Medically-Induced Menopause: Implications for Breast Cancer

Treatment-induced menopause (TIM) is an under-recognized health outcome for women with breast cancer. Treatment with chemotherapy, ovarian suppression therapy, or surgery to remove both ovaries can lead to infertility; negative effects on short-term and long-term medical outcomes; and severe symptoms that affect quality of life in women diagnosed with breast cancer. As survival rates for women with breast cancer improve, a greater percentage of women will live for years after the initial diagnosis, managing the early symptoms of hormone deficiency to prevent complications to bone, heart, sexual, and mental health. Developing frameworks for managing symptoms of treatment-induced menopause will help facilitate timely decision-making and guide women and their families to relevant resources to optimize quality of life from time of diagnosis through follow-up care and long-term survivorship.

Why It Matters

Women who experience early menopause due to medical treatment, may face more severe menopausal symptoms than women who experience natural menopause. The rapid decline of estrogen levels can bring on Hot flashes and night sweats, insomnia, mood swings, memory loss, “brain fog,” vaginal dryness, and decreased libido. These changes can interfere with daily life and ability to work. Symptoms may even interfere with recovery from cancer treatment or major surgery. Women in menopause also experience a wide range of emotions, including feelings of loss of identity, loss of childbearing potential, and loss of control over their bodies.

Unlike many women with breast cancer, who experience medically-induced menopause several years prior to their predicted age of menopause, the longer duration of time in the low-estrogen state can lead to more rapid bone loss and osteoporosis, as well as earlier fractures. In addition, women treated for breast cancer are generally on medications that have additional bone effects. The longer duration of hormone deficiency is also known to impact the cardiovascular risk factors, including cholesterol, blood pressure and body fat distribution both during and after cancer treatment.

In considering the benefit versus the burden of cancer treatment, ovarian suppression or oophorectomy leading to treatment-induced menopause in order to reduce recurrence risk in premenopausal women with early stage hormone-receptor positive breast cancer is no exception. Reducing estrogen levels is a well established means to decrease the stimulation of hormone sensitive cancer cells, but decreasing estrogen also results in symptoms of menopause which can be severe in some women. Furthermore long term outcomes relating to cardiovascular and bone health in this cohort of women are also potentially suboptimal. Thus treatment-induced menopause is not simply a consequence to be managed with symptomatic treatments, but must be a fundamental consideration in treatment decision making.

Quality of life is an important concern in cancer care. Unless symptoms are well managed, patients and their families may not reap the full benefit of life-prolonging treatments. For patients with breast cancer, hot flashes, fatigue, painful sex, and mood changes related to endocrine therapy can interfere with adherence to life-prolonging therapies. By refusing ovarian suppression or by stopping or not taking prescribed endocrine therapies – intended for curative or palliative intent – patients may reduce their chance of benefiting from these treatments. As a result, symptom management is not optional comfort care; it is a critical component of cancer care.

Women and their partners experience considerable uncertainty regarding medically-induced menopause, finding gaps in the cancer counseling and survivorship planning provided in multiple health care systems. Specifically, many report that they are not adequately prepared for the rapid onset of menopause, symptoms, and/or childbearing limitations. Additionally, women and their partners report receiving incomplete or sporadic advice about the issues that are most salient to them: fertility, sexual health, and long-term risk. Many women feel that they are sent out the door as soon as treatment is complete, without exploration of, or adequate preparation for, potential late effects.

Why Treatment-Induced Menopause Feels Different

The two scenarios both result in hormone deficiency, but the rate of hormone decline and consequently the rate of onset of symptoms can differ. Abrupt loss of hormones tends to result in more severe and earlier onset symptoms than does a gradual loss of hormones, such as that which occurs during the process of natural menopause. In the case of natural menopause, there is typically a period of erratic ovulation and unpredictable withdrawal bleeds before menstruation stops. In contrast, certain cancer therapies and surgeries (such as chemotherapy or prostate cancer in women) can result in a rapid loss of ovarian function. Patients experiencing these scenarios are therefore left to cope with severe night sweats and sleep disturbances, which may markedly increase fatigue and distress at a time when patients are already experiencing considerable physical and psychological stress from their cancer treatment.

