Questions and Answers About Menopause Therapy with Nathalie Gamache, MD, FRCPS(C)

By Nathalie Gamache, MD, FRCPS(C)

Gynecologist/Fellow in Menopause and Women’s Health

 

Does hormone therapy (HT) lead to increased risk of breast cancer?

Prior to 2002, hormone therapy (HT) had been prescribed to menopausal women for approximately 60 years in North America. Forty percent of menopausal women took HT for symptom control, and a third of prescriptions were for women older than 60 years. Based on large observational reports, HT also was recommended for prevention of osteoporosis and coronary heart disease (CHD). In 2002, the Women’s Health Initiative (WHI)—the first randomized controlled trial examining the association between HT and overall risks and benefits for chronic-disease prevention in postmenopausal women aged 50-79 years—was stopped prematurely because the rate of invasive breast cancer exceeded the established boundary for this adverse effect.

In the WHI, women were treated with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), or placebo. In all, more than 16,000 participants were studied for more than five years. The estimated hazard ratio (HR) for breast cancer was 1.26 for treatment vs. placebo, and the absolute excess risk per 10,000 person-years attributable to combined estrogen and progestogen was eight more cases of invasive breast cancer in the treated group; within the range of zero to one extra cases per 1,000 women per year of hormone use, an event rate defined as “rare” according to standard nomenclature.

Much can be said about the WHI’s inclusion of older women than originally intended, the questionable inclusion of a large proportion of less-than-healthy study subjects, and the failure to stratify by age in the original publication; but the media also had its role to play in reporting inexact interpretations, which contributed to plunging menopausal women and their health providers into a dark abyss. Fifteen years later, we still struggle to address unfounded fears about breast-cancer risk from HT for most women who could significantly gain from its established benefits.

Further reading:

1. Roussow JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288(3):321-33.

2. International Menopause Society. Hormone therapy and cardiovascular disease in the early postmenopause: the WHI data revisited. Press Statement. April 3, 2007.

3. Roussow JE, Manson JE, Kaunitz AM, et al. Lessons learned from the Women’s Health Initiative trials of menopausal hormone therapy. Obstet Gynecol 2013; 121(1):172-6.


Do types and components of HT matter when it comes to risk of breast cancer?

When the WHI re-analysis was published in 2007, it revealed that hysterectomized women in the estrogen-only group did not face an increased risk of breast cancer compared to women receiving CEE and MPA. Interestingly, in vitro studies dating back to 1999 had demonstrated high levels of cell proliferation and density in the breast tissue of women treated with MPA.

In 2008, the publication of the French E3N cohort study, which looked at more than 80,000 postmenopausal women receiving estrogen and various types of progestogens for 8.1 years, revealed the relative risk of breast cancer to be neutral in postmenopausal women receiving micronized progesterone (HR 1.0) but much higher with other types of progestogens (HR 1.69). This finding was substantiated by several in vitro studies which revealed the ability of micronized progesterone to induce apoptosis in breast cancer cells and its inability to cause proliferation of breast epithelium in ovariectomized adult female monkeys.

The E3N study found no difference in the risk of breast cancer according to the route of administration of estrogen, whether oral or transdermal; but compared to the WHI results, risks of breast cancer were higher in women receiving estrogen alone (HR 1.29). Several factors, including differences in population characteristics, types of estrogen, prior exposure, doses, as well as the fact that E3N was a cohort study, may explain the divergent results.

Based on all available studies to date—in vitro, animal, or human population—it is clearly established that the type of progestogen matters when it is time to choose HT treatments. It appears that micronized progesterone offers neutrality given its protective mechanism of action at the level of breast tissue, while other progestogens might contribute to elevated risks of breast cancer. In general, most studies also support neutrality in the risk of breast cancer for women with previous hysterectomy on estrogen-only therapy.

Further reading:

1. Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci 1998; 28(6):360-9.

2. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks of breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008; 107(1):103-11.

3. L’Hermite M, Simoncini T, Fuller S, et al. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas 2008; 60:185-201.

4. Gadducci A, Biglia N, Cosio S, Sismondi P, Genazzani AR. Progestagen component in combined hormone replacement therapy in postmenopausal women and breast cancer risk: a debated clinical issue. Gynecol Endocrinol. 2009;25(12):807-15.


Is a personal or immediate family history of cancer a contraindication to HT?

Aside from a personal history of most breast-cancer types, or a family history of two or more immediate relatives with breast cancer (especially when diagnosed before age 50 years), there are no absolute nor relative contraindications to HT in other cancer survivors or those with a family history.

A common belief is that gynecological cancers such as ovarian, uterine, and cervical cancers are hormonally-dependent. On the contrary, several studies have in fact suggested an advantage for survival and health in women treated with HT for postmenopausal symptoms. The endometrioid types of ovarian and uterine cancer might be an exception, but this remains to be fully understood since there have been too few studies with appropriate numbers-to-treat. Most gynecological oncologists will still allow these women to use low-dose HT for relief of moderate-to severe-menopausal symptoms.

