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Stopping systemic menopausal hormone therapy: Why, when and how
Accepted Manuscript Title: Stopping systemic menopausal hormone therapy: Why, when and how Author: Stephanie S. Faubion MD PII: DOI: Reference:
S0378-5122(16)30069-X http://dx.doi.org/doi:10.1016/j.maturitas.2016.03.020 MAT 6585
To appear in:
Maturitas
Author: Andrew M. Kaunitz MD PII: DOI: Reference:
S0378-5122(16)30069-X http://dx.doi.org/doi:10.1016/j.maturitas.2016.03.020 MAT 6585
To appear in:
Maturitas
Received date: Accepted date:
15-3-2016 22-3-2016
Please cite this article as: Kaunitz Andrew menopausal hormone therapy: Why, when http://dx.doi.org/10.1016/j.maturitas.2016.03.020
M.Stopping systemic and how.Maturitas
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Maturitas Editorial Stopping Systemic Menopausal Hormone Therapy: Why, When and How Stephanie S. Faubion, MD, FACP, NCMP, IF Women’s Health Clinic, Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN Andrew M. Kaunitz, MD, FACOG, NCMP Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL Corresponding Author: [email protected]
Keywords: discontinuation; menopausal hormone therapy; vasomotor symptoms
Introduction Helping women make sound decisions regarding discontinuation of systemic menopausal hormone therapy (MHT) represents a challenge for clinicians. The goal of striving for the lowest dose of MHT for the shortest amount of time would seem disconnected from the reality that many women experience vasomotor symptoms (VMS) for a decade or more.1,2 Thus, determining why, when and how to discontinue the use of MHT represent important clinical considerations.
Why discontinue MHT? Women most commonly start MHT in their late 40s or early 50s for management of moderate to severe VMS. MHT is also effective in the prevention of osteoporosis. Concerns regarding safety represent a primary consideration for discontinuation of MHT. In the Women’s Health Initiative (WHI), the use of combined estrogen and progestin therapy (EPT) with oral conjugated equine estrogens (CEE) and medroxyprogesterone acetate (median duration of use 5.6 years) was associated with a modest increased risk of breast cancer, as well as an increased risk of stroke. However, in women without a uterus, the use of estrogen therapy (ET) alone using oral CEE (median duration of use 7.2 years) was not associated with an increased risk of breast cancer.2 Other studies, including the observational Nurses’ Health Study, have shown an increased risk of breast cancer with >15 years of ET.1 In terms of coronary heart disease (CHD), women who initiate ET or EPT in their 50s experience no elevation in risk, while those while those who initiate MHT in their 70s do experience an elevated risk of CHD.2 Unfortunately,
existing clinical trial data do not address the risk to benefit balance of MHT use in women who initiate therapy at the time of menopause and continue long-term. The route of administration of MHT also appears to impact MHT safety. In contrast with the elevated risk of venous thromboembolism (VTE) with oral ET, 6 observational studies have concluded that transdermal does not elevate VTE risk.1 One study found that in contrast with oral estrogen, transdermal estradiol at doses less than or equal to 0.05 mg does not elevate risk of stroke.1 Given these safety advantages, and the elevated baseline risk of VTE as patient body mass index increases, transdermal ET may represent a preferred strategy for obese women, and possibly, those on long-term treatment.1,2 When to discontinue MHT? Menopausal VMS tend to improve with time since menopause. Based on expert opinion, it is reasonable to consider a trial of dose tapering, and if tolerated, discontinuation of MHT after several years of use. If a woman remains asymptomatic after tapering to the lowest dose, discontinuation may be attempted. Some women, however, may choose to continue low dose MHT indefinitely for perceived enhanced quality of life and/or for prevention of osteoporosis.1 Ongoing use of low dose MHT for prevention of osteoporosis may be particularly relevant for women at elevated baseline risk for osteoporosis, including slender women and those with a parental history of hip fracture. An additional challenge for patients and clinicians is the inclusion of estrogen on the list of potentially inappropriate medications for adults over the age of 65 years, making it likely that clinicians practicing in the United States will receive a letter from insurance companies referring
to potential risks of MHT in this population, and potentially denying financial coverage of the medication. This has prompted the American College of Obstetricians and Gynecologists and the North American Menopause Society to issue statements advocating against the arbitrary discontinuation of MHT at the age of 65 years.3,4 Instead, individualized assessment of the risk to benefit balance and shared decision making are recommended, taking into account patient preferences. How to discontinue MHT? Approximately 50% of women will experience recurrent symptoms upon discontinuation of MHT, regardless of the method used for discontinuation (slow taper versus abrupt discontinuation).5 A reasonable approach for women who are fearful of recurrence of bothersome VMS with tapering or discontinuation of MHT is providing reassurance that the last effective dose can be reinitiated (even without a follow up visit) if bothersome symptoms do recur.1 A note about genitourinary syndrome of menopause (GSM) While VMS improve with time, symptoms of GSM (or genital atrophy), including vaginal dryness, dyspareunia, urinary frequency and urgency, and urinary tract infections, tend to worsen with time. Accordingly, treatment with low dose vaginal estrogen therapy may be appropriate as the dose of systemic MHT is lowered or discontinued. While clinical trials of low dose vaginal estrogen therapy have demonstrated endometrial safety, and routine concomitant use of a progestogen is not appropriate, these trials have not extended beyond one year.
