Hormone replacement therapy Menopause Endometriosis

Navigating HRT for Menopause in Women with Endometriosis

Endometriosis, a chronic condition, is often associated with the fertile years of a woman’s life. But what happens when these women reach menopause? Can the symptoms of endometriosis persist, or even worsen, during this transition? This article aims to shed light on these questions and provide guidance for women with a history of endometriosis approaching menopause.

Understanding HRT and Endometriosis: A Quick Overview

Endometriosis is a medical condition characterized by the growth of endometrial-like tissue (the tissue that lines the uterus) outside the uterus. This condition, affecting approximately at least 10% of women in their reproductive years, can lead to debilitating pain, infertility, and other complications. However, the diagnosis of endometriosis often gets delayed due to the non-specific nature of its symptoms and the lack of reliable diagnostic tools.

The exact cause of endometriosis remains unclear, but estrogen dependence, progesterone resistance, inflammation, environmental factors and genetic predisposition are some of the known contributing factors. The primary treatment and support options for endometriosis include hormonal therapy, pain management, pelvic floor physical therapy and excisional surgery.

Read more: What causes endometriosis?

Endometriosis and Menopause: The Connection

Menopause, the cessation of menstruation, is a natural phase in a woman’s life. It is commonly believed that endometriosis, an estrogen-dependent condition, resolves after menopause due to the decline in estrogen levels. However, this belief is being challenged as more cases of postmenopausal endometriosis are reported.

The persistence or recurrence of endometriosis after menopause can be attributed to multiple factors. One factor may be persistent higher levels of estrogen in some women.  One common estrogen source is Hormone Replacement Therapy (HRT) to manage menopausal symptoms. HRT, which usually includes estrogen, may reactivate endometriosis in some cases. However, it is a complex interplay of estrogen, progesterone or progestins if they are included, receptor sensitivity and number and other molecular signaling factors, including the presence or absence of genomic alterations.  It’s also important to keep in mind that endometriosis cells and their surrounding support cells can locally produce estrogen.  Estrogen can also be generated by the interconversion of other hormones in your fat cells.  So, taking hormonal replacement is not the only potential source of estrogen after menopause.  

Postmenopausal Endometriosis: Case Studies and Observations

Numerous case reports and series have documented the recurrence of endometriosis or malignant transformation of endometriotic foci in postmenopausal women. In these reports, the majority of women had undergone surgical menopause (ovaries were removed) due to severe premenopausal endometriosis.

Read more: What would happen to the signs and symptoms of endometriosis after menopause?

Recurrence of Endometriosis

In several case studies, postmenopausal women reported symptoms similar to those experienced during their premenopausal years. These symptoms included abnormal bleeding if the uterus was still intact and pain, often in the genitourinary system. Notably, all women who experienced recurrence were on some form of Hormone Replacement Therapy (HRT), particularly unopposed estrogen therapy.

Malignant Transformation of Endometriotic Foci

Case studies have also reported instances of malignant transformation of endometriotic foci in postmenopausal women on HRT. These cases highlight the potential risk of exogenous estrogen in stimulating malignant transformation in women with a history of endometriosis.  It’s critical to point out that this is rare and that is why these are case reports rather than large studies.  When these steps towards malignant transformation  have been found they are usually associated with genetic alterations like PTEN, TP53 and ARID1A.  These alterations are more often found in deep infiltrating and endometrioma types of endometriosis, which are less common than the superficial variant. 

Read more: Understanding the Connection between Endometriosis and Cancer

Should HRT be Given to Women with Previous Endometriosis?

The decision to prescribe HRT to women with a history of endometriosis is complex and should be individualized on a holistic basis, looking at the risk and benefit overall. This includes risk and benefit for other symptoms and conditions like hot flashes, osteoporosis, heart disease, skin and vaginal changes, and more.  While HRT is the most effective treatment for these menopausal symptoms, it may increase the risk of recurrence or, more rarely,  malignant transformation of the endometriosis. 

Several observational studies and clinical trials have sought to assess the risks of HRT in women with a history of endometriosis. Although these studies suggested a small association between HRT and endometriosis recurrence, the differences between treatment and control groups were not statistically significant.  This means that for the vast majority, it is likely safe to take hormone replacement therapy, especially when considering the far more common benefits of such therapy.  

Whether or not the uterus has been removed or not is another  factor.  HRT for those with an intact uterus usually includes estrogen and a progestational agent, most often a synthetic progestin.  This is to protect against developing uterine endometrial cancer.  If the uterus is surgically absent, then only estrogen is usually administered.  There is a big reason for this.  The large Women’s Health Initiative (WHI) study performed over twenty years ago revealed that the risk of breast cancer mainly increases with hormone therapy that contains a progestin (synthetic progestational agent).  Estrogen alone does not increase this risk.  This is because progestins act as growth factors (mitogens) in breast tissue.  While natural progesterone was not evaluated in the WHI study, we know that it is not a mitogen from other studies.  So, if your uterus has not been removed, from a breast risk perspective, it may be reasonable to inquire about natural progesterone rather than a synthetic progestin as part of hormonal replacement therapy.  

It is also important to recognize that ectopic endometriosis cells are not as sensitive to progestational hormones as is eutopic endometrium, located in the uterine lining.   So, the real benefit of adding progestin or progesterone may not be as significant as it is in theory.  This requires more study, looking at the very complex molecular interplay of these hormones with their receptors located on and in endometriosis cells.  

Should HRT be Given Immediately Following Surgical Menopause?

Another question that arises is whether HRT should be initiated immediately after surgical menopause. Delaying the start of HRT could potentially allow any residual endometriotic tissue to regress before introducing exogenous estrogen. However, current research is inconclusive, with studies showing mixed results.

Read more: Integrative Therapies for Endometriosis

What Menopausal Treatments are Most Appropriate for Women with Previous Endometriosis?

If a woman with a history of endometriosis decides to opt for HRT, choosing the most suitable preparation is crucial. Current research suggests that combined HRT, which includes both estrogen and progestin (or progesterone), may be a safer option for women with residual endometriosis.  Keep in mind the caveat about breast tissue and synthetic vs natural progesterone. However, more research is needed to confirm these findings.

Read more: Postmenopausal Malignant Transformation of Endometriosis

Conclusions and Guidance

Navigating the transition to menopause can be challenging for women with a history of endometriosis. While HRT can be effective in managing menopausal symptoms, it may also increase the risk of endometriosis recurrence or malignant transformation.

Women with a history of endometriosis should have a thorough discussion with their healthcare providers about the overall potential risks and benefits of HRT.  It is also important to explore the risk and benefit of synthetic vs natural progestational agents. Not all practitioners are well versed in this innuendo.  

It’s also important to remember that each woman’s experience with endometriosis and menopause is unique. Therefore, individualized care that takes into account the symptoms, medical history, and personal preferences is crucial.  

Ultimately, more high-quality research is needed to better understand the molecular relationship between endometriosis and menopause, and to guide the management of menopausal symptoms in women with a history of endometriosis.



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