The Reality of Endometriosis in Peri- and Postmenopausal Women

Endometriosis is traditionally associated with women of reproductive age. However, it can persist or even recur in peri- and postmenopausal women, challenging the conventional understanding of its pathophysiology. Despite the decline in systemic estrogen levels after menopause, local estrogen production and residual lesions can sustain the disease, leading to persistent symptoms such as pelvic pain, abnormal bleeding, and organ dysfunction. For those who had surgery prior, hormone replacement therapy (HRT) can reactivate the condition if one singular endometriotic cell was left behind. Diagnosing and managing endometriosis in menopausal women requires a nuanced approach, as symptoms may differ, and the risk of complications, including malignancy, may increase. This article explores the reality of endometriosis in peri- and postmenopausal women.

The diagnosis of endometriosis in peri- and postmenopausal women uses the same criteria as in younger women, but symptoms can be different. Common signs like infertility and painful periods, which occur in women of reproductive age, don't apply after menopause, making diagnosis harder.

In menopausal women, endometriosis is most often found on the ovaries, followed by the ureter, bladder, and intestines, and less commonly in the vagina. Rare cases have even been found in the skin and liver. The symptomatic result from these infiltrations are followed by abnormal uterine bleeding, abdominal pain, rectal bleeding, and urinary dysfunction【1,2】.

If Endometriosis Is An Estrogen Dependent Disease, How Is It Still Active After A Hysterectomy Or Menopause?

A simpler explanation for the presence of endometriosis after menopause is that the disease often grows deep into tissues, making it hard to fully remove during surgery, even by experts. This is a fact we harp on in our book and the reason why your level of care needs to be raised. Any remaining endometriotic cells after a past surgery may become active and cause symptoms during perimenopause or could be reactivated by hormone replacement therapy used to treat menopause symptoms【3】. Therefore, most cases of endometriosis in peri- and post-menopausal women are thought to be a recurrence of the disease from before menopause.

Rarely do we see metaplastic transformations, where normal cells randomly become endometriotic cells. The majority, if not all women, had this disease prior【4】.

So how does this sustainment or reactivation of endometriosis happen? 

Well first lets examine and give a brief overview of the 5 main players in peri- & post- menopausal women.

1. Estrogen Post-Menopause:

• Even after menopause, estrogen can still be produced in the body, albeit in lower amounts compared to premenopausal levels. The primary sources of estrogen post-menopause are:
• Adipose tissue (fat cells), where androgens are converted to estrogen by the enzyme aromatase【5】.
• Peripheral tissues, including the endometriotic lesions themselves, which can have increased aromatase activity, allowing local estrogen production【6】.
• Estrogen is a key hormone that fuels the growth and activity of endometriotic tissue, including ectopic (outside the uterus) endometriotic implants found in endometriosis.

2. Endometriotic Lesions & Cells:.

• Endometriosis is an estrogen-dependent disease, meaning it thrives and worsens in the presence of estrogen.
• As a result, endometriotic cells and lesions are primed to create estrogen in the absence of systemic estrogen production.【7】

3. Dorsal Root Ganglion (DRG) Neurons:

• The dorsal root ganglion (DRG) is a cluster of sensory nerve cell bodies located along the spinal cord. These neurons transmit signals related to pain, including chronic pelvic pain, a hallmark symptom of endometriosis【8】.
• Estrogen can sensitize DRG neurons, making them more responsive to stimuli and contributing to the pain experienced in endometriosis.

4. Chemokines:

• Chemokines are small signaling proteins that direct the movement and activation of immune cells. In this context, DRG neurons, activated by estrogen, release chemokines【9】.
• These chemokines act as attractants and activators for immune cells like macrophages.

5. Macrophages:

• Macrophages are a type of immune cell that play a dual role in inflammation and tissue repair. In endometriosis:
• Macrophages are often recruited to endometriotic lesions.
• Instead of resolving inflammation, they can contribute to chronic inflammation and tissue remodeling, supporting the growth and survival of endometriotic tissue【10】.

Detailed Pathway Explanation
Now let's how described process works and how they interact with each other:

1. Estrogen Production:
• Post-menopause, estrogen levels are lower but not absent. Local production of estrogen by endometriotic lesions, via aromatase activity, becomes a major factor in sustaining the disease【6】.
2. Estrogen Activates DRG Neurons:
• Estrogen binds to estrogen receptors (ER) on DRG neurons, which are highly sensitive to hormonal changes【8】.
• This activation increases the excitability of these neurons, causing them to release chemokines.
3. Chemokines Recruit Macrophages:
• Chemokines, secreted by the activated DRG neurons, act as chemical signals to attract macrophages to the site of endometriotic lesions【9】.
4. Macrophage Activation:
• Once macrophages are recruited to the lesion site, they become activated by these chemokines and other local signals.
• Instead of resolving the inflammation, these macrophages create a pro-inflammatory environment by secreting cytokines (e.g., TNF-α, IL-6) and growth factors that promote:
• Angiogenesis (formation of new blood vessels to supply the lesions).
• Tissue growth and survival of endometriotic implants【10】.
5. Feedback Loop:
• Estrogen, inflammation, and macrophage activity form a vicious cycle:
• Estrogen promotes inflammation.
• Inflammation amplifies the local production of estrogen by increasing aromatase activity in the lesions【5,6】.

