Progesterone and Endometriosis: A Sex Hormone on the Wrong Track

The proper functioning of the human body is intricately tied to the action of hormones. Hormones regulate essential processes, such as maintaining the female menstrual cycle and facilitating pregnancy, and they also play a vital role in overall well-being. As previously mentioned, progesterone mainly exhibits a calming effect on the brain. The delicate interplay between the sex hormones estrogen and progesterone is of great significance in the context of endometriosis. This interplay often reveals a phenomenon known as ‘estrogen dominance,’ where estrogen levels are heightened compared to progesterone. It is a phenomenon that can be detected by medical professionals in patients with endometriosis. In essence, endometriosis can be characterized by excess estrogen and a progesterone deficiency. To fully grasp the full extent of this hormonal interplay, let us embark on a journey into the world of estrogen. Join me for an exploration of estrogen-progesterone dynamics.

Estrogen and Progesterone: Partners in the Menstrual Cycle

Estrogen is another vital sex hormone, and its harmonious coexistence with progesterone is crucial for a healthy endometrium. This collaboration relies on specialized receptors, cells, or cell components that process specific signals [6]. Unfortunately, it is at this very juncture that endometriosis appears to encounter difficulties. Studies have indicated that the signaling pathways for estrogen and progesterone become disrupted in this condition  [7]. You may wonder why malfunctioning signaling pathways are problematic. It carries significant consequences as it can lead to progesterone resistance. Unlike progesterone deficiency, where the hormone is insufficiently produced, progesterone resistance implies that adequate progesterone is present, but the responsible receptors fail to allow its effects to manifest fully. This, in turn, provides an advantage to estrogen. 

Examining Progesterone Receptors

Let us keep in mind that evidence suggests that endometriosis disrupts the signaling pathways for estrogen and progesterone. This disruption can elevate estrogen levels while concurrently reducing progesterone levels. A closer examination of progesterone receptors is particularly intriguing, as they appear to have a distinct role in endometriosis. As you may be aware, progesterone functions as an antagonist to estrogen, balancing the activities within a healthy cycle. This balancing act is crucial, especially in preparing the uterine lining for potential pregnancy. Progesterone takes over post-ovulation, maintaining the integrity of the uterine lining while orchestrating necessary remodeling. It resembles a relay race where smoothly passing the baton is imperative for an orderly cycle. Researchers have delved into how endometrial cells behave throughout these phases, discovering that endometriosis cells exhibit diminished sensitivity to progesterone. This reduced sensitivity may contribute to the condition’s emergence [1, 8].

Alterations in Progesterone Receptors

Endometriosis manifests morphological differences and exhibits altered behavior in comparison to healthy tissue. Now, let us delve into this modified behavior.

Scientific research has demonstrated that progesterone no longer elicits its typical response to estrogen within the localized foci [1, 9]. This mechanism results from endometriosis cells displaying reduced sensitivity to natural progesterone. Usually, the corpus luteum hormone supports the conversion of estradiol to estrone through the actions of enzymes. This conversion is pivotal as estrone is notably less potent. Therefore, progesterone typically mitigates estrogen’s influence. When endometriosis lesions disrupt this crucial conversion, it contributes to estrogen dominance. This hormonal imbalance, in turn, leads to inflammation and pain, a classic hallmark of endometriosis. But the impact extends further. Endometriosis tissue also displays differences in the density of progesterone receptors, particularly the absence of one crucial receptor, PR-B. This receptor is responsible for mediating progesterone’s effect on the endometrium. In normal circumstances, progesterone binds to this receptor, initiating a cascade of events known as progesterone action. Without the receptor or with a diminished number of receptors, the cell’s awareness of progesterone’s presence is significantly reduced. This results in a less pronounced effect of the available progesterone, a phenomenon referred to as progesterone resistance. Moreover, there are fewer representatives of another type of progesterone receptor, PR-A, which can exert an opposing influence on PR-B. Thus, these progesterone receptors have an intricate and delicate interplay, aiming for a balance [7, 9].

Regulatory Mechanisms and the Influence of Estrogen Receptors on Progesterone Levels

Further investigations have uncovered crucial findings; they attribute the lack of progesterone level response to the increased presence of steroid receptors in endometriosis tissue and alternative regulatory mechanisms [14]. Steroids constitute a group of hormones produced through the use of the basic substance sterane, which incorporates the intermediary cholesterol to facilitate the generation of female sex hormones like progestins and estrogen. Additionally, the more significant number of estrogen receptors, found in heightened quantities in endometriosis, plays a vital role in this context. However, it is essential to note that this does not apply uniformly to every receptor type. For instance, the ERβ receptor type significantly outweighs the ERα receptor type. This discrepancy is attributed to the capacity of ERβ to suppress ERα. Experts suggest this imbalanced ratio could result in higher estradiol levels and lower progesterone levels [15].

These discoveries reveal changes in hormone receptor binding sites within cells and offer a more profound understanding of this intricate interplay.