Introduction to Hormone Replacement Therapy (HRT)
Menopausal hormone therapy is the term used to describe the two hormones, estrogen and progestin (or progesterone) that are given to relieve bothersome symptoms of menopause such as hot flashes or vaginal dryness. Most experts agree that hormone therapy is safe for healthy women who have menopausal symptoms. Estrogen is the primary hormone that relieves the symptoms of menopause, though women with a uterus must also take progestin (or bioidentical progesterone) to prevent uterine cancer.
Menopausal hormone replacement therapy (HRT) is the most effective treatment for menopausal symptoms, including hot flashes, night sweats, insomnia, vaginal dryness, and loss of sexual desire—symptoms that can last an average of seven years. Yet many women do not realize that heart palpitations, joint and muscle aches, headaches, bladder problems, and depression are also often symptoms of menopause, which HRT can help alleviate.
The majority of expert panels consider the initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years, and do not have contraindications for HRT.
Alternative menopausal symptom management options include behavioural changes (dressing in layers, cooling rooms, managing stress, etc.), CBT, antidepressant medications, and herbal treatments. Although they may not be as effective as estrogen, they do provide some relief.
The average duration of symptoms is 7.4 years. Estrogen therapy lowers the frequency and severity of symptoms by 80-95%. There are no other treatments to date that come close in effectiveness.
Common Symptoms of Menopause
Bloating
Weight gain (abdomen)
Dry eyes
Vaginal dryness
Vaginal discharge
Bladder and urinary discomfort
Frequent urinary tract infections
Loss of sexual desire
Painful sexual intercourse
Mood swings
Thinning hair and skin
Dry skin
Depression
Nervousness
Poor concentration
Decreased energy reserve
Palpitations
Swelling of hands and feet
Joint pains
Insomnia
Night sweats
Hot flashes
Breast Cancer and Hormone Replacement
The current state of science indicates that HT may or may not cause breast cancer but the totality of data neither establish nor refute this possibility. Further, any association that may exist between HT and breast cancer appears to be rare and no greater than other medications commonly used in clinical medicine (including medications used to treat hypertension, elevated cholesterol, and antibiotics).
Hodis, H. N., & Sarrel, P. M. (2018). Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?. Climacteric, 21(6), 521-528.
Many researchers in this area now believe the possibility that menopausal HT may be promoting preexisting tumours rather than initiating tumours de novo (new growth). The average breast cancer cell takes a minimum of 5-10 years to become clinically detectable, thus short-term research cannot draw premature conclusions regarding breast cancer risk.
In the WHI the breast cancer risk “attributable” to use of EPT amounted to 8 additional cancers per 10, 000 users per year of use, or 0.8/1,000 annually. According to the classification of adverse events of the Council for International Organizations of Medical Sciences, this level of risk is “rare” (1 to 10 per 10,000).
Reid, R. L., Blake, J., Abramson, B., Khan, A., Senikas, V., & Fortier, M. (2009). Menopause and osteoporosis update 2009. Journal of Obstetrics and Gynaecology Canada, 31(1), S1-S3.
The Effect of Progestogens
There is both clinical and basic science evidence accumulating to suggest that there may indeed be clinically important differences between progestogens with respect to the breast.
A study of over 80,000 women for 12 years, found that breast cancer risk varied according to the progestogen used. The incidence of breast cancer was not increased in users of estrogen and [bio-identical] progesterone, but was increased in users of estrogen with a variety of other [synthetic, nonidentical] progestogens (1.69x).
Therefore, the use of bioidentical progesterone is preferred over synthetic progestogens, for both improved safety as well as tolerability and lower rates of side effects.
Seeger H, Wallweiner D, Mueck AO. The effect of progesterone and synthetic progestins on serum and estradiol-stimultaed proliferation of human breast cancer cells. Horm Metab Res 2003;35:76–80.
Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11.
Murkes D, Lalitkumar PGL, Leifland K, Lundström E, Söderqvist G. Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol 2012;28(Suppl 2):12–15. Epub 2012 July 27.
