June 28, 2020

July is Fibroid Awareness Month

This July month we reflect on the grave seriousness of uterine fibroids to women’s health. They cause significant bleeding and pain and interfere in a woman’s ability to work and lead a productive life. They can interfere with the ability to become pregnant and to carry a pregnancy to term and have an uncomplicated birth. This condition costs the United States an estimated $34.4 Billion a year (1). The cumulative incidence of uterine fibroids in American women is 70% in white women and 80% in black women (2).There are striking differences in fibroids between blacks and whites. Black women develop and are diagnosed with uterine fibroids at an earlier age, they have more numerous and larger fibroids and a growth pattern that is greater than that of white women as well as differences at the molecular level (3-7).  Everyone needs to become aware of these basic facts about uterine fibroids and to understand that we need to find more therapeutic options for treatments that target these differences. We need to have the will as a country to discover these options. Furthermore, uterine fibroids are a problem for women the world over and new treatments will help them as well.

We also need to make ourselves and others aware of current knowledge about the basic pathophysiology and the molecular pathobiology of fibroids.  New therapies will not happen until we really understand fibroid pathobiology. We have come a long way but we are not there yet. The data on the cumulative incidence show that uterine fibroids are extremely common. So common that women in the same family will have them. However, the pattern of inheritance in families does not support classical Mendelian genetics as the cause of fibroids. We know that fibroids are initiated by one cell, a stem cell and thus are clonal in origin. One cell begins to grow and divide and differentiate into smooth muscle cells, vascular smooth muscle cells, fibroblasts and stem cells (8). Fibroids grow by producing and secreting abundant collagens and that they develop in stages and at some point, usually at menopause they shrink in size (9). The collagen laid down in the fibroid is disarrayed and has altered fibrils (10). We know that fibroid stem cells are estrogen receptor( ERα) and progesterone (PR) deficient. However, the cells have surface receptors for cytokines and growth factors originating from surrounding fibroid cells in response to estrogen and progesterone that prompt them to grow (11, 12). Many cellular pathways are active in uterine fibroids and recently new understanding of the interaction or cross-talk between these pathways is beginning to be understood. The environment has also been shown to impact on the development of uterine fibroids and epigenetic mechanisms are implicated and are areas which need to be further explored (13).              

We now know that uterine fibroids are not all the same, they are quite heterogenous at the cellular level. Furthermore, they do not all look the same or grow in the same way and when studied at the time of surgery, the type of interstitial collagen varies as does the amount of collagen (14).  They are genetically different as well (15). Several studies show that 79-86% of uterine fibroids have somatic mutations in the mediator complex subunit 12, or MED12. The mediator complex is a multiprotein complex that functions to transmit signals and helps to activate or repress transcription of genetic information from DNA to messenger RNA. Fibroids that have a MED12 mutation are smaller, are larger number compared to fibroids without MED12 mutations. They are often subserosa in location and are inversely associated with the number of pregnancies a woman has had (15).  Other fibroids are characterized by expression of HMGA 2 or HMGA1, genes that code for a high mobility group of proteins that modulate transcription of DNA by altering chromatin structure.  Chromatin efficiently packages the long DNA molecules into a compact form so that it fits into chromosomes and into the nucleus of a cell.  We know that HMGA2 can be hypomethylated in fibroids and is overexpressed. In these situations, the chromatin can be open at this gene locus, a fixed position on the chromosome where the HMGA2 gene is located (16). This study also found that the gene HOXA13, a gene that is important in development and is expressed in the uterine cervix but not in the uterine body, is expressed in fibroids. This is most interesting as the cervix has an abundance of collagen. Overexpression of HOXA13 in myometrial cells induces these cells to develop a more cervix like cell that expresses genes that overlap those of fibroids (16). We need to understand more fully how this happens.

As the collagen and other components of the extracellular matrix accumulate in a fibroid it tends to become stiffer. The exact stiffness of a fibroid is variable both within the same tumor and among the tumors (14). As the fibroid grows it compresses the surrounding myometrium and a pseudocapsule develops. The pseudocapsule is a neurovascular structure with numerous blood vessels, nerves and collagen and is the source of angiogenic factors as well as neuropeptides and neurotransmitters (17, 18). The stiffness or firmness of fibroids is able to change cell behavior and to alter how the biochemical and metabolic pathways are activated and function.  This phenomenon is known as mechanotransdution or mechanical sensing (19).  When the fibroid becomes stiffer as collagen is accumulated and extracellular matrix components, such as glycosaminoglycans and interstitial fluid increase mechanical sensing is activated. Then additional collagen is secreted further stiffening the tumor (14). There is something unique to fibroid cells because they respond in an attenuated fashion to the mechanical force of the extracellular environment (20).  The exact way mechanical sensing occurs in fibroids is now the subject of research.

A novel approach to fibroid treatment being developed is the local injection directly into a fibroid of an enzyme, highly purified bacterial collagenase. The first clinical study showed that the injection of the collagenase does digest the collagen present in the fibroid and is well tolerated. In this study the collagenase decreased fibroid pain in the majority of the subjects. Furthermore, the collagenase affects the proliferation of fibroid cells and increases their death. It is therefore hoped that the treatment can prevent further fibroid growth and can be administered in an outpatient setting (Dr. JH Segars at Johns Hopkins is continuing to study this treatment). A nanoparticle that will act as a vehicle to contain the collagenase for injection and that will slowly release this enzyme is in development as well.  This nanoparticle vehicle can also contain two or more drugs for combination therapy (Dr. D Taylor at NCCU is working on this project).  The prospect of a local injectable treatment is exciting and at this point shows promise. These studies have been presented at scientific meetings and publications are planned.

The scientific community needs to continue to study fibroid pathobiology at the cellular and molecular level in order to fully develop more treatment options for women. It is hoped that Fibroid Awareness month will allow the general public to recognize the need for further studies and will encourage additional and important research funding for these necessary studies. Pharmaceutical companies also need to step up their interest in fibroid research and drug development. The cost to society is great, in fact given a recent publication indicating that hysterectomy with ovarian preservation  is associated with the long-term increase of high blood pressure, obesity, coronary artery disease, cardiac arrythmias, hyperlipidemia, depression, anxiety, brain and thyroid cancer, melanoma, arthritis, and chronic obstructive pulmonary disease the cost to society of uterine fibroids is even greater than the $34.4 billion dollars cited in this blog (21). In addition, hysterectomy can cause mortality at the time of the surgery (21).  Finally, the greatest awareness we must have is that we no longer can ignore the problem of uterine fibroids and the great harm they cause to women’s health.

Phyllis Leppert, MD. PhD, President 

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