Menopause after cancer: hormonal and nonhormonal management
Advances in cancer survival have led to more women living long enough to reach menopause or experiencing menopausal symptoms as a result of treatment. Management can be challenging in these cases, especially when hormone therapy is not appropriate. This article outlines the consequences of untreated menopause post-cancer, hormonal and nonhormonal treatment options, and when to refer to a specialist menopause service to support post-cancer patients in primary care.
- As cancer survival rates improve, more women are living long enough to reach menopause or enter early menopause induced by treatment, requiring management in the community setting.
- Cancer treatment-induced menopause often results in significant short- and long-term health impacts.
- Menopausal hormone therapy (MHT) remains the most effective treatment for menopause symptoms but is often contraindicated post-cancer, depending on hormone receptor status and cancer type.
- Several effective nonhormonal treatment options are available for women who are ineligible for, or prefer to avoid, MHT.
- GPs should refer women with complex or refractory menopause symptoms to a specialist menopause service such as the newly established Specialist Menopause Hubs in New South Wales.
As cancer survival rates improve in developed countries, survivorship issues related to menopausal symptoms, bone health and fertility implications are becoming more common.1 This pattern emerges from improved screening, earlier detection and treatment at younger ages.2 More cancer patients are also living long enough to reach menopause or enter early menopause as a side effect of their oncotherapy.3 Often, the symptoms of menopause are further exacerbated in some cancers by endocrine therapy that may continue for up to a decade. Such cases represent a particular challenge, as standard hormonal treatment regimens are often contraindicated.
Recently, an increased public awareness of the impacts of untreated menopause has led to a significant enhancement of government expenditure in this area. In New South Wales, four Specialist Menopause Hubs have been established as referral centres for complex and refractory menopause cases (https://aci.health.nsw.gov.au/networks/menopause/about).4 This project may see expansion to other states in the future.
These Specialist Menopause Hubs serve as referral and support services for GPs in the community, where most menopause care takes place. Women who are referred to a Specialist Menopause Hub will have their symptoms assessed and treatment initiated before returning to the community for ongoing care. GPs are therefore becoming increasingly involved in long-term menopause care, including in post-cancer cases. This article is a practical guide to caring for these women in the community.
Consequences of untreated iatrogenic menopause post-cancer
Short-term consequences
Cancer treatment can lead to an abrupt cessation of ovulatory function through surgical removal of the ovaries, chemotoxicity or radiotherapy.5-7 This type of acute iatrogenic menopause may be associated with more severe symptoms than those seen with physiological onset.6
Iatrogenic menopause may arouse sudden and severe vasomotor symptoms, sleep disturbance, fatigue, brain fog and vaginal dryness. These effects may be further compounded by ongoing chemotherapy, or endocrine therapy such as tamoxifen or aromatase inhibitors.5 Women often feel unprepared for and disturbed by these symptoms, as they expect to exit their arduous cancer treatment and return to ‘normal’ life.8 It is therefore important that they have access to effective information and treatment.
Long-term consequences
Although ovarian function may eventually return in some women, many will be rendered menopausal for the rest of their life.9 This early oestrogen deprivation is associated with a number of long-term health implications, including:
- accelerated bone loss and increased fracture risk10
- premature cardiovascular disease11
- severe and progressive genitourinary symptoms12
- persistent disturbing hot flushes and night sweats13
- infertility.
Therefore, it is important to discuss hormone replacement with eligible women and to consider nonhormonal alternatives for those who are ineligible for, or prefer to avoid, hormone therapy. The mechanisms by which cancer treatments induce menopause or aggravate symptoms are outlined in Box 1.1,5,10,14
Treatment selection
Hormone receptors
Although menopausal hormone therapy (MHT) is the most effective treatment for menopause symptoms, it is not suitable for all patients post-cancer. Several common cancers have receptors for oestrogen and progesterone, and hormone replacement can increase the likelihood of cancer recurrence.15 Cancers linked to oestrogen and progesterone receptors are presented in Box 2.3,16-18
The histopathology and hormone receptor status should therefore be confirmed in these cases, and cases of any rare malignancy, before commencing treatment. Most women with a history of oestrogen receptor-positive (ER+) or progesterone receptor-positive tumours require referral to a specialist menopause service, but nonhormonal treatment could be commenced in the meantime.
Hormonal treatment options
Systemic menopausal hormone therapy
In the absence of hormone receptors, systemic MHT may be considered.15 MHT is deemed the most effective approach for managing menopausal symptoms and offers potential benefits in preventing osteoporotic fractures, cognitive decline and cardiovascular issues, especially in those who are menopausal at under 45 years of age, while enhancing overall quality of life.12,19
Prescription of MHT in eligible women post-cancer follows the same principles as in physiological menopause cases, with some key additional considerations.
- Transdermal oestradiol is generally preferred because of the neutral effect on the risk of thromboembolism, which may be elevated during or after cancer treatment.20
- Younger women, or those with more abrupt cessations of ovulatory function, may require higher initial oestradiol doses.21
Ongoing follow-up and monitoring of hormone therapy should be carried out according to the usual prescribing principles. If menses return, the need for hormone replacement should be reviewed.
Vaginal hormonal therapies
For women with genitourinary symptoms of menopause, vaginal oestrogen is an effective treatment.22 Vaginal hormonal therapies act on the vaginal mucosa by increasing epithelial thickness, enhancing revascularisation and raising the number of superficial cells. These changes help restore the normal vaginal flora, including lactobacilli, and lower the vaginal pH, resulting in symptom improvement.23 Vaginal hormonal therapies may cause limited systemic absorption in some women.
