Hormone Therapy Position Statement 2022

Publication Date: June 30, 2022
Last Updated: July 19, 2022

EXPLAINING HORMONE THERAPY RISK

  • Findings from RCTs of hormone therapy can be interpreted with greater confidence than observational studies. (Level I)
  • Smaller effect sizes may be less clinically relevant, particularly for rare outcomes. (Level I)

FORMULATION, DOSING, ROUTES OF ADMINISTRATION, AND SAFETY

  • The appropriate, often lowest, effective dose of systemic ET consistent with treatment goals that provides benefits and minimizes risks for the individual woman should be the therapeutic goal. (Level III)
  • The various formulations, doses, and routes of prescription hormone therapy preparations have comparable high efficacy for relieving VMS. (Level I)
  • Formulation, dose, and route of administration for hormone therapy should be determined individually and reassessed periodically. (Level III)
  • Different hormone therapy doses, formulations, and routes of administration may have different effects on target organs, potentially allowing options to minimize risk. (Level II)
  • The appropriate formulation, dose, and route of administration of progestogen is needed to counter the proliferative effects of systemic estrogen on the endometrium. (Level I)
  • Overall, the increased absolute risks associated with EPT and ET are rare (<10/10,000/y) and include increased risk for VTE and gallbladder disease. In addition, EPT carries a rare increased risk for stroke and breast cancer, and if estrogen is inadequately opposed, an increased risk of endometrial hyperplasia and endometrial cancer. (Level I)
  • The absolute risks are reduced for all-cause mortality, fracture, diabetes mellitus (EPT and ET), and breast cancer (ET) in women aged younger than 60 years. (Level I)

FDA-APPROVED INDICATIONS

  • Hormone therapy is FDA approved for four indications: moderate to severe VMS; prevention of osteoporosis in postmenopausal women; treatment of hypoestrogenism caused by hypogonadism, BO, or POI; and treatment of moderate to severe vulvovaginal symptoms. FDA guidance for treatment of genitourinary symptoms related to menopause in the absence of indications for systemic ET suggests the use of low-dose topical vaginal ET. (Level I)

COMPOUNDED BIOIDENTICAL HORMONES

  • Compounded bioidentical hormone therapy presents safety concerns, such as minimal government regulation and monitoring, overdosing and underdosing, presence of impurities and lack of sterility, lack of scientific efficacy and safety data, and lack of a label outlining risks. (Level I)
  • Salivary and urine hormone testing to determine dosing are unreliable and not recommended. Serum hormone testing is rarely needed. (Level II/III)
  • Shared decision-making is important, but patient preference alone should not be used to justify the use of compounded bioidentical hormone preparations, particularly when government regulated bioidentical hormone preparations are available. (Level III)
  • Situations in which compounded bioidentical hormones could be considered include allergies to ingredients in a government approved formulation or dosages not available in government approved products. (Level III)

MENOPAUSE SYMPTOMS

Vasomotor symptoms

  • Vasomotor symptoms may begin during perimenopause, and frequent VMS may persist on average 7.4 years or longer. They affect quality of life and may be associated with CV, bone, and brain health. (Level I/II)
  • Hormone therapy remains the gold standard for relief of VMS. – Estrogen-alone therapy can be used for symptomatic women without a uterus. (Level I). For symptomatic women with a uterus, EPT or a TSEC protects against endometrial neoplasia. (Level I)
  • Shared decision-making should be used when considering formulation, route of administration, and dose of hormone therapy for menopause symptom management, with adjustment tailored to symptom relief, AEs, and patient preferences. (Level III)
  • Periodic assessment of the need for ongoing use of hormone therapy should be individualized on the basis of a woman’s menopause symptoms, general health and underlying medical conditions, risks, treatment goals, and personal preferences. (Level III)
  • Micronized progesterone 300 mg nightly significantly decreases VMS (hot flashes and night sweats) compared with placebo and improves sleep. Synthetic progestins have also shown benefit for VMS in some studies. No long-term study results are available, and use of progestogens without estrogen for either indication is off-label. (Level II)

Sleep disturbances

  • During the menopause transition, women with VMS are more likely to report disrupted sleep. (Level I)
  • Hormone therapy improves sleep in women with bothersome nighttime VMS by reducing nighttime awakenings. Estrogen may have some effect on sleep, independent of VMS. (Level II)

