue of untreated uterine myomas, PR content was significantly higher than that of ER and that gonadotropin-releasing hormone agonist (GnRHa) treatment can significantly decrease both ER and PR expression in fibroids [ 22 ]. To date, data on the effects of SPRM on the expression of estrogen and progesterone receptors in myomas remain scanty and somewhat ambiguous.…”

“…It has been argued that antifibrotic agents could be a therapeutic target, limiting leiomyoma growth and associated clinical symptoms [ 31 , 32 ]. Khan et al indicated that in case of the implementation of GnRHa therapy, the occurrence of diffuse fibrosis in myomas may impair the effectiveness of this hormonal treatment [ 22 ]. Recent studies proved a dose-dependent inhibition of leiomyoma fibrosis treated with ulipristal acetate [ 26 ].…”

Levofloxacin or gonadotropin releasing hormone agonist treatment decreases intrauterine microbial colonization in human endometriosis

“…Addition of an antimicrobial agent may also reduce the risk of subsequent occurrence or recurrence of endometriosis once GnRHa treatment is stopped thereby may improve reproductive outcome in women with endometriosis. In clinical practice, GnRHa is commonly used for the alleviation of pain, decreasing the risk of intraoperative bleeding and/or for reducing the size of ovarian endometrioma and uterine myoma [14]. This hypothesis is supported by one recent study using animal model of endometriosis.…”

Dietary Natural Compounds and Vitamins as Potential Cofactors in Uterine Fibroids Growth and Development

“…Some data suggest that Vitamin D supplementation reduces leiomyoma cell proliferation and thus prevents leiomyoma growth [56,[69][70][71]. A significant downregulation of ER-α, PR-A, PR-B, and steroid receptor coactivators in human myoma cells may be one of the mechanisms-an effect similar to that observed during the course of hormone therapy with GnRH analogues and ulipristal acetate (UPA) [50,72,73]. Halder et al and Li et al point to the antifibrotic activity of Vitamin D [74,75].…”