Human myometrium and leiomyomas express gonadotropin-releasing hormone 2 and gonadotropin-releasing hormone 2 receptor

Parker, Jason; Malik, Minnie; Catherino, William H.

doi:10.1016/j.fertnstert.2006.11.098

Cited by 23 publications

(26 citation statements)

References 54 publications

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“…A recent study demonstrated that leuprolide acetate may act directly on fibroids by an increase in the ECM genes, COL1A1, fibronectin, and veriscan variant 0, followed by return to normal after five days of treatment (as discussed by [80]). These findings were supported by the presence of GnRH receptors in uterine fibroid and subject-matched myometrium (as discussed by [81]). Similar to the concept of reciprocity for mechanical stress, hydration of the ECM requires an osmotic response regulated by the transcription factor, nuclear factor of activated T cells-5 (NFAT5) that coordinates expression of hyperosmolarity response genes, such as aldose reductase and sodium myoinositol transporter 1 (SMIT), all of which were increased in fibroid cells, compared to myometrial cells (as discussed by [82]).…”

Section: Extracellular Matrix Of Uterine Fibroidssupporting

confidence: 57%

The Extracellular Matrix Contributes to Mechanotransduction in Uterine Fibroids

Leppert

Jayes

Segars

2014

Obstetrics and Gynecology International

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The role of the extracellular matrix (ECM) and mechanotransduction as an important signaling factor in the human uterus is just beginning to be appreciated. The ECM is not only the substance that surrounds cells, but ECM stiffness will either compress cells or stretch them resulting in signals converted into chemical changes within the cell, depending on the amount of collagen, cross-linking, and hydration, as well as other ECM components. In this review we present evidence that the stiffness of fibroid tissue has a direct effect on the growth of the tumor through the induction of fibrosis. Fibrosis has two characteristics: (1) resistance to apoptosis leading to the persistence of cells and (2) secretion of collagen and other components of the ECM such a proteoglycans by those cells leading to abundant disposition of highly cross-linked, disoriented, and often widely dispersed collagen fibrils. Fibrosis affects cell growth by mechanotransduction, the dynamic signaling system whereby mechanical forces initiate chemical signaling in cells. Data indicate that the structurally disordered and abnormally formed ECM of uterine fibroids contributes to fibroid formation and growth. An appreciation of the critical role of ECM stiffness to fibroid growth may lead to new strategies for treatment of this common disease.

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Section: Extracellular Matrix Of Uterine Fibroidssupporting

confidence: 57%

The Extracellular Matrix Contributes to Mechanotransduction in Uterine Fibroids

Leppert

Jayes

Segars

2014

Obstetrics and Gynecology International

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“…These menopause-like symptoms limit applicability to short-term therapy. Prior studies have demonstrated extrahypothalamic presence of GnRH receptors in mammalian reproductive tissues (33,34), and in uterine leiomyoma tissues (18,35). These findings suggest that GnRH-a could be used locally to avoid systemic morbidity.…”

Section: Discussionmentioning

confidence: 76%

“…Analysis of microarray data, confirmed by quantitative real-time polymerase chain reaction (PCR) and immunohistochemical studies, reveal the expression of GnRH receptors in leiomyoma and patient-matched myometrium (18). The presence of receptors for GnRH hormones in leiomyomas is further evidenced by the direct regulation of GnRH analogues (GnRH-a) on leiomyoma cell ECM gene expression and protein production in culture (19).…”

mentioning

confidence: 94%

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Malik

Britten

Cox

et al. 2016

Fertility and Sterility

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This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy.

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“…Direct activation of the GnRH receptors onˆbroids is presumed to be involved inˆbroid shrinkage. 17 Crow and colleagues suggested that response to GnRHa treatment is aŠected by other histopathological features, including rate of cell proliferation, degree of in‰ammatory cell inˆltration, and density of estrogen receptors. 18 These factors may work to change vascularity as well as volume of theˆbroid, which could make it more di‹cult to predict AUC reduction.…”

Section: Discussionmentioning

confidence: 99%

Reduction in the Vascular Bed Volume of Uterine Fibroids after Hormonal Treatment: Evaluation with Dynamic Double-Echo R2* Imaging

et al. 2012

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Purpose: To demonstrate the reduction in vascular bed volume (VBV) of uterineˆbroids after administration of gonadotropin-releasing hormone analogue (GnRHa) using magnetic resonance (MR) imaging including dynamic double-echo R 2 * imaging (DDE-R 2 *I) and to assess the value of DDE-R 2 *I as a predictor of such reduction.Methods: Twenty-one women with uterine intramuralˆbroids underwent MR imaging including DDE-R 2 * I before GnRHa treatment. DDE-R 2 * I was acquired using a single-section, double-echo, fast spoiled gradient recalled acquisition in the steady state (SPGR) sequence. We calculated the area under the curve (AUC) of the signal intensity on R 2 *I within a 3×3-cm 2 region of interest that served to represent the VBV. We repeated MR imaging after 2 administrations of GnRHa and repeated image analyses. We statistically analyzed correlations between (A) pre-treatment AUC (AUC(pre)) and AUC reduction and (B) AUC(pre) and volume reduction.Results: The interval between the 2 MR studies ranged from 56 to 119 days (mean: 80.4 days). The average volume of theˆbroids before GnRHa treatment was 647.8 mL compared with 463.4 mL after the therapy (decreased by an average of 28.5z; Pº0.0001). Meanwhile, measured AUC was reduced by 55.3z (483.4 vs. 206.5; Pº0.0001). AUC(pre) correlated with volume reduction (r＝0.68), but not AUC reduction.Conclusions: We conˆrmed reduction in the VBV ofˆbroids using DDE-R 2 * I. The measurement of AUC(pre) on DDE-R 2 *I aids prediction ofˆbroid volume reduction but correlates poorly with the percentage of AUC reduction.

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Human myometrium and leiomyomas express gonadotropin-releasing hormone 2 and gonadotropin-releasing hormone 2 receptor

Abstract: A second form of GnRH and corresponding receptor exists in the fibroid and myometrium. We speculate that an autocrine loop exists. Our findings provide further evidence that GnRH agonists may interact directly with GnRH receptors present in uterine fibroids.

Cited by 23 publications

References 54 publications

The Extracellular Matrix Contributes to Mechanotransduction in Uterine Fibroids

The Extracellular Matrix Contributes to Mechanotransduction in Uterine Fibroids

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Reduction in the Vascular Bed Volume of Uterine Fibroids after Hormonal Treatment: Evaluation with Dynamic Double-Echo R2* Imaging

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