Managing Menopause With Endometriosis and HRT

Navigating HRT for Endometriosis and Menopause in Women

Endometriosis, a chronic condition, is often associated with the fertile years of a woman’s life. Can the symptoms of endometriosis persist, or even worsen, during the menopausal transition? This article explores these questions and offers guidance for those with a history of endometriosis approaching menopause.

Understanding HRT and Endometriosis: A Quick Overview

Endometriosis is characterized by the presence of endometrial-like tissue, which normally lines the uterus, growing outside the uterus. This condition affects at least 10% of women in their reproductive years and can lead to debilitating pain, infertility, and other complications. Diagnosis is often delayed due to non-specific symptoms and the lack of reliable diagnostic tools.

The exact cause of endometriosis remains unclear. Contributing factors include estrogen dependence, progesterone resistance, inflammation, environmental influences, and genetic predisposition. Primary treatment and supportive approaches include hormonal therapy, pain management, pelvic floor physical therapy, and excisional surgery.

Endometriosis and Menopause: The Connection

Menopause, the cessation of menstruation, is a natural phase in a woman’s life. Although endometriosis is estrogen-dependent and commonly thought to resolve after menopause due to declining estrogen levels, increasing reports of postmenopausal endometriosis challenge this assumption.

Persistence or recurrence after menopause may reflect multiple influences. Some women have persistently higher estrogen levels, and Hormone Replacement Therapy (HRT), commonly used to manage menopausal symptoms, can in some cases reactivate disease. The biology is complex, involving estrogen and progesterone or progestins if they are included, variations in receptor sensitivity and number, and other molecular signaling factors, including the presence or absence of genomic alterations. Endometriosis cells and surrounding stromal cells can locally produce estrogen, and estrogen can also be generated by the interconversion of other hormones in adipose tissue. This means HRT is not the only possible estrogen source after menopause.

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

Recurrence of Endometriosis

In several case studies, postmenopausal women reported symptoms resembling those from their premenopausal years. These included pain, often within the genitourinary system, and abnormal bleeding when the uterus was still present. All women who experienced recurrence were using some form of HRT, particularly unopposed estrogen therapy.

Malignant Transformation of Endometriotic Foci

Case reports have documented malignant transformation of endometriosis in postmenopausal women on HRT. These observations suggest a potential risk that exogenous estrogen may stimulate malignant transformation in those with a history of endometriosis. This is rare, which is why the literature largely consists of case reports rather than large studies. When malignant progression has been identified, it is usually associated with genetic alterations such as PTEN, TP53, and ARID1A. These alterations are more frequently linked to deep infiltrating endometriosis and endometriomas, which are less common than superficial disease.

Should HRT Be Given to Women with Previous Endometriosis?

The decision to prescribe HRT for women with a history of endometriosis is nuanced and should be individualized with a holistic assessment of risks and benefits. Considerations extend to symptoms and conditions such as hot flashes, osteoporosis, heart disease, skin changes, vaginal health, and more. HRT is the most effective treatment for menopausal symptoms, yet it may increase the risk of recurrence or, more rarely, malignant transformation of endometriosis.

Observational studies and clinical trials have explored the risks of HRT in this population. Although a small association between HRT and recurrence has been suggested, differences between treatment and control groups have generally not reached statistical significance. For the vast majority, it is likely safe to use hormone replacement therapy, especially when weighed against the more common benefits.

Whether the uterus is intact is another key factor. When the uterus is present, HRT typically combines estrogen with a progestational agent, most often a synthetic progestin, to protect against endometrial cancer. If the uterus has been surgically removed, estrogen alone is usually prescribed. The large Women’s Health Initiative (WHI) study conducted over twenty years ago showed that breast cancer risk mainly increases with hormone therapy that contains a progestin, whereas estrogen alone does not increase this risk. Progestins act as growth factors (mitogens) in breast tissue. While natural progesterone was not evaluated in the WHI, other studies indicate it is not a mitogen. Therefore, for those with an intact uterus, it may be reasonable to inquire about natural progesterone rather than a synthetic progestin from a breast risk perspective.

It is also important to recognize that ectopic endometriosis cells are less sensitive to progestational hormones than eutopic endometrium in the uterine lining. Consequently, the theoretical benefit of adding progestin or progesterone may not be as substantial in practice. Further research is needed to clarify the complex molecular interactions among these hormones and their receptors in endometriosis.

Should HRT Be Started Immediately After Surgical Menopause?

Another common question is whether to initiate HRT immediately after surgical menopause. Delaying therapy might allow residual endometriotic tissue to regress before exposure to exogenous estrogen. Current research is inconclusive, and findings are mixed.

What Menopausal Treatments Best Fit Women with Endometriosis?

For women with a history of endometriosis who opt for HRT, choosing an appropriate regimen is critical. Current evidence suggests that combined HRT containing both estrogen and a progestin or progesterone may be a safer choice for those with residual disease, with careful consideration of the differences between synthetic progestins and natural progesterone in relation to breast tissue. More research is needed to validate these recommendations.

Conclusions and Guidance

Navigating menopause can be particularly challenging for women with a history of endometriosis. HRT is effective for menopausal symptoms but may increase the risk of recurrence or, more rarely, malignant transformation. Women should have comprehensive discussions with their healthcare providers to weigh overall risks and benefits, including the distinctions between synthetic progestins and natural progesterone. Not all clinicians are equally familiar with these nuances.

Each woman’s journey with endometriosis and menopause is unique, so individualized care that reflects symptoms, medical history, and personal preferences is essential. More high-quality research is needed to better understand the molecular relationship between endometriosis and menopause and to guide optimal management of menopausal symptoms in this population.