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, Parkinsons disease, eye disorders, and overall mortality.[3a] 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. [3a]

• Effective management may include appropriate doses of HT along with calcium, vitamin D, exercise, and screenings to detect medical issues. 
• Hormone therapy is recommended at least until the average age of menopause (approximately age 52 y), with an option for use of oral contraceptives in healthy younger women, unless there are other health issues that will be negatively affected by HT. 
• Results of the Women’s Health Initiative (WHI) studies in older women [7] do not apply to women with early menopause. [3a]
• Fertility preservation and counseling should be explored for young women at risk for POI.
• Keeping the ovaries is recommended when hysterectomy is performed to treat benign conditions in premenopausal women at average risk for ovarian cancer.

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 assessments 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. [3a]

• In women with both ovaries removed before the average age of menopause, early initiation of ET, with endometrial protection if the uterus is preserved, reduces VMS, genitourinary symptoms, risk for osteoporosis and related fractures, cardiovascular disease and overall mortality. 
• 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. The estrogen in HT is highly effective at preventing menopause-related bone loss. [2][3a]

• Hormone therapy prevents bone loss in healthy postmenopausal women, with dose-related effects on bone density. 
• Hormone therapy reduces fracture risk in healthy postmenopausal women. 
• Discontinuing hormone therapy results in rapid bone loss; however, no excess in fractures was seen in the WHI after discontinuation of HT. 
• Hormone therapy is FDA approved for prevention of bone loss, but not for treatment of osteoporosis.
• In women aged younger than 60 years or within 10 years of menopause onset, systemic hormone therapy is an appropriate therapy to protect against bone loss, unless there are other health reasons to avoid HT.
• Women with premature menopause without prior fragility fracture or osteoporosis are best served with hormone therapy or oral contraceptives to prevent bone density loss and reduce fracture risk, rather than other bone-specific treatments, until the average age of menopause, when treatment may be reassessed. 
• Decisions regarding initiation and discontinuation of hormone therapy should be made primarily on the basis of non-bone related benefits (ie, reduction of VMS) and risks.

Bone Health

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

• 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 research is lacking regarding a role for hormone therapy in mitigating these changes.
• Hormone therapy appears to decrease the risk of age-related macular degeneration but not early or late-stage macular degeneration. 
• Estrogen therapy appears to reduce the pressure inside the eye (intraocular pressure) and mitigate the risk for open-angle some types of glaucoma in Black women. 
• Evidence of hormone therapy effects on cataracts, optic nerve disease, dry-eye disease, and hearing loss is mixed.
• Little is known about hormone therapy effects on olfactory changes. 
• In small trials, hormone therapy appears to decrease dizziness or vertigo and improve postural balance. 

Skin, Hair & Nails

Hormone therapy containing estrogen can be beneficial for joint pain. Direct binding of estrogen to estrogen receptors in joint tissues protects the  biomechanical structure and function and helps maintain overall joint health. [3a]

• Women in the Women’s Health Initiative (WHI) and other studies have shown less joint pain or stiffness on HT compared with those on placebo. 
• There is a need for further understanding of estrogen’s potential effect on joint health.

Joint Pain

Sarcopenia, the loss of muscle as you age, 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. 
• Development of frailty with aging is a health risk. 
• Intervention to improve energy exchanges (bioenergetics) and prevent loss of muscle mass, strength, and performance is needed.
• 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 of gallstones with transdermal hormone therapy than with oral, and with oral estradiol compared with CEE, but neither observation is confirmed in RCTs. 
• In women with hepatitis C and with fatty liver, a slower fibrosis progression has been observed with use of hormone therapy, but RCTs are needed to establish the potential benefits and risks 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 is appropriate in otherwise healthy women with pre-existing type 2 diabetes and may help control blood sugars when used for menopause symptom management. 
• Although hormone therapy may help reduce the accumulation of fat around the abdomen and weight gain associated with the menopause transition, the effect is small

Metabolism and Weight Changes

• There is some evidence that ET has antidepressant effects similar to those observed with antidepressant agents when administered to depressed perimenopausal women with or without VMS symptoms. 
• Estrogen therapy is ineffective as a treatment for depressive disorders in postmenopausal women. This suggests there is a possible ‘window of opportunity’ for the effective use of ET to manage depressive disorders during the menopausal transition.
• There is some evidence that ET enhances mood and improves well-being in nondepressed perimenopausal women. 
• Transdermal estradiol with micronized progesterone may prevent the onset of depressive symptoms in non-depressed perimenopausal women, but the evidence is not sufficient to recommend estrogen-based therapies for preventing depression in asymptomatic perimenopausal or postmenopausal women. The risks and benefits must be weighed carefully. 
• Estrogen-based therapies may be used in addition to antidepressants in midlife and older women, preferably when also indicated for other menopause symptoms such as VMS. 
• Most studies on hormone therapy for the treatment of depression examined the effects of unopposed estrogen. Data on EPT or for different progestogens are sparse and inconclusive. 
• Estrogen is not government approved to treat mood disturbance.

Mood Changes & Rage Anxiety & Depression

• Based on current research, hormone therapy is not recommended at any age to prevent or treat a decline in cognitive function or dementia.
• Initiating hormone therapy in women aged older than 65 years increases the risk for dementia, with an additional 23 cases per 10,000 person-years seen in women randomized to CEE plus MPA in the WHI Memory Study. [13]
• The effect of hormone therapy may be impacted by initial cognitive function, with more favorable effects in women with normal cognitive function before starting hormone therapy. 
• Estrogen therapy may have cognitive benefits when initiated immediately after hysterectomy with removal of both ovaries, but hormone therapy in the early natural post menopause period has neutral effects on cognitive function.