An alternative local treatment is intravaginal prasterone, also known as dehydroepiandrosterone (DHEA).24,25 DHEA is converted locally into small amounts of active sex steroids, depending on the specific physiology of each cell and tissue.24 When used intravaginally, it has shown highly positive effects on the symptoms and signs of vulvovaginal atrophy, with minimal to no systemic oestrogen absorption and a theoretical improvement in libido.24 Vaginal prasterone is usually used nightly.
Typically, vaginal hormonal therapy is prescribed as an initial daily induction regimen for a minimum of two weeks before down-titration to at least twice a week on an ongoing basis.
Nonhormonal treatment options
In lieu of hormonal options, extensive research has been conducted into nonhormonal treatments for menopausal symptoms. Nonhormonal options are typically less effective for treating menopausal symptoms; however, they remain the primary option for women with a history of ER+ cancers. A summary of the nonhormonal treatment options is presented in the Table.14,21,26-35 In general, lifestyle changes such as exercise, weight loss and smoking cessation may also help improve the tolerability of symptoms but do not directly modify vasomotor symptoms.
Treatment of menopause symptoms after breast cancer
Breast cancer is the most commonly diagnosed cancer worldwide and the most commonly diagnosed malignancy in women who are 40 years of age and younger.2 Women whose quality of life is significantly affected by menopausal symptoms may be more likely to discontinue breast cancer treatment, increasing the risk of recurrence and reducing survival.36 Therefore, proactive treatment of post-cancer menopause symptoms is crucial.
Hormone receptor-positive breast cancers
Women experiencing menopause symptoms following hormone receptor-positive breast cancers should be managed with nonhormonal treatment options, as outlined in the Table.14,21,26-35,37 Systemic hormone replacement in such cases has shown an increased risk of cancer recurrence.16,19 This risk also extends to the use of the synthetic steroid tibolone, which has similarly been linked to higher rates of breast cancer recurrence.19,38 Many women will tolerate daytime hot flushes but seek relief from disruptive night sweats. Nighttime administration of oxybutynin (0.5 to 1 mg) or gabapentin (300 to 900 mg) is often effective for these individuals, although both are prescribed off-label.
Hormone receptor-negative breast cancers
Breast cancers classified as triple-negative may exhibit undetectable hormone receptor levels at diagnosis or may develop hormone receptors during metastasis.39 Therefore, nonhormonal options are typically first-line treatments. However, women with triple-negative breast cancers tend to be younger and there is a low threshold for prescribing systemic MHT if needed. Studies have not demonstrated an increased risk of cancer recurrence associated with MHT in this group.19 In general, women who have had breast cancer should be referred to a specialised menopause service.
Vaginal symptoms
Topical vaginal oestrogen is generally considered safe to use in women with a history of hormone receptor-positive breast cancer if nonhormonal moisturisers are not effective. Although a meta-analysis showed that local oestrogen in women receiving aromatase inhibitor therapy was not associated with systemic absorption of sex hormones, it is recommended to use the lowest effective dose.37,40,41 Aromatase inhibitors are not oestrogen receptor blockers; instead, they work by suppressing systemic oestrogen production. Some oncologists remain concerned that even minimal systemic absorption of vaginal oestrogens could potentially increase the risk of recurrence in patients with a history of ER+ breast cancer.
Intravaginal prasterone can also be considered for off-label usage as studies using mass spectrometry have not detected oestrogenic nor androgenic molecules in the serum of patients using this product; however, this has not been studied extensively in post-cancer populations.37 It may be wise to periodically test oestrogen serum levels using mass spectrometry in patients who are receiving an aromatase inhibitor and using vaginal DHEA.
Vaginal CO2 laser has been explored as a nonhormonal treatment of vaginal atrophy, but studies have not shown a benefit.42
Testosterone
Off-label use of systemic testosterone for low libido is contentious following hormone receptor-positive breast cancer because of concerns around peripheral aromatisation into oestrogen.43 However, there is evidence that androgens have a suppressor role on ER+ breast cancer, and androgens were often used as endocrine therapy before tamoxifen.44,45 Nonetheless, this discussion should be referred to a specialist menopause service.
Treatment of menopause symptoms after endometrial cancers
Endometrial cancer is the sixth most common cancer worldwide and usually affects women around or after the time of menopause.14 At an early stage, survival rates are excellent with a five-year survival rate of up to 97%.15 Treatment normally involves removal of the uterus, fallopian tubes and ovaries. This generates an abrupt iatrogenic menopause.
Some types of endometrial cancer cells may have oestrogen receptors, and therefore there may be reservations about prescribing systemic hormone replacement.15 However, most women with early-stage endometrial cancer will not have any residual cancer cells following surgery.15 Therefore, MHT can be prescribed as unopposed oestrogen for women with stage 1 or 2 disease if nonhormonal treatment options are inadequate. This process should take place in a specialist menopause service.
Conclusion
With increasing cancer survivorship, a growing number of women are living long enough to reach menopause or experience menopausal symptoms as a consequence of their treatment. Management can be complex, particularly when hormonal therapies are contraindicated. GPs can refer women with complex and refractory symptoms to a specialist menopause service. ET
COMPETING INTERESTS: Professor Eden: None. Dr Brown has received payment for lectures by HealthEd.
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