Although the role HT plays in the mutation of breast-cancer cells remains debated and challenged, there is fairly clear evidence that certain types of HT can enhance proliferation and invasion of yet-to-be-diagnosed abnormal mammary cells. Based on this, there is general consensus against HT treatment for women with truly hormone-dependent cancer types. Exceptions can be made for women who suffer from intractable symptoms, who have not responded to alternative therapies, and who have been appropriately informed of potential risks. Women who carry the BrCa1 gene, or who have demonstrated no hormone dependence, can consider HT as an option to resolve postmenopausal symptoms; and, of course, judicious HT choices (especially progestogen types) should be made in these cases.

What about younger women in need of hormone replacement therapy (HRT)? The evidence favoring treatment with HRT is solidly established for young women below the natural age of menopause whose treatments such as radiation or chemotherapy induce the arrest of ovarian function, or who experience surgical menopause after a bilateral oophorectomy. In these women, maintenance of neurological, immune, muscular and connective-tissue integrity; prevention of inflammatory processes; protection against osteoporosis, heart disease, metabolic syndrome; and promotion of wellness are achieved by replacement of age-adjusted physiological levels of estrogen, progesterone, and potentially testosterone, until they reach the average age of menopause. Under no circumstance should HRT be considered to put these women at the same dose- or duration-related risks as spontaneously menopausal women of more advanced age.

Finally, breast-cancer survivors often report urogenital symptoms and dyspareunia caused by estrogen withdrawal after treatment, which often impacts sexual wellbeing in a profound manner. As with systemic HT for women with estrogen-dependent breast cancer types, local estrogen to recover vaginal health has long been considered risky for recurrence, and therefore thought of as contraindicated. However, more recent studies looking at women receiving selective estrogen receptor modulators or aromatase inhibitors have not demonstrated an increased risk of recurrence. This offers a valid option for women who have not responded to other non-hormonal treatments.

Further reading:

1. Schifren JL, Gass MLS. The North American Menopause Society Recommendations for clinical care of midlife women. Menopause 2014; 21(10):1-25.

2. Wills S, Ravipati A, Venuturumilli P, et al. Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. J Oncol Pract 2012 ;8:144-8.

3. Trinkaus M, Chin S, Wolfman W, et al. Should urogenital atrophy in breast cancer survivors be treated with topical estrogens? The Oncologist 2008; 13:222-31.

4. Rees M. Gynaecological oncology perspective on management of the menopause. EJSO 2006; 32:892-7.


Does HT need to be stopped after five years?

When the WHI trial ended at 5.2 years due to the excess cases of invasive breast cancer in women receiving HT compared to placebo, the impact was immediate, and a dramatic reduction was observed in the number of HT prescriptions written in North America. From the results, it was concluded that HT treatment was probably safe for up to five years in healthy women suffering from postmenopausal symptoms.

In 2004, the International Menopause Society (IMS) issued their Statement on HT, emphasizing the importance of age to determine the risk profile of HT, and that healthy women in their early postmenopause period should not be concerned about the risks of HT. Accordingly, when the WHI figures were re-analyzed in 2007, stratified by age groups and by intact uterus vs. hysterectomy, the data revealed no extra risk of breast cancer during the first seven years of standard doses of estrogen and progestin. Furthermore, estrogen-only therapy in women of all ages with a prior hysterectomy was associated with significant protection against invasive breast cancer at 7.1 years, with an HR of 0.67.

In 2012, the Danish Osteoporosis Prevention Study was published. Also a prospective randomized controlled trial, it studied 1,006 young and healthy recently menopausal women receiving HT (oral estradiol and norethisterone acetate) vs. placebo for 10 years, followed for a total of 16 years. The occurrence of breast cancer after 10 years was not significantly different between the groups, and trended towards statistically non-significant reduction in events in the HT group. Again, women with a previous hysterectomy receiving estrogen alone showed a decreased risk of breast cancer compared to women in the control group.

Since most women with moderate symptoms of menopause will experience significant improvement or complete resolution five to seven years after meno­pause, recent studies including the WHI suggest that HT will not increase the risk of breast cancer during that duration of treatment. For women struggling with symptoms beyond 10 years, relevant studies are lacking, and international guidelines on HT suggest using the lowest dose needed to maintain the benefits for which they were initiated, for as long as required. Appropriate surveillance, counselling, and reduction of modifiable risks such as excess weight, lack of physical activity, and alcohol consumption can play a significant role and are advisable for all postmenopausal women.

Further reading:

1. Belisle S, Reid R, Mills C. Canadian Consensus on Menopause, 2006 Update: Chapter 10 Cancer. J Obstet Gynaecol Can 2006; 28(2):S89.

2. International Menopause Society. Hormone therapy and cardiovascular disease in the early postmenopause: the WHI data revised. Press Statement. April 3, 2007.

3. L’Hermite M, Simoncini T, Fuller S, et al. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas 2008; 60:185-201.

4. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 2012; 345:1-11.


Development of this article was made possible through the financial support of Merck Canada Inc. The opinions expressed herein are those of the author and do not necessarily reflect the views and opinions of Merck Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.