Cognitive Changes

• 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.
• For healthy symptomatic women aged younger than 60 years or within 10 years of menopause onset, the positive effects of hormone therapy on CHD and all-cause mortality should be considered against potential rare increases in risks of breast cancer, blood clots, and stroke. 
• Hormone therapy is not government approved for protection of the cardiovascular system.  
• Personal and familial risk of CVD, stroke, blood clots, and breast cancer should be considered when initiating hormone therapy. 
• The effects of hormone therapy on CHD may vary depending on when hormone therapy is initiated in relation to a woman’s age or time since menopause onset. 
• Initiation of hormone therapy in recently postmenopausal women reduced or had no effect on the progression of hardening and calcification of the arteries (atherosclerosis) in randomized, controlled trials.
• Observational data and meta-analyses show reduced risk of CHD in women who start hormone therapy when aged younger than 60 years or within 10 years of menopause onset. Meta-analyses show no impact of hormone therapy on CHD after excluding open-label trials, or trials where patients and healthcare providers know what treatment is being given (most clinical trials are ‘blind’ or ‘double-blind’ where neither the patient or healthcare provider is aware which treatment is being used). 
• Women who initiate hormone therapy aged older than 60 years or more than 10 or 20 years from menopause onset are at higher absolute risks of CHD, VTE, and stroke than women initiating hormone therapy in early menopause. 

Different types of estrogen may have different effects on the breast so the results of studies are limited and they should not be generalized. 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. 

• The risk of breast cancer related to hormone therapy use is low, with estimates indicating a rare occurrence – less than one additional case per 1,000 women per year of hormone therapy use or three additional cases per 1,000 women when used for 5 years with CEE plus MPA (conjugated equine estrogens plus progestogen (medroxyprogesterone acetate). 
• Women should be counseled about the risk of breast cancer with hormone therapy, putting the data into perspective, with risk similar to that of modifiable risk factors such as two daily alcoholic beverages, obesity, and low physical activity. 
• The effect of hormone therapy on breast cancer risk may depend on the type of hormone therapy, duration of use, regimen, prior exposure, and individual characteristics. 
• Different hormone therapy regimens may be associated with increased breast density, which may obscure mammographic interpretation, leading to more mammograms or more breast biopsies and a potential delay in breast cancer diagnosis. 
• A large quantity of data does not show an additive effect of underlying breast cancer risk (age, family history of breast cancer, genetic risk of breast cancer, benign breast disease, personal breast cancer risk factors) and hormone therapy use on breast cancer incidence. 
• Observational evidence suggests that hormone therapy use does not further increase risk of breast cancer in women at high risk because of a family history of breast cancer. 
• Systemic hormone therapy is generally not advised for survivors of breast cancer, although hormone therapy use may be considered in women with severe VMS that does not respond to non hormonal options. This decision should be shared with a woman’s oncologist.  
• For survivors of breast cancer with genitourinary syndrome of menopause (GSM), low-dose vaginal ET or DHEA may be considered in consultation with their oncologists if bothersome symptoms persist after a trial of nonhormone therapy. 
• Regular breast cancer surveillance is advised for all postmenopausal women based on current breast cancer screening guidelines, including those who use hormone therapy. 

• Unopposed systemic ET (estrogen without opposing progestogen) in a postmenopausal woman with an intact uterus increases the risk of endometrial cancer, so adequate progestogen is recommended. 
• Low-dose vaginal ET does not appear to increase endometrial cancer risk, although trials with endometrial biopsy end points are limited to 1 year in duration. 
• Use of hormone therapy is an option for the treatment of bothersome menopause symptoms in women with surgically treated, early stage, low-grade endometrial cancer in consultation with a woman’s oncologist if non hormonal therapies are ineffective. 
• Systemic hormone therapy is not advised with high-grade, advanced-stage endometrial cancers or with endometrial stromal sarcomas or leiomyosarcomas.

• Use of oral contraceptives is associated with a significant reduction in ovarian cancer risk. 
• Current and recent use of hormone therapy is associated with a small but statistically significant risk of ovarian cancer in observational studies, principally for serous type, although there was no increase in ovarian cancer risk in women randomized to estrogen + progestogen therapy (EPT) in the WHI. 
• In women with a history of ovarian cancer, benefits of hormone therapy use generally outweighs risks, especially with bothersome VMS or during early menopause; use of hormone therapy is not advised in women with hormone-dependent ovarian cancers, including granulosa-cell tumors and low-grade serous carcinoma. 
• Short-term hormone therapy use appears safe in women with BRCA1 and BRCA2 genetic variants who undergo risk-reducing surgery to remove both ovaries and fallopian tubes (bilateral salpingo-oophorectomy or BSO) before the average age of menopause.

• Observational studies suggest a reduced incidence of colorectal cancer in current hormone therapy users, with reduced mortality. 
• In the WHI, EPT, but not ET alone, reduced colorectal cancer risk, although cancers diagnosed in EPT users were diagnosed at a more advanced stage. There was no difference in colorectal cancer mortality with either EPT or ET.

• There appears to be an overall neutral effect of hormone therapy on lung cancer incidence and survival. 
• Quitting smoking should be encouraged, with increased lung cancer surveillance for older smokers, including current or past users of hormone therapy.