Breast Density and Screening Mammography on HRT
Women receiving postmenopausal HT in the WHI were found to have increased breast density and a greater frequency of abnormal mammograms compared with those receiving placebo. Even though breast density can be increased by the use of estrogen with a progestin, it has never been shown that an acquired increase in density, as in HT, increases breast cancer risk.
Estrogen alone and low-dose or transdermal combination therapy appear to have less impact on breast density.
Putting Breast Cancer Risk into Context:
Although most women perceive the risk of breast cancer to constitute their greatest lifetime medical risk, there is ample evidence that this perception is distorted and that women are at far
greater lifetime risk of death from CVD. Any “risk” attributable to HRT, rates about the same as early menarche (first period before age 12 or 13), late menopause, and a variety of lifestyle-associated risks, such as excessive alcohol consumption and failure to exercise. Analysis of modifiable risk factors that could be altered after menopause suggested that
“a substantial fraction of postmenopausal breast cancers (34%) may be avoided by purposeful changes in lifestyle later in life”.
To put those risks further into perspective;
As many women die from osteoporotic hip fracture as from breast cancer. Long term HT is more effective in preventing femoral fractures than other medications, which also have more side effects and risks than estrogen.
A woman is 7 times more likely to die of heart disease than to die of breast cancer. After 40, a woman’s risk of dying from heart disease is greater than her risk of dying from breast cancer. Estrogen therapy alone may decrease heart disease by 30-50%.
HT begun in menopause and continued, increases longevity by three to four years.
Sprague BL, Trentham-Dietz A, Egan KM, Titus-Ernstoff L,Hampton JM, Newcomb PA. Proportion of invasive breast cancer attributable to risk factors modifiable after menopause. Am J Epidemiol 2008;168:404–11.
The Women's Health Initiative (WHI) Study:
A summary of the effects of orally administered CEE alone or combined with MPA (both synthetic, non-bioidentical agents) in women ages 50 to 59 years during intervention phase of WHI (of which had many flaws, though is still considered the standard reference).
Number of cases (additional or fewer) per 1,000 women per 5-years of hormone use when compared with placebo:
Oral Estrogen Therapy:
Hip fracture – 1.5 additional cases
Pulmonary embolism – 1.5 additional cases
CHD – 5.5 fewer cases
Invasive breast cancer – 2.5 fewer cases
Stroke – 0.5 fewer cases
Colorectal cancer – 0.5 fewer cases
All-cause mortality –5.5 fewer events
Oral Estrogen + Oral MPA [synthetic progestin]:
Endometrial cancer – No difference
Coronary heart disease (CHD) – 2.5 additional cases
Invasive breast cancer – 3 additional cases (21% increased BrCA risk)
Stroke – 2.5 additional cases (51% increased risk of stroke)
Pulmonary embolism – 3 additional cases (2.0x risk of Pulmonary Embolism)
Colorectal cancer – 0.5 fewer cases (20% reduction in Colorectal cancer risk)
Hip fracture – 1.5 fewer cases (83% reduced risk of hip fracture)
All-cause mortality –5 fewer events (33% reduced all-cause mortality)
Type 2 Diabetes & Insulin resistance - 11 fewer cases (65% less)
Osteoarthritis (hip, knee) –40% lower risk
Note: the effect on stroke risk, pulmonary embolism, and coronary heart disease is likely negated with the use of topical estrogens and a non-synthetic progesterone. The risk of VTE appears to be lower with transdermal compared with oral estrogen preparations. In addition, the risk may vary by type of progestin (higher with MPA). Additionally, an increase in gallbladder disease was seen with oral estrogen use. In a large pooling of studies, NO excess risk of VTE was observed in women taking transdermal estrogen, even in those with prothrombotic mutations or high body mass index (BMI).