The Hidden Long-Term Impact

Many silent long-term consequences of early menopause and breast cancer occur before we notice their effects, often long after the first symptom appears. For example, bone loss caused by early menopause may seem harmless until a fracture occurs. However, bone loss may start sooner than that first fracture. Women diagnosed with breast cancer often experience several negative cardiometa- bolic changes, some of which begin shortly after treatment due to decreased physical activity and weight gain. A survivorship plan that monitors for these negative consequences and prevents their occurrence can help reduce harm while building on a woman’s breast cancer recovery.

For Some Patients and Families Patients with breast cancer diagnosed at a young age are particularly affected by the effects of infertility concerns and early onset of hormone deficiency. While chemotherapy can cause temporary or permanent cessation of ovarian function in some women, for others it can lead to chemotherapy-induced ovarian failure, which can be treated with medications for months or even years. Others may choose surgical oophorectomy, leading to immediate menopause. Many of these patients have not completed their family, making discussions of fertility particularly important. These decisions are often timely and sensitive.

One of the more difficult symptom-management trade-offs that physicians face revolve around patients with hormone-receptor positive breast cancer. In order to reduce the risk of recurrence in these patients, many require some form of estrogen-lowering therapy. For premenopausal women, this may take the form of ovarian suppression in addition to endocrine therapy, such as tamoxifen or an aromatase inhibitor, that can exacerbate the very difficult menopausal symptoms of hot flashes and weight gain. Since systemic hormone therapy is contraindicated in hormone-sensitive disease, treatment of symptoms and sexual function issues is limited to nonhormonal interventions. Counsel-ing women with breast cancer and their families about these issues is essential, in addition to closely monitoring patients for any signs of toxicity and taking a shared decision-making approach.

Patients at risk for osteoporosis or cardiovascular disease prior to starting treatment should be monitored more closely as they transition through early menopause. Patients with other factors such as low body weight, vitamin D deficiency, history of fracture in first degree relatives, smoking history, long term use of steroids or decreased mobility may have accelerated bone loss. Patients with hypertension, diabetes, kidney disease or a strong family history of heart disease for atherosclerotic disease should be aware of their pre-treatment cardiovascular risk and have this risk evaluated pre- and post-treatment.

All clinicians from all clinical fields (oncology, gynaecology, primary care, reproductive medicine, mental health, sexual health) need to be aware of the possibility of a medical menopause as a result of treatment and know how to signpost patients to relevant services for support. Oncologists will focus on curing the patient of their cancer, while the patient and the gynaecology and primary care teams focus on cure of their menopausal symptoms. Reproductive specialists can provide counselling on options for fertility preservation before treatment, and mental health specialists can support patients who have been affected by their illness and the loss of their future options for motherhood, and also address issues of anxiety, low body esteem, and relationship issues following treatment.

Health systems and payers play critical roles in ensuring that individuals and families have access to the services and care needed to manage the late effects of cancer. Variability exists in coverage and access for costly and time-sensitive fertility preservation options, as well as for effective symptom management and risk-based prevention strategies. Further, there is variable access to bone-protective therapies, pelvic floor therapy, sexual counseling, and effective nonhormonal treatments for vasomotor symptoms. However, systems that have invested in survivorship clinics, implemented nurse navigation, and provided multidisciplinary counseling have achieved optimal outcomes and prevented additional morbidity.

Equity and Access Considerations

While access to medical care for breast cancer patients is not equal across the board, unequal access to health care could potentially exacerbate long- and short-term health disparities for women. Patients from disadvantaged neighborhoods may lack access to physicians who treat conditions of the female reproductive system as well as to doctors and health-care providers who can address symptoms of menopause and other issues related to breast cancer treatment. They also may not have access to health-care providers who can address pelvic floor dysfunction and sexual health issues in women who have had breast cancer, as well as patients who have survived breast cancer and can provide new patients with guidance, support and resources. Other barriers to access to sexual health care for patients with breast cancer may include transportation and time constraints, language and communication barriers, and stigma and shame around issues of sexuality and intimacy. Building these pathways to equity will require early counseling and referral support, the use of telehealth to provide patients with timely access to health care, and clear policies about which costs related to fertility preservation will be covered expeditiously.

What Changes

• Early counseling becomes standard: Patients should receive counseling about the risk of treatment-induced menopause and fertility preservation options at diagnosis so they can weigh trade-offs before starting therapy.
• Care becomes multidisciplinary: Effective management requires coordination among oncology, reproductive medicine, primary care, mental health, and sexual health specialists to address short- and long-term needs.
• Survivorship planning expands: Follow-up care should incorporate bone health monitoring, cardiovascular risk assessment, and targeted symptom management tailored to those who entered menopause prematurely.

