It is time to take another look at hormone replacement therapy.
These women then came in with complaints of hot flashes, mood changes and vaginal dryness. These symptoms interfered with their quality of life. Unable to sleep and suffering, these patients were desperate. Now unable to have intercourse without pain, their relationships also suffered.
As a clinician, it was disheartening to see these women whose lives were changed within days of this publication. The WHI was a large, randomized trial designed to study the use of HRT (Hormone Replacement Therapy) for the primary prevention of cardiovascular disease (ages 50-79; mean age 63). The mean time since menopause was equal to/greater than 12 years. Women with a history of hysterectomy (N=10,739) were randomized to either conjugated equine estrogen (0.625 mg) or placebo. The other arm of the study included women randomized to conjugated equine estrogen (0.625mg) + medroxyprogesterone acetate (2.5mg) or placebo (N=16,608).
After 5 years of the study, the data monitoring and safety board recommended ceasing the study due to a noted increase in the hazard ratios of breast cancer (1.26), stroke (1.41), coronary heart disease (1.24), venous thromboembolism (2.11) and pulmonary embolism ((2.13). What was not highlighted was in women taking CEE alone, there was a lower HR (benefit) in coronary heart disease (HR= 0.91) and breast cancer (0.77). In both groups, there was no change in overall mortality.
Since then, the data have been reanalyzed in numerous publications. Reanalysis showed the use of CEE + MPA (medroxyprogesterone acetate) and CEE alone were associated with a neutral risk of coronary heart disease and increased risk of stroke and venous thromboembolism. And further, the time since menopause influenced the risk for coronary heart disease – it was neutral for women less than 10 years since menopause and increased for women greater than 20 years post-menopause. This led to the “timing hypothesis”: is there a differential effect on atherosclerosis progression and clinical events based on when HRT is initiated?
Previously, observational studies indicated benefits for HRT. The ELITE trial reported decreased carotid intimal thickness (used a marker for CHD) in women who started treatment less than 6 years since menopause, supporting the concept that hormone therapy reduces early atherosclerosis but not established lesions.
In summary, estrogen therapy is not recommended for primary prevention of heart disease but may be associated with less progression of subclinical atherosclerosis when initiated within 6 years of menopause but not greater than 10 years. Several randomized trials report there is no evidence that hormone therapy should be used for secondary prevention of cardiovascular disease.
What about increasing breast cancer risk? The revised global consensus statement on HT and breast cancer notes: “the risk of breast cancer attributable to MHT (Menopausal Hormone Therapy) is rare. It equates to an incidence of <1.0 pr 1,000 women per year of use. This is similar or lower than the increased risk associated with common lifestyle factors such as sedentary lifestyle, obesity and alcohol consumption.”
However, 20 years later, many providers are still reluctant to support its use. And medical students and residents are not being trained regarding the management of menopause. Although it is not for every woman (see *contraindications below) or a panacea for aging, some women can benefit from the use of HRT and improve their quality of life. Particularly during perimenopause, when symptoms can be most disruptive. Furthermore, there are many Food and Drug Administration (FDA) approved natural (bioidentical) options now for treatment. Transdermal estrogen is less likely to be associated with DVT/PE as it avoids the first-pass effect through the liver for metabolism.
When is Hormone Replacement Therapy Beneficial?
Treatment of Vasomotor Symptoms (VMS). VMS include hot flashes, hot flushes and night sweats. Up to 75% of perimenopausal women experience hot flashes. Typically, they begin during late perimenopause then increase during the perimenopause transition, with the greatest frequency and severity in the first two years of the final menstrual period. Then they decline over time. However, VMS can last several years – as long as 12 years – and for some, they never go away.
VMS are a marker also for metabolic syndrome. For some women, lifestyle changes may provide some relief: enhancing relaxation with yoga, meditation, regular exercise, dressing in layers, maintaining a healthy body weight, identifying triggers such as alcohol or spicy food. Systemic estrogen therapy (or estrogen/progesterone therapy in those with a uterus), offers relief for moderate to severe VMS and is its primary indication for use.
Clinically, the question is how much and how long therapy should be continued. It is prudent to recommend the lowest dose that treats symptoms and revisit whether to continue at least annually, assessing the patient’s treatment goals, benefits and risks as she ages. Dose adjustments can be made over time.