Progesterone Therapy Alone
Treatment with micronized progesterone (300 mg daily) alone (without estrogen) reduces the frequency and severity of hot flashes in comparison with placebo. Progestogens can be used to control VMS in women with contraindications to estrogen therapy, or those who wish to not take estrogens. Micronized progesterone has fewer side effects than synthetic progestins and is generally well tolerated.
Hormone Therapy in Family History of Breast Cancer
Women with a single first-degree family member (mother, sister, or daughter) in whom breast cancer was diagnosed after age 50 years have little increase in risk over the approximately 12% risk of the general population. Having 2 such relatives doubles a woman’s lifetime risk (to approximately 24%). Those with first-degree relatives in whom breast cancer was diagnosed before age 50 years have an approximate risk of 24% with 1 relative and 48% with 2 relatives. In a study designed to address the safety of HT in women with a positive family history, the use of hormones was found not to be associated with an increase in the overall risk of breast cancer, yet was associated with a reduced overall mortality rate. Similar conclusions were drawn in another analysis. This is likely explained by the fact that genetics likely overshadows any small potential increment resulting from lifestyle or hormonal exposure.
The Effects of HRT on Cardiovascular Disease (CVD)
CVD remains the leading cause of death and an important contributor to illness and disability among women: half of all postmenopausal women will have CVD, and one third will die from it. Eighty percent of all CVD is preventable. The INTERHEART trial revealed that 94% of CVD risk could be attributed to modifiable factors such as: diabetes mellitus (2.37x), hypertension (1.91x’s), abdominal obesity (1.62x), current smoking (2.87x), and psychosocial stress (2.67x).
HT and Heart Attack Risk
Considering all current studies, healthy recently menopausal women who are considering HT for relief of symptoms should be reassured that there does not appear to be a significant cardiovascular risk; some argue that there is benefit.
A “critical-window” or “critical-timing” hypothesis has been proposed, which may explain why HT at the onset of menopause could be cardioprotective whereas later initiation could cause adverse coronary events as seen in the WHI.
In summary, earlier initiation of HT seems to be protective against CVD, in contrast to later onset (> 60 years or > 10 years post menopause).
HT and Stroke Risk
There is increasing evidence to suggest that lower doses of estrogen, either oral or transdermal, are associated with a lower or no increase in risk of stroke, despite past concerns. The absolute risk of ischemic stroke due to HT in younger menopausal women is low (0.15 versus 0.13 cases per 100 women per year).
HT and VTE’s
Venous thrombotic events (blood clots in the leg) in otherwise healthy women increase in incidence with age and obesity. HT increases the risk; BUT events are associated more with oral than with transdermal preparations and more with non-bioidentical progestin use than with estrogen alone, or with bioidentical progesterone. Synthetic progestins may pose a greater risk than bioidentical progesterone. The absolute increased risks associated are 4.7 and 1.3 additional cases per 1000 women per five years of combined oral estrogen-progestin or unopposed oral estrogen use, respectively.
Diabetes and Insulin Resistance
A meta-analysis (pool of multiple studies) of 107 trials examining components of the metabolic syndrome concluded that HT reduced abdominal obesity, insulin resistance, the incidence of new-onset diabetes, lipid levels, and blood pressure in women without diabetes and reduced insulin resistance and fasting glucose levels in women with diabetes. Additionally, some sources cite a reduction of diabetes and weight gain by roughly 20%.
Longevity and HRT
Women ages 50 to 59 years, the group most likely to be taking HT, the estimate of mortality benefit in one analysis was 5 fewer deaths per 1,000 per five years. One review showed that 1 in every 119 women treated with HRT did not die at five years compared with untreated patients (no HRT use).
Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66. doi: 10.1210/jc.2009-2509. Epub 2010 Jun 21. PMID: 20566620; PMCID: PMC6287288.
UpToDate: Menopausal hormone therapy: Benefits and risks Authors: Kathryn A Martin, MD Robert L Barbieri, MD Section Editors: Peter J Snyder, MD William F Crowley, Jr, MD Deputy Editor:Jean E Mulder, MD.