Hormone Replacement Therapy [HT]

Women with early or premature natural menopause (when periods stop before the age of 40) and Primary Ovarian Insufficiency (POI – a condition where the ovaries stop working properly for no obvious medical reason) experience an extended period of time without ovarian hormone activity leading to a potential estrogen deficiency in all tissues compared with women experiencing normal menopause.

Health risks of early natural menopause and primary ovarian insufficiency (POI) may include persistent vasomotor symptoms (VMS – hot flashes and night sweats), bone loss, genitourinary syndrome, mood changes, and increased risk of heart disease, dementia, stroke, Parkinson’s disease, eye disorders, and overall mortality.[3] As well, women with POI have a higher risk of death from ischemic heart disease (heart disease caused by narrowed arteries) as well as from all causes, compared with women who have a normal age of natural menopause, which may be reflective of premature aging. They also have a higher risk of digestive tract cancer but a decreased risk of mortality from breast, uterine, and endometrial cancer. [3]
Effective management may include appropriate doses of HT along with calcium, vitamin D, exercise, and screenings to detect medical issues.
Results of the Women’s Health Initiative (WHI) studies in older women [7] do not apply to women with early menopause, and observational evidence suggests benefits for HT taken to the average age of menopause. [3]
Hormone therapy such as transdermal (through the skin) estradiol in higher doses with adequate endometrial protection may be superior to oral contraceptive therapy to restore or maintain bone mineral density.[3]

When both ovaries are surgically removed (bilateral oophorectomy), the loss of ovarian hormones – estrogen, progesterone, and testosterone – is abrupt. This can trigger vasomotor symptoms as well as a variety of estrogen deficiency-related symptoms and diseases that can have a major effect on quality of life (QOL). You can assess your own Quality of Life here .

Potential adverse events (AEs) can occur in the cardiovascular system, and on bone health, mood, sexual health, and cognition. All of these have been shown (in clinical observational studies ) to be improved by estrogen therapy. [3]

Unless contraindications are present, estrogen therapy (ET) is indicated for women who have had a bilateral oophorectomy and are low in estrogen to reduce the risk for genitourinary symptoms, painful sex and improved bone health.

Observational data suggest a benefit on atherosclerosis (hardening or thickening of the arteries) and other cardiovascular disease, cognitive decline and dementia.

Younger women may require higher doses for symptom relief and/or protection against bone loss.

One review study showed that hormone therapy provides a significant benefit for menopause-specific quality of life in midlife women, mainly through relief of symptoms. Treatment can also cause an increase in the overall quality of life. [6a]

Women who experience severe symptoms tend to experience statistically significant improvement in both health-related and menopause-specific quality of life measures. Similar levels of improvement are not shown to be statistically significant for women who do not experience severe symptoms as measured during clinical trials.[6a]

Another review study also concluded that HT improves quality of life of symptomatic menopausal women. This study also found reliable evidence on quality of life improvements beyond just a reduction in vasomotor symptoms.[6b]

Visit our resources page here to find the tools to assess your Quality of Life.

Standard-dose ET and HT prevent bone loss in postmenopausal women by inhibiting bone resorption, which is the process by which osteoclasts (a type of bone cell) break down the tissues making up bones and release those minerals causing a transfer of calcium from bone tissue to the blood. ET or HT also result in a reduced rate of bone remodeling from a healthy state to a more fragile state. The estrogen in HT is highly effective at preventing menopause-related bone loss. [2][3]

• Hormone therapy prevents bone loss in healthy postmenopausal women, with dose-related effects (larger doses produce larger effects).
• Women with premature menopause who require prevention of bone loss are best served with HT or oral contraceptives (which are less effective than HT) rather than other bone-specific treatments until the average age of menopause, when treatment may be reassessed, unless there are contraindications.
• Randomized, controlled trials and observational studies show that standard-dose HT reduces postmenopause osteoporotic fractures, including hip, spine, and all non-spine fractures, even in women without osteoporosis.
• HT using estrogen, together with a minimum of 800 IU of vitamin D, 1200 IU Calcium and smoking cessation is effective at preserving bone mineral density and reducing fracture incidence and risk.