Additional context and clinical considerations

Fertility preservation is one of the most time-sensitive issues that patients and families need to consider. Decisions regarding the option of egg or embryo freezing can be made within days of diagnosis, and in some cases even before initial treatment begins. The success of using medications to suppress ovulation and preserve ovarian function to allow fertility postponement varies based on the specific cancer treatment plan under development.

Consideration of bone and cardiovascular health. Estrogen has a protective effect on the bone as well as certain aspects of heart health. Early loss of the ovarian hormones can add years to the time it typically takes for adverse effects on the bone and increased risk of cardiovascular disease to become apparent. Consider baseline assessment of bone density for these survivors and include healthy lifestyle habits, adequate calcium and vitamin D and appropriate medications to protect the bone. Counsel the survivor regarding her risk for and management of cardiovascular disease especially if on therapies that have cardiovascular effects.

Sexual health and psychosocial well-being are often poorly addressed in cancer survivorship. Symptoms such as vaginal dryness, pain during vaginal intimacy, decreased sexual desire, and negative body-image change are common yet stigmatising issues that affect quality of life yet are often not addressed by survivors or their clinicians. There is evidence to support the use of a number of nonhormonal interventions and therapies, including pelvic floor therapy, vaginal moisturizers and other strategies that address issues related to sexual health and psychosocial issues. There is also strong evidence that indicate survival is impeded by clinicians’ lack of willingness to initiate topics related to sexual health. Ready access to appropriate treatment and referrals is also needed.

Systemic hormonal menopause treatment with hormone replacement therapy (HRT) is contraindicated in women with a history of breast cancer. Furthermore, many women with a history of breast cancer, particularly those with hormone receptor-positive breast cancer, fear that taking HRT will stimulate any remaining cancer cells. For women with prior mastectomy/surgical menopause, treatment options for hot flashes and night sweats are limited. In these cases, both patients and providers must weigh available nonhormonal pharmacologic and device-based options.

System and policy implications

Ensuring that cancer survivors have equitable access to use of fertility preservation, as well as to prevention and treatment of menopause is a concern for policymakers. Currently, payers in the United States and in other regions and countries do not have consistent policies for coverage of egg or embryo freezing, of consultation with a reproductive endocrinologist or surgeon, or of pharmacologic treatment of osteoporosis for prevention of bone loss. A number of policy and programmatic strategies—including mandates for coverage, bundled cancer care pathways, and incentives for programs and research focused on cancer survivorship—could reduce disparities and promote better health outcomes for young women with cancer.

Training and workforce development, in addition to research and medical solutions, is needed to ensure that all cancer survivors and their families have access to quality care. Clinicians, particularly oncologists, gynecologists, and primary care physicians, require more and better training to identify and manage common and distressing menopause symptoms experienced by survivors of cancer. Additionally, physicians such as oncologists should receive education and training on fertility counseling, menopause, and late effects, as well as training on how to discuss these topics with patients and provide management and referral for them. Including nurse navigators, social workers, and other reproductive specialists in the oncology care team can facilitate timely treatment decisions and provide crucial support and follow-up to women diagnosed with cancer during their reproductive years in the months and years following diagnosis.

What’s next

Future research and clinical care should facilitate patients and their families making informed decisions about planned treatment, and potential support needs for management of symptoms during and after treatment for a cure, based on the probability of a relapse, as well as patient and family preferences.

There is an ongoing need for development and translation of effective, safe, nonhormonal therapies for patients with germline mutations, in addition to the continued development and translation of hormonal therapies for certain subsets of patients.

Additionally, there is an ongoing need for improvement of existing technologies for fertility preservation. Furthermore, there is a need for the health care system to standardize high-quality cancer diagnosis counseling, to ensure timely insurance coverage for fertility preservation options, and to implement routine surveillance for bone and cardiovascular events in long-term survivors.

The patient voice needs to be heard more! Those who have gone through medically-induced menopause describe feeling a sense of loss or even a change of identity. Cancer treatment planning tends to focus on the endpoint and then patients are generally left to their own devices to plan and manage their ongoing care and life in the wake of cancer. These issues need to be recognized as critical to quality cancer care and programs and systems need to be created to provide timely education, options and follow-up care to support the health and quality of life of these survivors.

References:

https://www.breastcancer.org/treatment-side-effects/menopause