Knowing that the largest study conducted did not show increased breast cancer risks for use less than 5 years may be reassuring to patients. Getting through the times of the most severe symptomatology can improve her quality of life. Will VMS return after going off treatment in 3-5 years? Maybe, but most often not to the extent that they were earlier in the transition.
There is one FDA-approved non-hormonal medication, paroxetine (Brisdelle), which is 7.5mg to be taking nightly. Other non-hormonal medications are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, or gabapentin.
Prevention of Osteoporosis. Menopause is associated with a few years of rapid bone loss due to lower circulating levels of estrogen. Estrogen inhibits bone resorption. Systemic estrogen (or estrogen/progesterone) is approved for the prevention of osteoporosis in the United States and Canada (not treatment of osteoporosis). Standard doses of HRT reduce fracture risk in postmenopausal women.
Half of all women over the age of 50 will experience an osteoporotic fracture in their lifetime. In addition to the healthcare costs of the care for fractures, there is concern for the decline in one’s quality of life from loss of mobility, independent self-care, post-fracture dysfunction and premature death.
Genitourinary syndrome of menopause. This includes vaginal atrophy, vulvovaginal atrophy and urethral symptoms such as urgency, dysuria and frequent UTIs. In the U.S., 20-50% of women experience distressing vulvovaginal symptoms during post-menopause. Vaginal dryness and painful intercourse (dyspareunia) are common concerns.
Treatment with topical estrogen (does not have to be systemic) restores vaginal blood flow, decreases vaginal pH and improves the thickness of the vulvovaginal tissues.
There are many delivery systems available vaginally – cream, suppositories, tablets and a ring (estring). When used as directed, there is no need for progesterone (twice weekly for cream). Higher dosing may need additional progesterone or surveillance for endometrial thickness (hyperplasia or cancer).
Other options for management include ospemiphene (Osphena), a selective estrogen receptor modulator FDA-approved for moderate to severe dyspareunia associated with vulvovaginal atrophy, an oral medication taken daily. Prasterone (Intrarosa) a DHEA suppository used daily, has been approved for the treatment of vulvovaginal atrophy.
There is no doubt that in developed countries, women are living longer. According to the 2010 U.S. Census, more than 7 million women (about twice the population of Oklahoma) reached the age of 80 years or older, and 44,000 were 100 years or older. Since the mean age of menopause is 51, that is many years to be in a hypoestrogenic state.
How long should women use HRT? The WHI studies provided information regarding CEE and MPA for 5 years and CEE for 7 years, but most authorities recommend use for up to 10 years. With screening and risk assessment, counseling and patient-centered care, it is time to take another look at hormone replacement therapy and facilitate a better quality of life for those who opt to use it.
*Contraindications to hormone therapy: Hormone sensitive cancer (such as breast or uterine), unexplained vaginal bleeding, history of deep vein thrombosis/pulmonary embolism, uncontrolled hypertension, confirmed coronary vascular disease, active liver disease, migraine with aura, history of transient ischemic attack or stroke.
Kase NG, Freidman EG, Brodman M. The midlife transition and the risk of cardiovascular disease and cancer Part II: strategies to maximize quality of life and limit dysfunction and disease. AJOG December 2020: 834-847.
Hodis HN, et al. N Engl J Med 2016: 374: 1221-1231.
Manson JE, Chlebowski RT, Stefanick MI, et al. JAMA 2013.
Revised global consensus on MHT. De Villiers TJ, et al. Climacteric 2016.
Avis NE, et al. Duration of menopausal vasomotor symptoms over the menopause transition. Study of Women’s Health Across the Nation. JAMA Internal Med. 2015 April; 175(4): 531-539.
Rossouw JE, 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 Jul 17: 288(3): 321-33.
Dr. Dolan is a board-certified obstetrician-gynecologist and Professor of Gynecology and Obstetrics who has been in practice at Emory University since 2005. Dr. Dolan attended Duke University for undergraduate education, then Emory University for medical school and attained a dual degree (MD/MPH). She completed her residency at the University of North Carolina, Chapel Hill. Dr. Dolan is the Director of Midlife and Menopausal Medicine at Emory Women’s Center at Saint Joseph’s Hospital.