Implications & Summary of This Mechanism

• Chronic Pain: DRG neuron activation is linked to increased pain perception, making endometriosis-associated pelvic pain worse【8】.
• Sustained Inflammation: The interaction between neurons, chemokines, and macrophages creates a microenvironment that perpetuates chronic inflammation, preventing lesion regression【9,10】.
• Focused Therapeutic Targets: The identification of this pathway highlights potential treatment strategies.

So What Are The Current Approaches You Will See Recommended?

Surgery is the “Gold Standard” for peri- or postmenopausal endometriosis because of the perceived increased risk of cancer (though the actual risk is less than 1% of all cases,) the disease's ability to spread to nearby organs, and the potential for urinary or intestinal blockages【11】. Since fertility is no longer a concern, aggressive removal of the uterus, fallopian tubes, ovaries, and all visible endometriosis lesions is recommended to optimize treatment and reduce the risk of cancer【11】.

The surgical solution is a problem again, if you remember earlier on, the main reason for post-menopausal endometriosis is the fact that lesions were missed. For severe cases, surgery is an absolute must, but proper post-operative care is imperative for maximal impact and optimal results to prevent the same results. Quality of life should be a first and foremost a primary concern.

For patients who cannot undergo surgery, medical treatments are available. These include GnRH agonists and antagonists, progestins, aromatase inhibitors, birth control pills, and intrauterine devices that release levonorgestrel【6,12】. For example:

• Aromatase inhibitors: Block local estrogen production in endometriotic lesions【6】.
• Neuro-modulatory therapies: Target DRG neurons to reduce their sensitivity and chemokine production【8】.
• Immune-modulating drugs: Intervene in macrophage activation to disrupt the pro-inflammatory environment【10】.

However, as you have already seen, this condition uses multiple pathways. To use one pathway specific therapy in light of these facts is arbitrary. Though this one pathway approach is common in modern treatments.

Summary

These pathways underpin the chronic nature of endometriosis and its symptoms, even in post-menopausal women, emphasizing the importance of targeting not only estrogen and inflammatory pathways but other factors, such as angiogenesis, immune modulation and more.

Aromatase inhibitors are typically the first choice of treatment recommended by medical professional. They have shown a good result in treating symptomatic endometriosis in menopausal patients, by inhibiting the synthesis of extra-ovarian estrogen. The synthesized estrogen through the pathways described promotes the proliferation of endometriosis lesions and the progression of the disease, and subsequently their potential malignant transformation.

However, for us, this is an incomplete approach as this does come with its own risk such as increased risk of osteoporosis, lethargy, increased hot flashes, essentially magnifying all symptoms of menopause. Adding to the fact that endometriotic lesions will adapt to the decreased estrogen. In short, you need to find a way to allow the body to function with estrogen, not make it the enemy, by tackling other intrinsic factors that endometriotic lesions use to grow and maintain themselves.

This has been the ENDOLLS approach since 2019 and the reason we have had such a high success rate. If you are needing extra help in this peri- postmenopausal journey, do not hesitate to reach out and ask questions.

References:

1. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-279.
2. Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557-571.
3. Redwine DB. Treatment of endometriosis in menopausal patients. J Minim Invasive Gynecol. 2004;11(1):52-55.
4. Nisolle M, et al. Metaplasia in Endometriosis. Hum Reprod Update. 2006;12(1):51-56.
5. Simpson ER, et al. Aromatase and Estrogen Synthesis. Endocr Rev. 2002;23(5):616-630.
6. Attar E, Bulun SE. Aromatase and steroidogenic genes in endometriosis. Hum Reprod Update. 2006;12(1):49-56.
7. Zondervan KT, et al. Endometriosis genetics and risk factors. Nat Rev Endocrinol. 2018;14(5):285-298.
8. Berkley KJ, et al. Endometriosis pain pathways. Neuroscience. 2005;132(2):615-628.
9. Tokushige N, et al. Chemokines and endometriosis. Hum Reprod. 2006;21(3):782-787.
10. Harada T, et al. Role of macrophages in endometriosis. Fertil Steril. 2001;76(1):1-10.
11. Leyland N, et al. Endometriosis: Surgical management guidelines. J Obstet Gynaecol Can. 2010;32(9):830-846.
12. Bedaiwy MA, et al. Medical management of endometriosis in chronic pain. Semin Reprod Med. 2008;26(2):122-134.