Bone Health

Hormone therapy can be used to manage symptoms that affect the skin, hair, sight, hearing and balance. [3]

• Estrogen therapy appears to have beneficial effects on skin thickness and elasticity and collagen when given at menopause.
• Changes in hair density and female pattern hair loss worsen after menopause, but no positive role has been identified for HT.
• Hormone therapy appears to increase the risk of dry eye symptoms but may decrease the risk of cataracts and primary glaucoma. As the research shows conflicting results – in some cases HT helps, in others it doesn’t – this use of HT needs further study.
• Hormone therapy may play a role in hearing loss and olfactory changes.
• In small trials, HT appears to decrease dizziness or vertigo and improve postural balance.

Direct binding of estrogen to estrogen receptors in joint tissues provides protection of the biomechanical structure and function and helps maintain overall joint health. [3]

• Women in the Women’s Health Initiative (WHI) and other studies have shown less joint pain or stiffness compared with those on placebo.

Sarcopenia results in frailty and is associated with adverse events such as falls, hospitalization, disability, and death. While skeletal muscle does contain estrogen receptors, little is known about the interactions between estrogen and muscle.

• Sarcopenia and osteoporosis are related to aging, estrogen depletion, and the menopause transition.
• Preclinical studies suggest a possible benefit of ET when combined with exercise to prevent the loss of muscle mass, strength, and performance.

Scientific paper on sacropenia

• Risk of gallstones, inflammation of the gallbladder, and the need to surgically remove the gallbladder is increased with oral estrogen-alone and combination HT.
• Observational studies report lower risk with transdermal HT than with oral and with oral estradiol compared with CEE, but neither observation is confirmed in RCTs. An association of HT with slower fibrosis progression in hepatitis C and with fatty liver has been observed, but randomized trials are needed to establish any potential benefits and risks of HT in postmenopausal women with liver disease.

• Hormone therapy significantly reduces the diagnosis of new-onset type 2 diabetes, but it is not currently FDA approved for this purpose.
• Hormone therapy may help attenuate abdominal fat accumulation and the weight gains that are often associated with the menopause transition.

Metabolism and Weight Changes

• In the absence of more definitive findings, HT cannot be recommended at any age to prevent or treat a decline in cognitive function or dementia.
• Caution should be taken in initiating some types of HT in women aged older than 65 years, as there is a relatively small or infrequent increase in risk for dementia.
• Estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause, but HT in the early natural postmenopause period has neutral effects on current cognitive function.
• Only limited support (observational studies) is available to support the use of HT in Alzheimer disease prevention.
• The effect of HT may be modified by baseline cognitive function, with more favorable effects in women with normal cognitive function before HT initiation.
• Evidence is insufficient to support HT use in the treatment of clinical depression. In small randomized control studies, ET was effective in improving clinical depression in perimenopausal but not postmenopausal women.
• Progestins may contribute to mood disturbance.
• Women whose depression improves with HT are likely to experience a worsening of mood after estrogen withdrawal.

Mood, Depressions and Cognition

A research study out of the United Kingdom looked at whether HT increases the risk for dementia, and gives estimates for risks of developing dementia and Alzheimer’s disease in women exposed to different types of menopausal hormone therapy for different durations. The results showed no increased risks of developing dementia overall. There was, however, a slightly increased risk of developing Alzheimer’s disease among long term users of oestrogen-progestogen therapies. [8a]

• Newer observational data and reanalysis of older studies by age or time since menopause, including the WHI, suggest that for healthy, recently menopausal women, the benefits of HT (estrogen alone or with a progestogen) outweigh its risks, with fewer cardiovascular events in younger versus older women.
• In women who initiate HT more than 10 years after the onset of their menopause, there is potential for increased risk of coronary heart disease.
• The analysis of data combined from multiple independent studies of randomized control trials found no increased risk of stroke in women aged younger than 60 years or who were within 10 years of menopause onset. Note that the results of observational study findings are mixed. There is an increased risk of stroke in women who initiate HT when aged older than 60 years and/or who are more than 10 years from menopause onset.
• If HT is initiated when aged younger than 60 years, the absolute risk of venous thromboembolism (VTE – blood clots) was rare but significantly increased.
• Personal and familial risk of CVD, stroke, and VTE should be considered when initiating HT.

