Uterine fibroids (leiomyomas) are common, non-cancerous tumors arising from the smooth muscle tissue of the uterus. These growths affect many women of reproductive age, often causing symptoms like heavy bleeding, pelvic pain, or pressure. Fibroids depend on ovarian steroid hormones for development and growth. While often associated solely with estrogen, fibroid growth is fundamentally driven by a complex interplay involving both estrogen and progesterone.
The Collaborative Action of Estrogen and Progesterone
Fibroids respond to the hormonal environment because their cells contain a greater number of both estrogen and progesterone receptors compared to healthy uterine tissue. Neither hormone acts alone; they exhibit a powerful synergy. Estrogen acts as the primer, stimulating the initial proliferation of cells and upregulating the expression of progesterone receptors within the fibroid tissue. This increase in receptors makes the fibroid cells highly sensitive and responsive to progesterone.
Progesterone acts as the primary promoter of sustained growth, taking over during the second half of the menstrual cycle. This hormone facilitates the continued expansion of the tumor by triggering specific anti-death and survival mechanisms. While estrogen multiplies the cellular building blocks, progesterone ensures those cells survive and accumulate into a larger mass.
Progesterone’s Direct Impact on Fibroid Growth
The molecular mechanism by which progesterone promotes fibroid growth is highly specific, mediated by its interaction with progesterone receptors (PRs). Fibroid cells typically overexpress both major isoforms of the receptor, Progesterone Receptor-A (PR-A) and Progesterone Receptor-B (PR-B), initiating a cascade of events that fuel tumor expansion when progesterone binds.
One significant effect is the inhibition of apoptosis, the process of programmed cell death. Progesterone signaling upregulates the expression of anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2). This action blocks the natural elimination of old or damaged fibroid cells, ensuring the cell population continues to accumulate and leading to tumor growth.
Progesterone also drives growth by influencing the production of various signaling molecules, including specific growth factors. For example, progesterone binding stimulates the increased expression of Transforming Growth Factor-beta (TGF-beta) and Epidermal Growth Factor (EGF). These factors further promote growth, proliferation, and the excessive deposition of extracellular matrix—the dense, fibrous material that gives fibroids their characteristic hard structure.
Hormonal Therapies Targeting Progesterone Receptors
The discovery of progesterone’s role as a growth promoter has shifted therapeutic strategies toward targeting its receptors. This led to the development of Selective Progesterone Receptor Modulators (SPRMs), a class of medications designed to interfere with progesterone signaling. SPRMs, such as ulipristal acetate and mifepristone, act as antagonists by binding to the receptor and preventing the natural hormone from initiating growth. By modulating the receptor, SPRMs can effectively reduce fibroid volume and control heavy bleeding, offering a non-surgical option.
The action of these medications directly counteracts the anti-apoptotic and pro-growth pathways triggered by progesterone. This antagonism results in a reduction in cell survival and a decrease in the production of supportive fibrous tissue.
Conversely, the use of progestins, synthetic versions of progesterone, presents a more complex situation. Progestins are often used in treatments like hormonal intrauterine devices or birth control pills to manage heavy menstrual bleeding. As agonists, they mimic progesterone and can sometimes stimulate fibroid growth, depending on the specific compound and dosage. However, in other cases, they control bleeding without causing significant growth, emphasizing the need for individualized treatment.
Fibroid Changes During Pregnancy
Pregnancy represents a unique hormonal state characterized by high, sustained levels of both estrogen and progesterone. During the first trimester, when hormone production rapidly increases, fibroids may experience rapid growth, often visibly increasing in size. However, despite continued high hormone levels, fibroid growth often stabilizes or even reverses in the second and third trimesters. This change is likely due to factors such as alterations in blood supply or the saturation of hormone receptors. A clinical implication during this time is the risk of “red degeneration,” a painful condition where the fibroid outgrows its blood supply and tissue death occurs. After delivery, when pregnancy hormones drop, fibroids commonly shrink back to their pre-pregnancy size or smaller.