Should spotting or bleeding occur during use of vaginal estrogen, endometrial evaluation should be performed.5 Summary Despite the lack of clinical trial data to inform decisions regarding long-term use of MHT, this issue is commonly encountered and remains important for clinicians who care for menopausal women. Indications for extended use of MHT include treatment of VMS, perceived enhanced quality of life and prevention of osteoporosis. For women with a uterus who require the use of a progestogen with estrogen, the modest increased risk of breast cancer after about five years of therapy (equivalent to the elevated risk associated with between 1 and 2 glasses of wine daily) remains a concern, and should be reviewed with patients.2 For women without a uterus, the use of estrogen alone provides more flexibility in terms of duration of use. Transdermal estrogen may offer safety benefits (lower VTE and stroke risk) over oral estrogen, particularly in obese women, and may be a better option for those who wish to continue MHT long-term. Finally, as women lower their dose of or discontinue systemic MHT, use of low dose vaginal estrogen therapy may become appropriate.
Contributors Both authors made substantive contributions to the manuscript.
Conflict of interest None declared.
Funding The authors have received no funding for this article.
Provenance and peer review This article is commissioned; not externally peer reviewed.
References 1. Kaunitz AM. Extended duration use of menopausal hormone therapy. Menopause. 2014;21:679-681. 2. Kaunitz AM, Manson JE. Management of Menopausal Symptoms. Obstetrics and gynecology. 2015;126:859-876. 3. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstetrics and gynecology. 2014;123:202-216. 4. Gass ML, Maki PM, Shifren JL, et al. NAMS supports judicious use of systemic hormone therapy for women aged 65 years and older. Menopause. 2015;22:685-686. 5. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19:257-271.
S0378-5122(16)30069-X http://dx.doi.org/doi:10.1016/j.maturitas.2016.03.020 MAT 6585
To appear in:
Maturitas
Author: Andrew M. Kaunitz MD PII: DOI: Reference:
S0378-5122(16)30069-X http://dx.doi.org/doi:10.1016/j.maturitas.2016.03.020 MAT 6585
To appear in:
Maturitas
Received date: Accepted date:
15-3-2016 22-3-2016
Please cite this article as: Kaunitz Andrew menopausal hormone therapy: Why, when http://dx.doi.org/10.1016/j.maturitas.2016.03.020
M.Stopping systemic and how.Maturitas
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Maturitas Editorial Stopping Systemic Menopausal Hormone Therapy: Why, When and How Stephanie S. Faubion, MD, FACP, NCMP, IF Women’s Health Clinic, Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN Andrew M. Kaunitz, MD, FACOG, NCMP Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL Corresponding Author: [email protected]
Keywords: discontinuation; menopausal hormone therapy; vasomotor symptoms
Introduction Helping women make sound decisions regarding discontinuation of systemic menopausal hormone therapy (MHT) represents a challenge for clinicians. The goal of striving for the lowest dose of MHT for the shortest amount of time would seem disconnected from the reality that many women experience vasomotor symptoms (VMS) for a decade or more.1,2 Thus, determining why, when and how to discontinue the use of MHT represent important clinical considerations.