Different types of estrogen may have different effects on the breast so the results of studies are limited in how generalized they can be. The type and severity of breast cancer risk from HT varies depending on the type of HT, the dosage, the duration of the treatment, the time the treatment is initiated and individual patient characteristics.

• Estrogen-alone HT:
  • Compared with women who received placebo, women who received conjugated equine estrogens (CEE) alone in the WHI study [7] showed a nonsignificant reduction in breast cancer risk after an average of 7.2 years.
  • The nonsignificant pattern of reduction in breast cancer remained evident for up to a median of 13 years’ cumulative follow-up
  • A statistically significant reduction of breast cancer risk resulting from CEE was observed overall in women who were at least 80% compliant with therapy and in women with no prior HT use versus those women who had prior use of HT.
  • There are no randomized controlled trials designed yet to inform the understanding of long durations of ET and the risk of breast cancer.
• Estrogen-Progestogen HT:
  • In the WHI study [7], daily continuous-combined CEE with medroxyprogesterone (MPA) (CEE + MPA) resulted in increased risk of breast cancer, with 9 additional breast cancer cases per 10,000 person-years of therapy.
  • In subgroup analysis after the study, the increased incidence of breast cancer was limited to women who had prior exposure to HT, whereas in women without prior exposure to HT, breast cancer incidence was not significantly affected.
  • The attributable risk of breast cancer in women (mean age, 63 years) randomized in the study to the CEE + MPA in the WHI is less than 1 additional case of breast cancer diagnosed per 1,000 users annually. This is a risk slightly greater than that observed with one daily glass of wine, less than with two daily glasses, and similar to the risk reported with obesity, low physical activity, and other medications.
• Early hormone therapy in women at genetic risk for breast cancer:
  • One study looked at 1,419 sister-matched cases of breast cancer in women aged younger than 50 years compared to 1,665 controls. The results showed no increased risk of young-onset breast cancer with use of Estrogen-Progestogen HT, whereas estrogen-only HT was associated with a reduced diagnosis of young-onset breast cancer. [9]
• Hormone therapy after breast cancer:
  • The use of systemic (body-wide) HT in survivors of breast cancer is generally not advised.
  • Observational studies and randomized trials report both neutral effects and increased risk of breast cancer recurrence.
  • However, low-dose vaginal ET remains an effective treatment option for genitourinary issues, with minimal systemic absorption. Treatment may be considered in consultation with an oncologist. [3]
• Different HT regimens may be associated with increased breast density, which may obscure mammographic, leading to more mammograms or more breast biopsies.

• The use of HT may be considered in symptomatic women with surgically treated, early stage endometrial cancer (low risk) if other options are not effective, particularly in women with early surgical menopause who are at higher risk of health consequences related to estrogen loss.
• Non-hormone therapies are recommended for women with more advanced cancer or higher-risk endometrial cancer.

• There are no convincing data that estrogen initiates or promotes the development of epithelial ovarian cancer.
• In the WHI, the only randomized trial to date to study ovarian cancer, CEE + MPA HT had no significant effect on the incidence of ovarian cancer relative to placebo after 5.6 years’ active therapy and 13 years’ follow-up.

• Observational studies suggest a reduced incidence of colorectal cancer with HT, particularly if initiated early in menopause.
• The use of low-dose conjugated equine estrogen (CEE) + medroxyprogesterone acetate (MPA) as HT reduced colorectal cancer incidence across all ages during treatment.

• There appears to be an overall neutral effect of HT on lung cancer incidence.[3]