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Natural Medicine Journal

August 7, 2024

Vaginal Estrogen Therapy in Breast Cancer Survivors

Findings from a population-based cohort study

Kaycie Rosen Grigel

ND
Does replenishing estrogen after estrogen depletion increase mortality risk from breast cancer?

Reference

McVicker L, Labeit AM, Coupland CAC, et al. Vaginal estrogen therapy use and survival in females with breast cancer. JAMA Oncol. 2024;10(1):103-108.

Study Objective

To determine whether the use of vaginal estrogen therapy is associated with higher mortality from breast cancer in breast cancer survivors vs survivors who did not use vaginal estrogen

Key Takeaway

Breast cancer survivors who used vaginal estrogen therapy did not have a higher breast cancer–specific mortality rate than those who did not use estrogen. 

Design

Population-based cohort study

Participants

The 2 cohorts were comprised of 49,237 women between 40 and 79 years of age with newly diagnosed breast cancer who were identified from national cancer registry records in Scotland and Wales.      

The Scottish cohort was drawn from diagnoses from 2010 to 2017, and over 80% of the participants had stage 1 or 2 disease. The Welsh cohort was recruited from 2000 to 2016, and at least 74% of participants had stage 1 or 2 disease. The cohorts were followed for breast cancer–specific mortality until 2020. Exclusion criteria included any previous diagnosis of cancer, with the exception of nonmelanoma skin cancer. 

Interventions

Investigators divided dose and duration of vaginal estrogen therapy by: 1 to 4 prescriptions vs 5 or more prescriptions; and low-dose (1–24 µg tablets) vs high-dose (25 µg tablets) therapy. They also recorded use of systemic hormone replacement therapy (HRT).

Study Parameters Assessed

In addition to the use of vaginal or systemic hormone therapy, patient characteristics that investigators recorded included: age, year of diagnosis, socioeconomic status, hysterectomy or oophorectomy before or after diagnosis, hormone receptor status, cancer stage and grade, cancer treatments received, and hormone-modifying treatment. They also recorded comorbidities, use of other medications, such as statins, aspirin, metformin, or oral contraceptive pills (OCPs).

Primary Outcome

The primary outcome was time to breast cancer–specific mortality for vaginal-estrogen-therapy users vs nonusers.

Key Findings

The median duration of the follow-up was 8 (5–12) years in the Wales cohort and 5 (3–7) years in the Scotland cohort.

Overall, 5 percent (N=2,551) of the participants used vaginal estrogen after their breast cancer diagnosis.

A small decrease in breast cancer–specific mortality was found in those who used vaginal estrogen, in the pooled, fully adjusted model (HR 0.77; 95% CI, 0.63–0.94).      

Similarly, there was no increase in risk when limiting the analysis to estrogen receptor–positive breast cancer participants only (HR, 0.88; 95% CI, 0.62–1.25). 

Again, when assessing those who were taking an aromatase inhibitor, the investigators found there was no increase in breast cancer–associated mortality (HR, 0.72; 95% CI, 0.58–0.91).

Transparency

The study was funded by grants from Cancer Research UK. Researchers on this study reported receiving funding from Cancer Research UK, Northern Ireland Department for the Economy, Queen’s University Belfast, and UK Research and Innovation. One researcher received fees from pharmaceutical firms including Roche, Lilly, MSD, AstraZeneca, BD, and Novartis.

Practice Implications & Limitations

This study offers an important data point in the ongoing conversation around how to help breast cancer survivors regain and retain health in spite of estrogen depletion as a result of their treatment. Estrogen deprivation is common in breast cancer survivors for a number of reasons. For example, chemotherapy can induce premature ovarian failure in premenopausal breast cancer patients. Also, for the 80% of breast cancer survivors who have had a tumor that is hormone-dependent, the standard recommendation is anti-estrogen therapy, either as an aromatase inhibitor or selective estrogen receptor modulator (like tamoxifen). For these women, estrogen depletion is actually the goal of therapy, which puts survivors in a uniquely complex and uncomfortable position. Estrogen depletion, particularly for those women diagnosed before menopause, can create a whole host of health issues. This can include negative impacts on bone and cardiovascular health, as well as serious quality-of-life issues associated with menopausal symptoms such as hot flashes, night sweats, joint and muscle pain, anxiety, depression, and more. 

One particularly distressing impact of anti-estrogen therapy is the genitourinary syndrome of menopause (GSM). This is a collective term for a range of issues experienced by postmenopausal women, which can include vaginal dryness, itching, irritation, atrophic vaginitis, dyspareunia, dysuria, and chronic urinary tract infections. It is extremely common in the general population—around 50% of postmenopausal women experience this issue. However, over 70% of breast cancer survivors experience GSM. It can be painful and inconvenient and can significantly reduce quality of life. This is a primary cause of discontinuation of estrogen-blocking medications, which could potentially lead to an increase in cancer recurrence.1

So if estrogen deprivation is the cause of this issue and replacing estrogen will solve the issue, it follows to ask the question: What are the actual risks and benefits of estrogen use in breast cancer survivors?

In the past 20 years, it has become the standard to avoid the use of HRT in breast cancer survivors. Through the Million Women Study results published in 2003, it was found that current users of HRT at recruitment were more likely than never users to develop breast cancer.2 Similarly, an article from 2019 in The Lancet reported that for women over 50, estrogen use increased incidence of breast cancer by 1 in 200 users.3 Since the publication of the Million Women Study, it has become standard to strongly advocate against the therapeutic use of hormones for any breast cancer survivor, and patients are often hesitant to use hormones regardless of their breast cancer risk or personal history. 

