Influence of Menopausal Hormone Therapy on the Breast: Counseling Your Patients Before You Prescribe

Introduction

The influence of endogenous hormones on the breast is well studied, and changes in hormone levels, such as those that occur during puberty, breastfeeding, menstruation, ovulation, and menopause, can modify breast tissue and lead to breast symptoms throughout the course of a woman's life. For example, during the late luteal phase of the menstrual cycle, women can experience breast pain. The pain is due to the effects of estrogen on the ductal tissue and progestogen on the stromal tissue, and it resolves with the onset of menstruation. ¹

Hormone fluctuations can also affect mammographic breast density (MBD). In premenopausal women undergoing mammography, breast density and the background parenchymal enhancement are higher during the luteal phase (days 15–21 of the menstrual cycle) than during the follicular phase (days 8–14). Women ideally would undergo breast imaging such as mammography or magnetic resonance imaging during the follicular phase of the menstrual cycle. ² For most women nearing menopause, the decline in estrogen levels causes involution of breast tissue and a decrease in MBD. ³ However, for women who are receiving menopausal hormone therapy (HT), the rate of involution is slower and leads to maintenance of dense breast tissue.

HT is prescribed to treat symptoms associated with low estrogen levels. The most common forms of HT are estrogen therapy alone for women without a uterus and combined estrogen and progestogen therapy (EPT) for women with an intact uterus. With EPT, progestogen can be administered either continuously (every day) or sequentially (days 1–12). Estrogen and progestogens are available in several different formulations such as oral, transdermal, intramuscular, or topical medications.

The standard recommendation is to use the lowest effective dose of estrogen and progestogen with the clearest benefit for women <60 years or <10 years of menopause. Treatment should be individualized, and the risks are influenced by the type, dose, duration, route of administration, timing of initiation, and whether a progestogen is used for therapy. ⁴

Influence of HT on Breast Symptoms and MBD

Breast symptoms such as fullness, swelling, tenderness, pain, and nipple sensitivity are common adverse effects reported by perimenopausal or postmenopausal women starting HT. These symptoms are usually mild-to-moderately severe and resolve over time. In the Kronos Early Estrogen Prevention breast pain ancillary studies, treatment with either lower dose conjugated equine estrogen (CEE; 0.45 mg) or transdermal estrogen (50 μg) with cyclic progesterone for 4 years did not increase breast pain in most healthy recently menopausal women. ⁵ However, women who reported new-onset breast discomfort had a 3.9% increase in percentage MBD, whereas women without discomfort had a 0.6% increase in percentage MBD (β = 0.033; p < 0.001). ⁶

The term MBD refers to radiopaque epithelial and connective tissue versus radiolucent fatty tissue. The American College of Radiology uses the Breast Imaging Reporting and Data System (BI-RADS) to classify breast density into four categories: almost entirely fat (category A), scattered areas of fibroglandular density (category B), heterogeneously dense (category C), and extremely dense (category D). ⁷ Increased breast density influences breast cancer (BC) risk in two ways. First, MBD is an independent risk factor for BC, and women with category D breast tissue are four to six times more likely to have BC compared with women with category A tissue. ⁸

Second, increased density alters mammographic clarity by causing a masking effect, as dense breast tissue has the same density as BC. This masking effect can lead to increased recall rates, thereby increasing health care costs. ⁹ The sensitivity of mammograms for women with category D breast tissue can be as low as 30% to 48%, whereas for women with category A tissue, sensitivity is 80% to 95%. ⁷ False-negative test results lead to missed cancers at screening and increased rates of interval cancers (cancers detected between scheduled mammograms), and dense breasts may be associated with advanced-stage BC at the time of diagnosis. ¹⁰

All forms of HT have been associated with increased MBD in multiple population-based, observational, cohort, and case–control studies. ^11,12 Continuous HT use has been associated with a greater increase in MBD when compared with sequential use or estrogen therapy alone. ¹³ However, other studies have shown that the timing of progestogen administration (sequential vs. continuous) does not influence MBD if the cumulative dose is similar. A dose-dependent relationship between progestin use and MBD has been reported, with lower doses having minimal effects. MBD increases occur with many progestin therapies, including levonorgestrel, norethindrone, drospirenone, and medroxyprogesterone acetate (MPA). ^{11 –13}

