You are leaving Medscape Education
Cancel Continue
Log in to save activities Your saved activities will show here so that you can easily access them whenever you're ready. Log in here CME & Education Log in to keep track of your credits.



Managing the Side Effects of Aromatase Inhibitor Therapy

  • Authors: Ruth M. O'Regan, MD
Start Activity

Target Audience and Goal Statement

This activity is intended for oncologists, oncology nurses, pharmacists, primary care practitioners, obstetricians/gynecologists, and other healthcare professionals who treat patients with breast cancer.

The goal of this activity is to discuss the most up-to-date data on endocrine therapy and the key issues involved in its optimal use for patients with breast cancer.

Upon completion of this activity, participants will be able to:

  1. Identify patients with breast cancer for whom aromatase inhibitors (AIs) should be considered and describe how they should be used based on current evidence
  2. Discuss the incidence of AI-associated musculoskeletal syndrome in patients receiving AI therapy
  3. Identify the risk for nonadherence among patients taking AIs, and evaluate strategies to improve adherence



It is UT Southwestern's policy that participants in CME activities should be made aware of any affiliation or financial interest that may affect the speaker's presentation(s). Each speaker has completed and signed a conflict of interest statement. The faculty members' relationships will be disclosed in the course materials.


Because this course is meant to educate physicians with what is currently in use and what may be available in the future, there may be "off-label" use discussed in the presentations. Speakers have been requested to inform the audience when off-label use is being discussed.


  • Ruth M. O'Regan, MD

    Associate Professor, Department of Hematology and Medical Oncology, Emory University School of Medicine; Medical Director, Emory Breast Center, Winship Cancer Institute, Atlanta, Georgia


    Disclosure: Ruth M. O'Regan, MD has disclosed the following relevant financial relationships:
    Received grants for clinical research from: Novartis Pharmaceuticals Corporation, Pfizer Inc.
    Served as an advisor or consultant for: Novartis Pharmaceuticals Corporation

    Dr. O'Regan does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the US Food and Drug Administration (FDA) for use in the United States.

    Dr. O'Regan does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Charlotte Warren

    Scientific Director, Medscape, LLC


    Disclosure: Charlotte Warren has disclosed no relevant financial relationships.

CE Reviewer

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Nurse Planner

  • Laurie E. Scudder, DNP, NP

    Nurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC


    Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

Accreditation Statements

    For Physicians

  • The University of Texas Southwestern Medical Center at Dallas is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    The University of Texas Southwestern Medical Center at Dallas designates this educational activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

    Contact This Provider

    For Nurses

  • Medscape, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

    Awarded 1.00 contact hour(s) of continuing nursing education for RNs and APNs; 1 contact hours are in the area of pharmacology.

    Accreditation of this program does not imply endorsement by either Medscape, LLC or ANCC.

    Contact This Provider

    For Pharmacists

  • Medscape, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

    Medscape, LLC designates this continuing education activity for 1.00 contact hour(s) (0.1 CEUs) (Universal Activity Number 0461-9999-11-13-H01-P).

    Contact this provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Follow these steps to earn CME/CE credit*:

  1. Read the target audience, learning objectives, and author disclosures.
  2. Study the educational content online or printed out.
  3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape Education encourages you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.


Managing the Side Effects of Aromatase Inhibitor Therapy

Authors: Ruth M. O'Regan, MDFaculty and Disclosures



The use of aromatase inhibitors (AIs) has been demonstrated to improve outcome compared with tamoxifen in patients with early-stage and metastatic hormone receptor (HR)-positive breast cancer.[1-4] Although AIs are generally well tolerated with few serious adverse events, a number of troublesome side effects that affect quality of life have been noted. These types of side effects can lead to nonadherence -- a significant concern considering these agents have clearly been demonstrated to improve survival in patients with early-stage HR-positive breast cancer. Adherence with the prescribed 5 years of tamoxifen has been demonstrated to fall as low as 50% over the course of therapy,[5] and approximately one third of patients prescribed anastrozole are found to be nonadherent.[6] Along with intrinsic resistance, it is likely that a lack of adherence with hormonal therapy may explain the poor outcome for a subset of patients with HR-positive early-stage breast cancer. Appropriate management of the side effects associated with hormonal therapy is therefore of critical importance to ensure adherence -- and hopefully improve outcomes for patients with early-stage HR-positive breast cancer.

