Endometriosis is a common gynecological condition where tissue similar to the lining of the uterus grows in abnormal locations outside the uterine cavity. This ectopic tissue, most often found on the ovaries, fallopian tubes, and pelvic lining, responds to the body’s hormonal cycles, leading to inflammation and pain. Progesterone is a major sex hormone that regulates the uterine lining. The relationship between endometriosis and progesterone is complex, involving both potentially low circulating hormone levels and a failure of the misplaced tissue to respond to the hormone.
Progesterone’s Function in the Menstrual Cycle
Progesterone is principally produced by the corpus luteum, a temporary structure in the ovary that forms from the follicle after ovulation. This surge marks the start of the luteal phase. The hormone’s main function is to prepare the endometrium for potential pregnancy by causing it to thicken and become receptive to a fertilized egg.
Progesterone also stabilizes the uterine lining, preventing premature shedding. If a pregnancy does not occur, the corpus luteum begins to break down after about 9 to 10 days, causing progesterone levels to decline rapidly. This drop in the hormone signals the breakdown of the thickened uterine lining, resulting in menstruation. Sustained high levels of progesterone during pregnancy maintain the uterine environment.
How Endometriosis Affects Progesterone Production
Endometriosis can be associated with Luteal Phase Defect (LPD), which is characterized by insufficient progesterone secretion after ovulation. This defect means the corpus luteum may not produce enough progesterone, or it may produce it for a shorter duration than is typical. Studies have shown that women with endometriosis may experience a delay in achieving adequate progesterone levels during the luteal phase, which can affect fertility.
The chronic inflammatory state caused by endometriotic lesions may disrupt the hormonal signaling necessary for progesterone production. The inflammation and resulting molecules, like prostaglandins, might interfere with the function or maturation of the corpus luteum. Although the correlation between endometriosis and LPD has been studied for decades, some clinical studies fail to find a correlation. Therefore, while some women may experience low circulating progesterone, this is not a universal finding, and the more significant problem often lies in how the tissue responds to the hormone.
The Mechanism of Progesterone Resistance
The primary explanation for the disease’s progression is progesterone resistance—the failure of the ectopic tissue to respond to the hormone. This resistance means that even if a woman’s blood tests show normal progesterone levels, the endometriotic lesions do not react to the hormone’s stabilizing and growth-inhibiting signals. This inability allows the lesions to continue growing and fueling inflammation, unlike the normal uterine lining, which stops growing under progesterone’s influence.
The cellular mechanism involves a defect in the progesterone receptors (PRs) within the endometriotic cells. Progesterone’s effects are mediated by two main receptor isoforms, PR-A and PR-B. In endometriotic lesions, there is often a reduced expression of PR-B, which is the full-length, active form of the receptor. The loss of this receptor is linked to epigenetic changes, such as the hypermethylation of the PR-B promoter region, which silences the gene’s ability to produce the receptor.
This deficiency in PR-B prevents the hormone from carrying out its normal functions, such as suppressing the growth factors and inflammatory cytokines that promote the disease. Progesterone resistance also impairs the hormone’s ability to regulate estrogen metabolism, a major driver of endometriosis growth. Because the endometriotic tissue is resistant to progesterone’s effects, it behaves in an estrogen-dependent manner, leading to continued proliferation and shedding. The resulting chronic inflammation contributes to this resistance, creating a self-perpetuating cycle of growth and pain.
Hormonal Treatments for Endometriosis
Understanding the concept of progesterone resistance informs the hormonal treatment strategies for endometriosis. Synthetic versions of progesterone, known as progestins, are a primary medical treatment. These treatments are administered in continuous, high doses to suppress the growth of the ectopic tissue and counteract the effects of natural estrogen.
Progestins work by binding to the remaining progesterone receptors in the endometriotic cells, aiming to induce anti-estrogenic, anti-inflammatory, and anti-proliferative effects. By creating a sustained, non-cyclic hormonal environment, these medications inhibit the monthly fluctuations that stimulate lesion growth and shedding. The goal is to induce a state of quiescence, where the lesions shrink or stop growing, leading to reduced pain and symptoms.
Progestin-only treatments, such as oral pills, injections, or intrauterine devices, prevent ovulation and lower estrogen levels, which limits the activity of the disease. However, the underlying progesterone resistance means that some individuals may have only partial improvement or may not respond to progestin therapy at all. This variability in response is a subject of ongoing research, focusing on overcoming the cellular resistance mechanisms to develop more universally effective therapies.