Why discontinue MHT? Women most commonly start MHT in their late 40s or early 50s for management of moderate to severe VMS. MHT is also effective in the prevention of osteoporosis. Concerns regarding safety represent a primary consideration for discontinuation of MHT. In the Women’s Health Initiative (WHI), the use of combined estrogen and progestin therapy (EPT) with oral conjugated equine estrogens (CEE) and medroxyprogesterone acetate (median duration of use 5.6 years) was associated with a modest increased risk of breast cancer, as well as an increased risk of stroke. However, in women without a uterus, the use of estrogen therapy (ET) alone using oral CEE (median duration of use 7.2 years) was not associated with an increased risk of breast cancer.2 Other studies, including the observational Nurses’ Health Study, have shown an increased risk of breast cancer with >15 years of ET.1 In terms of coronary heart disease (CHD), women who initiate ET or EPT in their 50s experience no elevation in risk, while those while those who initiate MHT in their 70s do experience an elevated risk of CHD.2 Unfortunately,
existing clinical trial data do not address the risk to benefit balance of MHT use in women who initiate therapy at the time of menopause and continue long-term. The route of administration of MHT also appears to impact MHT safety. In contrast with the elevated risk of venous thromboembolism (VTE) with oral ET, 6 observational studies have concluded that transdermal does not elevate VTE risk.1 One study found that in contrast with oral estrogen, transdermal estradiol at doses less than or equal to 0.05 mg does not elevate risk of stroke.1 Given these safety advantages, and the elevated baseline risk of VTE as patient body mass index increases, transdermal ET may represent a preferred strategy for obese women, and possibly, those on long-term treatment.1,2 When to discontinue MHT? Menopausal VMS tend to improve with time since menopause. Based on expert opinion, it is reasonable to consider a trial of dose tapering, and if tolerated, discontinuation of MHT after several years of use. If a woman remains asymptomatic after tapering to the lowest dose, discontinuation may be attempted. Some women, however, may choose to continue low dose MHT indefinitely for perceived enhanced quality of life and/or for prevention of osteoporosis.1 Ongoing use of low dose MHT for prevention of osteoporosis may be particularly relevant for women at elevated baseline risk for osteoporosis, including slender women and those with a parental history of hip fracture. An additional challenge for patients and clinicians is the inclusion of estrogen on the list of potentially inappropriate medications for adults over the age of 65 years, making it likely that clinicians practicing in the United States will receive a letter from insurance companies referring
to potential risks of MHT in this population, and potentially denying financial coverage of the medication. This has prompted the American College of Obstetricians and Gynecologists and the North American Menopause Society to issue statements advocating against the arbitrary discontinuation of MHT at the age of 65 years.3,4 Instead, individualized assessment of the risk to benefit balance and shared decision making are recommended, taking into account patient preferences. How to discontinue MHT? Approximately 50% of women will experience recurrent symptoms upon discontinuation of MHT, regardless of the method used for discontinuation (slow taper versus abrupt discontinuation).5 A reasonable approach for women who are fearful of recurrence of bothersome VMS with tapering or discontinuation of MHT is providing reassurance that the last effective dose can be reinitiated (even without a follow up visit) if bothersome symptoms do recur.1 A note about genitourinary syndrome of menopause (GSM) While VMS improve with time, symptoms of GSM (or genital atrophy), including vaginal dryness, dyspareunia, urinary frequency and urgency, and urinary tract infections, tend to worsen with time. Accordingly, treatment with low dose vaginal estrogen therapy may be appropriate as the dose of systemic MHT is lowered or discontinued. While clinical trials of low dose vaginal estrogen therapy have demonstrated endometrial safety, and routine concomitant use of a progestogen is not appropriate, these trials have not extended beyond one year.
Should spotting or bleeding occur during use of vaginal estrogen, endometrial evaluation should be performed.5 Summary Despite the lack of clinical trial data to inform decisions regarding long-term use of MHT, this issue is commonly encountered and remains important for clinicians who care for menopausal women. Indications for extended use of MHT include treatment of VMS, perceived enhanced quality of life and prevention of osteoporosis. For women with a uterus who require the use of a progestogen with estrogen, the modest increased risk of breast cancer after about five years of therapy (equivalent to the elevated risk associated with between 1 and 2 glasses of wine daily) remains a concern, and should be reviewed with patients.2 For women without a uterus, the use of estrogen alone provides more flexibility in terms of duration of use. Transdermal estrogen may offer safety benefits (lower VTE and stroke risk) over oral estrogen, particularly in obese women, and may be a better option for those who wish to continue MHT long-term. Finally, as women lower their dose of or discontinue systemic MHT, use of low dose vaginal estrogen therapy may become appropriate.
Contributors Both authors made substantive contributions to the manuscript.
Conflict of interest None declared.
Funding The authors have received no funding for this article.
Provenance and peer review This article is commissioned; not externally peer reviewed.
References 1. Kaunitz AM. Extended duration use of menopausal hormone therapy. Menopause. 2014;21:679-681. 2. Kaunitz AM, Manson JE. Management of Menopausal Symptoms. Obstetrics and gynecology. 2015;126:859-876. 3. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstetrics and gynecology. 2014;123:202-216. 4. Gass ML, Maki PM, Shifren JL, et al. NAMS supports judicious use of systemic hormone therapy for women aged 65 years and older. Menopause. 2015;22:685-686. 5. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19:257-271.