Side Effects of Aromatase Inhibitors

The most common side effects reported with AIs are exacerbation of menopausal symptoms as a result of low estrogen levels and musculoskeletal complaints.[1-3] The more serious side effects include bone loss, a possible increased incidence of coronary heart disease, and changes in cognitive function.[1-3] What follows is a discussion of some of the most common symptoms associated with AI therapy that are most likely to interfere with the patient's quality of life, along with strategies for ameliorating these side effects.

Menopausal Symptoms

A general exacerbation of menopausal symptoms, particularly hot flashes, is the most common complaint in patients taking AIs.[1-3] Estrogens, including topical estrogens, which result in systemic absorption of estrogen and are generally thought of to relieve menopausal symptoms, are not recommended, because AIs exert their therapeutic effects by profoundly suppressing estrogen levels in postmenopausal patients.

Vasomotor Symptoms

Hot flashes are the most common side effect reported with the use of all of the AIs. Although they were significantly less common among patients taking anastrozole or letrozole compared with tamoxifen,[1,2] hot flashes were still reported in approximately one third of patients taking AIs in the pivotal AI trials (range 30%-40%).[1-3]

The pathogenesis of vasomotor symptoms such as hot flashes is unknown, but serotonin receptors are felt to play a role, and serotonin inhibitors such as fluoxetine and paroxetine and the bi-cyclic antidepressant, venlafaxine, have been demonstrated to improve hot flashes in survivors of breast cancer.[7-9] It is likely that they may also be beneficial in patients taking AIs. In contrast to tamoxifen, which is metabolized through CYP2D6, there is little likelihood of interactions between the serotonin inhibitors and AIs. Another option that has shown benefit in reducing vasomotor symptoms in survivors of breast cancer, including those who did not benefit from antidepressants, is the antiepileptic medication gabapentin, which inhibits norepinephrine uptake.[10] In a study of 91 patients, higher doses of gabapentin appeared more effective but also were more toxic.[10] Acupuncture is also being investigated for the treatment of hot flashes in postmenopausal women and has demonstrated some activity.[11]

Gynecologic Symptoms

The pivotal AI trials demonstrated that the AIs have a more favorable gynecologic toxicity profile than tamoxifen because they are less likely to cause vaginal bleeding and are not associated with an increase in endometrial cancer.[1-3] However, none of these trials specifically collected data on quality-of-life issues such as vaginal dryness, sexual problems, and effects on libido. Subsequent analyses have demonstrated that AIs are associated with sexual dysfunction, and that women taking AIs are more likely to complain of vaginal dryness and dyspareunia compared with patients taking tamoxifen.[12]

Healthcare providers should ask patients taking AIs about vaginal dryness and sexual issues because many patients are unlikely to initiate this discussion. Vaginal moisturizers and lubricants can decrease vaginal discomfort. Topical estrogen should generally be avoided because systemic absorption of estrogen could interfere with the activity of AIs.

Musculoskeletal Complaints

Musculoskeletal issues, including joint pains, are a very significant issue for patients taking AIs and can result in nonadherence. The incidence of joint complaints ranged from 20% to more than 30% in the pivotal AI trials, and was significantly higher in patients receiving AIs compared with those treated with tamoxifen.[1-3] Still, it appears likely that the trials underreported these side effects. More recent retrospective reviews have demonstrated a much higher rate of musculoskeletal issues, with some types of musculoskeletal complaints occurring at some grade in approximately half of patients taking AIs.[13,14] The higher incidence reported in more recent analyses is likely because the pivotal trials recorded some but not all musculoskeletal events noted by patients. For example, the ATAC [Arimidex, Tamoxifen, Alone or in Combination] trial[1] reported musculoskeletal events in about 30% of patients, whereas the BIG [Breast International Group] 1-98 trial[2] reported only arthralgia, which occurred in about 20% of patients. In contrast, the IES [Intergroup Exemestane Study] trial[3] more precisely defined the musculoskeletal events as arthritis, osteoarthritis, arthralgias, carpal tunnel syndrome, or musculoskeletal pain. Because it is likely that patients complained of more than one of these complaints, it is not possible to quantify the actual number of patients experiencing musculoskeletal issues. Therefore, at this point, it is not clear that the AIs differ significantly in their association with musculoskeletal issues, and some patients may experience problems with one agent but not with another.