However, in the past 5 years, studies have created more questions around the actual risk of breast cancer associated with the use of estrogen alone, rather than estrogen plus progestin combinations. Results from the Women’s Health Initiative, which followed more than 27,000 postmenopausal women for over 20 years, found that in women with a prior hysterectomy, the use of conjugated equine estrogen (CEE) alone reduced the risk of breast cancer by 23% and breast cancer death by 40%. In contrast, CEE plus medroxyprogesterone acetate (MPA) was associated with statistically significantly higher breast cancer incidence.4,5 Similarly, several articles from the past 2 years have contrasted the findings of the Women’s Health Initiative with results from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study. Ultimately, they all advocate for the use of estrogen-alone therapy for postmenopausal women with a prior hysterectomy.6

This information is reassuring for women who would like to use estrogen, but what about breast cancer survivors in particular? In general, articles from the past 2 years have shown detrimental effects from estrogen-progestin combinations, but no increased risk of mortality from using estrogen-only combinations, with or without tamoxifen or aromatase inhibitors.7,8 Based on the potential health benefits to breast cancer survivors suffering from estrogen depletion, some studies have been recommending the use of estrogen alone for survivors.9,10

But what about recurrence risk? In the study we are reviewing here, there was no increased risk of mortality, but investigators did not evaluate recurrence. A few trials have shown no increased risk of recurrence in survivors who have used estrogen. For instance, in a 2023 trial similar to the 1 under review here, a claims-based analysis was performed of more than 42,000 women aged over 13 years with a diagnosis of GSM after breast cancer diagnosis. Of these, 5% were given vaginal estrogen. Risk of recurrence was comparable between those who had used vaginal estrogen and those who had not, regardless of the tumor’s estrogen-receptor status.11 In contrast, a recent Danish study found that while neither vaginal nor systemic estrogen therapy resulted in an increased incidence of recurrence or mortality in breast cancer survivors, in survivors who were also taking aromatase inhibitors, there was an increased risk of local recurrence, but not mortality and not distant recurrence.12 So, while the use of vaginal estrogen after a diagnosis of breast cancer does not appear to increase the risk of mortality, the impact on local recurrence while taking anti-estrogen treatment is still unclear.

So, while the use of vaginal estrogen after a diagnosis of breast cancer does not appear to increase the risk of mortality, the impact on local recurrence while taking anti-estrogen treatment is still unclear.

With this in mind, how do we counsel our breast cancer survivor patients who are suffering from GSM? First, we know that there are many factors, many of which are modifiable, that can contribute to the likelihood of a recurrence. These include family history and genetics, obesity, the use of oral contraceptives, smoking, alcohol consumption, stress, and environmental exposures to chemicals and xenoestrogens.13-15 Fortunately, some of the same things we know to be important lifestyle modifications for breast cancer prevention can also benefit GSM: These include healthy diet, smoking cessation, losing weight, decreasing stress, maintaining adequate vitamin D and calcium levels, limiting alcohol, and regular physical activity. Smoking cessation, in particular, may decrease the atrophic effects due to increased capillary refill, while weight loss of 5% to 10% of total body weight has been shown to improve urinary incontinence. Also, if regular sexual activity can be maintained, this increases blood flow to the genital area, which can help to keep the tissues healthy.16

Beyond lifestyle changes, a range of nonhormonal topical products and pelvic-support options are available as a first-line therapy. This includes vaginal moisturizers, lubricants, pelvic-floor physical therapy, and dilator therapy. Some interest has been shown in the use of a hyaluronic acid gel; 1 trial found that applying this 3 to 5 times per week improved vulvovaginal health and sexual function in breast cancer survivors.17

If nonhormonal measures are unsuccessful, using vaginal estrogen products is recommended as a good next choice, followed by systemic HRT.18-20 With the concern for the potential of recurrence, which has not been definitively resolved, it is worthwhile to consider the dosage of vaginal estrogen used. We know that some amount of vaginal estrogen will be absorbed systemically, but there is no “acceptable” standard limit for estrogen levels in survivors, even for those taking aromatase inhibitors.21,22 However, if maintaining low estrogen is the goal, in very low-estrogen preparations (4 µg or less of estradiol), very low to no systemic absorption has been measured.23

Another option to consider is vaginal estriol preparations. Several trials of vaginal estriol in breast cancer survivors taking aromatase inhibitors have shown an improvement in GSM symptoms, with no increase in circulating estradiol levels.24-26 While the dosage of vaginal estrogen preparations varied widely in this trial, no change in mortality rate was found with any dosage, even that of 25 µg or higher. 

The benefits of estrogen are clear: management of climacteric symptoms and GSM, improved cardiovascular health, protection of cognitive health, and maintenance of healthy bone density. However, there is a legitimate concern among providers of breast cancer survivors that utilizing estrogen of any kind to improve and maintain health could lead to an increased risk of recurrence. Following the results of the Women’s Health Initiative, some researchers and providers have started thinking again about the possibility of using estrogen in this population. 27-29 This trial gives us 1 more piece of data to help us understand the nuances of how we can best support the long-term health and vitality of our patients who are breast cancer survivors.    

Categorized Under

Kaycie Rosen Grigel

ND

Kaycie Grigel, ND, is a 2003 graduate of Bastyr University. She has owned the Golden Naturopathic Clinic, LLC, since 2006 and is the creator of Thriving Survivors, which offers online courses and support programs to help breast cancer patients and survivors maintain and recover their vitality through and after treatment. Her clinical practice focuses on endocrine support for women and breast cancer survivors. She lives and practices in Golden, Colorado.

References

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  3. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168. 
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