Research Article: Evidence of biomechanical and collagen heterogeneity in uterine fibroids

Date Published: April 29, 2019

Publisher: Public Library of Science

Author(s): Friederike L. Jayes, Betty Liu, Liping Feng, Nydea Aviles-Espinoza, Sergey Leikin, Phyllis C. Leppert, Dragana Nikitovic.


Uterine fibroids (leiomyomas) are common benign tumors of the myometrium but their molecular pathobiology remains elusive. These stiff and often large tumors contain abundant extracellular matrix (ECM), including large amounts of collagen, and can lead to significant morbidities. After observing structural multiformities of uterine fibroids, we aimed to explore this heterogeneity by focusing on collagen and tissue stiffness.

For 19 fibroids, ranging in size from 3 to 11 centimeters, from eight women we documented gross appearance and evaluated collagen content by Masson trichrome staining. Collagen types were determined in additional samples by serial extraction and gel electrophoresis. Biomechanical stiffness was evaluated by rheometry.

Fibroid slices displayed different gross morphology and some fibroids had characteristics of two or more patterns: classical whorled (n = 8); nodular (n = 9); interweaving trabecular (n = 9); other (n = 1). All examined fibroids contained at least 37% collagen. Tested samples included type I, III, and V collagen of different proportions. Fibroid stiffness was not correlated with the overall collagen content (correlation coefficient 0.22). Neither stiffness nor collagen content was correlated with fibroid size. Stiffness among fibroids ranged from 3028 to 14180 Pa (CV 36.7%; p<0.001, one-way ANOVA). Stiffness within individual fibroids was also not uniform and variability ranged from CV 1.6 to 42.9%. The observed heterogeneity in structure, collagen content, and stiffness highlights that fibroid regions differ in architectural status. These differences might be associated with variations in local pressure, biomechanical signaling, and altered growth. We conclude the design of all fibroid studies should account for such heterogeneity because samples from different regions have different characteristics. Our understanding of fibroid pathophysiology will greatly increase through the investigation of the complexity of the chemical and biochemical signaling in fibroid development, the correlation of collagen content and mechanical properties in uterine fibroids, and the mechanical forces involved in fibroid development as affected by the various components of the ECM.

Partial Text

Uterine fibroids, also called leiomyomas, are benign tumors that arise from myometrium. Seventy to eighty percent of women will develop uterine fibroids by age 50 [1], and many suffer from pressure, pain, infertility, and severe bleeding. While these widespread tumors have been the subject of basic and translational studies for decades [2–5], their molecular pathobiology remains elusive and as a result current treatment options are limited.

Previously, we and others have reported on the abundant extracellular matrix, especially collagen and glycosaminoglycans content in fibroids and their contribution to mechanical signaling mechanisms and fibroid stiffness [7, 8, 10–13, 15]. In this paper, our observations provide novel evidence that fibroid structural properties and collagen content vary widely. The variations we found in gross appearance of uterine fibroids were striking. In addition, large differences in collagen content and composition as well as stiffness were noted both within and among individual fibroids. Variations in fibroid biology may be associated with different stages of growth and underlying differences in gene expression, protein synthesis, and mechanical signaling and other second messenger production or release. Increased awareness of these differences and intentional consideration of these variations when designing studies and interpreting data will lead to a better understanding of the etiology and pathophysiology of uterine fibroids. The findings reported here lead to the generation of hypotheses ripe for investigations.