The etiology of musculoskeletal issues induced by AIs is currently unclear. There is evidence to suggest that musculoskeletal issues may be associated with low circulating estrogen levels, although this is not felt to be a direct effect of estrogen deprivation. The incidence of musculoskeletal issues appears to be highest in patients who are in transition into menopause, including patients who experience a loss of ovarian function secondary to chemotherapy.[15] Musculoskeletal issues appear to be most significant during the initial period that patients take AIs; they then improve over time. A retrospective analysis of the ATAC trial suggested that the presence of joint symptoms may be associated with a decreased risk for recurrence,[16] although such an association was not confirmed in an analysis of the MA.27 trial.[17]

The management of musculoskeletal issues is challenging and poorly defined to date. Anti-inflammatory agents may be helpful in some patients, while many other patients can function without intervention, particularly as symptoms improve over time. There is anecdotal evidence to suggest that changing to an alternative AI may ameliorate symptoms, but as stated above, there is no evidence to suggest that one agent is less likely to cause musculoskeletal issues than another. In some patients, switching to tamoxifen, which has a lower incidence of musculoskeletal issues, may be necessary. There is some evidence to suggest that vitamin D may play some role in musculoskeletal complaints associated with AIs. In one study,[18] patients with normal or high vitamin D levels were less likely than those with low levels to report arthralgias when taking AIs. With vitamin D deficiency having been reported in more than two thirds of patients with early-stage breast cancer,[19] it would seem appropriate to check vitamin D levels and replace as necessary in patients in whom AI therapy is planned.

Cardiovascular Issues

In the pivotal trials in which AIs were compared with tamoxifen in patients with early-stage breast cancer, there was a nonsignificant higher incidence of cardiovascular events in those treated with AIs.[1-3] Tamoxifen is known to have a beneficial effect on the lipid profile, lowering low-density lipoprotein cholesterol, but it has not definitively been shown to decrease cardiovascular events in placebo-controlled trials. In contrast, AIs have a negative effect on the lipid profile, which could potentially increase the risk for cardiovascular events. However, in the placebo-controlled MA.17 trial, the incidence of cardiovascular events was not different in patients treated with letrozole compared with placebo.[20]

Given the possible risk for cardiovascular events in patients treated with AIs, it is prudent to monitor patients for symptoms suggestive of coronary artery disease and to measure cholesterol on a regular basis. The choice of endocrine therapy in patients with a history of coronary artery disease should be made based on the overall recurrence risk of their breast cancer; tamoxifen may be appropriate in selected cases.

Cognitive Brain Function

Given the profound estrogen deprivation induced by AIs and that estrogen appears to play a role in cognitive function and memory, there has been concern that these agents may have a negative effect on cognitive functioning. There is, however, an overall paucity of data on the effects of endocrine agents on memory and cognitive functioning. A prospectively defined cohort of the BIG 1-98 trial demonstrated minimal differences in cognitive functioning in patients treated with letrozole or tamoxifen.[21] In fact, there was a slightly higher rate of memory changes in patients treated with tamoxifen. Of note, these minimal effects on cognitive function resolved within a year of patients stopping endocrine therapy.[22] To date, there are minimal data comparing the effects of AIs with the effects of placebo on cognitive functioning. Additionally, many patients experience a decrease in cognitive function following adjuvant chemotherapy.

Patients taking AIs should be asked about memory changes; other causes of memory loss, such as depression, should be ruled out and managed appropriately. In severe cases, AIs may need to be discontinued temporarily to see whether symptoms improve.

Other Side Effects

Patients may complain of multiple other symptoms, including gastrointestinal complaints and rash. Stopping treatment with the AI temporarily may relieve these symptoms, and switching to an alternative AI can be considered.


The use of adjuvant AI therapy decreases the risk for recurrence and improves survival in patients with early-stage HR-positive breast cancer. However, troublesome side effects can result in nonadherence. It is essential that patients be monitored for side effects and managed appropriately to allow full adherence and decrease their risk for recurrence.

Supported by an independent educational grant from Pfizer.

  • Print