The Women's Health Initiative randomized studies of estrogen and progestin therapy versus placebo showed that after 1 year, MBD increased by a mean of 7.7% (95% CI, 5.9%–9.5%) for women receiving HT and declined by a mean of 1.1% (95% CI, 0.3%–1.9%) for women receiving a placebo. ¹⁴ In addition, EPT was associated with having an almost four times increased risk of having an abnormal mammogram at year 1 (relative risk, 3.9; 95% CI, 1.5–10.2; p = 0.003) compared with placebo. ¹⁴

A subgroup analysis of women from the randomized placebo-controlled Postmenopausal Estrogen/Progestin Interventions trial showed that 12 months of treatment with CEE alone did not affect percentage MBD. However, women randomly assigned to any of the three CEE–progestin combination treatment arms (continuous MPA, cyclic MPA, or cyclic micronized progesterone) showed a 3% to 5% increase in MBD, irrespective of the progestogen used. ¹²

Transdermal EPT or transdermal estrogen therapy causes smaller changes in MBD and less breast tenderness compared with oral EPT. ¹⁵ Furthermore, the addition of transdermal testosterone to oral EPT does not induce any additional changes to MBD after 6 months. ¹⁶ In a randomized trial by Harvey et al., ¹⁷ 39.1% of transdermal HT users had no change in MBD after 1 year, whereas only 15.7% of oral users reported no changes.

The influence of HT on MBD seems to be greater in women with pre-existing dense breast tissue, and for these women, EPT appears to increase their risk of aggressive BC. ^18,19 Whether this increased cancer risk is mediated through MBD is unknown, and currently, HT-induced high MBD is not considered a surrogate marker for increased BC risk. The increase in MBD with HT is a dynamic process, and the effects are most prominent in the first year after starting treatment. MBD stabilizes with longer term HT use and returns to baseline usually within a few weeks after HT is discontinued, probably through apoptosis. ^11,15 The decline in MBD after cessation of HT does not appear to be influenced by age, race, body mass index, or type or duration of HT, but it could be influenced by genetic factors. ²⁰

Influence of HT on Abnormal Mammograms and BC Risk

Estrogen therapy and EPT are associated with an increased rate of abnormal mammograms with short interval follow-up recommendations (BI-RADS 3). EPT is also associated with higher grade abnormal mammograms (BI-RADS 4), with features that suggest malignancy and prompt breast biopsies. Furthermore, HT decreases the sensitivity of mammograms, especially in women with higher breast density. ²¹ In a population-based cohort study by Kavanagh et al., ²¹ the sensitivity of mammograms for 65-year-old women decreased from 82.2% for those who did not use HT to 66.1% for those who did (p < 0.001).

Decreased sensitivity translates to an increased rate of false-negative results. In a randomized controlled study of 1704 women undergoing screening mammography, recall rates were 12.3% for women who stopped HT for 1 month before imaging, 9.8% for women who stopped HT for 2 months, and 11.3% for women who continued HT. ²² Thus, although short-term suspension of HT for 1 to 2 months can slightly improve MBD, it does not appear to improve mammography recall rates.

Estrogen leads to breast epithelial cell proliferation, and this effect is augmented by progestin; thus, it is biologically plausible that epithelial hyperplasia may lead to BC. This mechanism is supported by studies showing that antiestrogen medications, such as selective estrogen receptor modulators and aromatase inhibitors, reduce MBD and BC risk. ²³ Furthermore, immunohistochemical studies show that estrogen causes cell proliferation and ductal growth and inhibits apoptosis. ²³ The Women's Health Initiative studies clearly showed that the addition of progestin to HT formulations was associated with a slightly increased BC risk after 5 years, but the effect of progesterone on MBD or BC remains unclear. ²⁴

Although sensitivity and response to progestogens clearly vary among individuals, progestogens may encourage cell proliferation, lobular growth, and possibly carcinogenesis in breast epithelial tissue. ²⁵ Breast cell proliferation observed with combined EPT is localized to the terminal duct lobular unit of the breast, which is the site where most BCs develop. ²⁶ These studies and others provide substantial evidence that long-term administration of estrogen (to a lesser extent) and progestogens (to a greater extent) is mitogenic for the human breast. Women should be counseled regarding this risk before initiating HT.

Conclusion

Before HT initiation, women should be counseled about the following risks:

Although HT (particularly combination therapy) is commonly noted to increase MBD, not all women who receive HT will have an increase in MBD.