Endometriosis is a common condition where tissue resembling the lining of the uterus develops outside the uterine cavity, often leading to chronic pelvic pain. This misplaced tissue is responsive to hormonal signals, particularly the female sex hormone estrogen, which typically drives its growth and activity. Since estrogen promotes the proliferation of these lesions, the idea that a person with endometriosis could also experience low levels of this hormone seems contradictory. However, it is entirely possible to have active endometriosis while simultaneously having a low systemic estrogen level. This apparent paradox is explained by the intricate and localized hormonal environment of the disease, which allows the tissue to persist even when the body’s overall hormone profile is suppressed.
The Estrogen-Dependent Nature of Endometriosis
Endometriosis is traditionally understood as an estrogen-driven disease because the ectopic tissue responds similarly to the endometrium. Estradiol, the primary form of estrogen, stimulates the growth and thickening of this tissue. This hormonal influence is why symptoms often intensify in a cyclical pattern, worsening when natural estrogen levels are at their peak.
Estrogen promotes tissue growth and contributes to the chronic inflammatory state that defines the condition. As the lesions grow and respond to hormonal fluctuations, they can bleed and shed inside the body, causing irritation and inflammation in the surrounding pelvic cavity. This cyclical hormonal stimulation and subsequent inflammatory reaction are responsible for much of the characteristic pain associated with the disease, which is why medical treatments often focus on lowering the body’s hormone levels.
Causes of Systemic Low Estrogen
A patient with endometriosis may develop low systemic estrogen levels for several reasons. The most common natural cause is the transition into perimenopause or post-menopause, where the ovaries naturally decrease their production of estradiol over time. While the severity of endometriosis symptoms usually lessens after the complete cessation of the menstrual cycle, the lesions can remain active for some individuals.
A more direct cause of low systemic estrogen is medical treatment specifically designed to manage the condition. Medications like gonadotropin-releasing hormone (GnRH) agonists and antagonists intentionally suppress the signaling pathway between the brain and the ovaries. This suppression effectively puts the patient into a reversible state of low estrogen, often referred to as a medical menopause. Other factors, such as extreme physical training, certain eating disorders, or premature ovarian insufficiency, can also lead to systemic estrogen deficiency.
The Persistence of Endometriosis Despite Low Systemic Estrogen
The ability of endometriosis to remain active and cause symptoms despite low circulating estrogen is explained by the implants’ ability to actively create their own estrogen. Specialized enzymes within the lesion tissue, most notably aromatase, convert circulating adrenal androgens into local estradiol.
This localized production establishes a microenvironment of high estrogen concentration directly surrounding the lesion. Endometriotic cells often exhibit an increased expression of Estrogen Receptor-beta (ER-\(\beta\)), which contributes to the growth and inflammation of the implants. This unique hormonal profile allows the lesions to self-sustain their growth and activity, even when the ovaries are suppressed by medication or natural menopause.
Beyond hormonal self-sufficiency, pain persistence in low-estrogen states is also driven by non-hormonal factors. The chronic inflammation associated with the condition leads to the release of compounds like prostaglandins, which sensitize nearby nerves. This chronic inflammatory signaling can activate and remodel the nervous system, leading to a state of central sensitization where pain is felt more intensely, irrespective of the current hormonal level. Fibrosis, or scar tissue, is another non-hormonal factor that contributes to pain by binding and distorting pelvic organs and structures.
Treatment Considerations for Co-existing Conditions
Treating a patient with active endometriosis symptoms and low systemic estrogen requires balancing disease suppression with preventing hormone deficiency side effects. For patients on GnRH agonist therapy, the resulting low estrogen can lead to side effects, including bone mineral density loss and menopausal symptoms like hot flashes. To mitigate these risks, physicians often prescribe “add-back” therapy, which involves giving low doses of estrogen and progestin.
This add-back regimen provides just enough hormone to protect bone health and manage side effects without stimulating the endometriotic implants. Management in post-menopausal individuals also requires a cautious approach, as menopausal hormone therapy can reactivate dormant lesions. In these cases, non-hormonal pain management strategies are often prioritized for symptoms driven by inflammation or nerve sensitization, such as nerve-blocking medications and pelvic floor physical therapy.