Genitourinary symptoms

  • Low-dose vaginal ET preparations are effective and generally safe for the treatment of GSM, with minimal systemic absorption, and are preferred over systemic therapies when ET is used only for genitourinary symptoms. (Level I)
  • For women with breast cancer, low-dose vaginal ET should be prescribed in consultation with their oncologists. (Level III)
  • Progestogen therapy is not required with low-dose vaginal estrogen, but RCT data are lacking beyond 1 year. (Level II)
  • Non estrogen prescription FDA-approved therapies that improve VVA in postmenopausal women include ospemifene and intravaginal DHEA. (Level I)
  • Vaginal bleeding in a postmenopausal woman requires thorough evaluation. (Level I)

Urinary tract symptoms (including pelvic floor disorders)

  • Systemic hormone therapy does not improve urinary incontinence and may increase the incidence of stress urinary incontinence. (Level I)
  • Low-dose vaginal ET may provide benefit for urinary symptoms, including prevention of recurrent UTIs, overactive bladder, and urge incontinence. (Level II)
  • Hormone therapy does not have FDA approval for any urinary health indication. (Level I)

Sexual function

  • Both systemic hormone therapy and low-dose vaginal ET increase lubrication, blood flow, and sensation of vaginal tissues. (Level I)
  • Systemic hormone therapy generally does not improve sexual function, sexual interest, arousal, or orgasmic response independent of its effect on GSM. (Level I)
  • If sexual function or libido are concerns in women with menopause symptoms, transdermal ET may be preferable over oral ET because of minimal effect on sex hormone-binding globulin and free testosterone levels. (Level II)
  • Low-dose vaginal ET improves sexual function in postmenopausal women with GSM. (Level I)
  • Non estrogen alternatives FDA approved for dyspareunia include ospemifene and intravaginal DHEA. (Level I)

PRIMARY OVARIAN INSUFFICIENCY

  • Women with POI and premature or early menopause may be at increased risk for fracture, CVD, heart failure, DM, overall mortality, persistent VMS, loss of fertility, bone loss, genitourinary symptoms, sexual dysfunction, cognitive and mood changes, increased risk of dementia, open-angle glaucoma, depression, and poor quality of life. (Level II)
  • In the absence of contraindications, 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. (Level II)
  • Results of the WHI trials in older women do not apply to women with POI or premature or early menopause. (Level II)
  • In women with BO 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, and likely CVD and overall mortality, with benefit seen in observational studies for CV mortality and cognitive impairment or dementia. (Level II)
  • Fertility preservation and counseling should be explored for young women at risk for POI. (Level III)
  • Ovarian conservation is recommended when hysterectomy is performed for benign indications in premenopausal women at average risk for ovarian cancer. (Level II)

SKIN, HAIR, AND SPECIAL SENSES

  • Estrogen therapy appears to have beneficial effects on skin thickness and elasticity and collagen when given at menopause. (Level II)
  • 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. (Level II)
  • Hormone therapy appears to decrease the risk of neovascular and soft drusen age-related macular degeneration but not early or late-stage macular degeneration. (Level II)
  • Estrogen therapy appears to reduce intraocular pressure and mitigate the risk for open-angle glaucoma in Black women.(Level II)
  • Evidence of hormone therapy effects on cataracts, optic nerve disease, dry-eye disease, and hearing loss is mixed. (Level II)
  • Little is known about hormone therapy effects on olfactory changes. (Level II)
  • In small trials, hormone therapy appears to decrease dizziness or vertigo and improve postural balance. (Level II)

HORMONE THERAPY AND QUALITY OF LIFE

  • Menopause symptoms are associated with poorer health-related and menopause-specific quality of life. (Level II)
  • Systemic hormone therapy can improve menopause-specific quality of life in women experiencing menopause symptoms. (Level II)

OSTEOPOROSIS

  • Hormone therapy prevents bone loss in healthy postmenopausal women, with dose-related effects on bone density. (Level I)
  • Hormone therapy reduces fracture risk in healthy postmenopausal women. (Level I)
  • Discontinuing hormone therapy results in rapid bone loss; however, no excess in fractures was seen in the WHI after discontinuation. (Level I)
  • Hormone therapy is FDA approved for prevention of bone loss, but not for treatment of osteoporosis. (Level I)
  • In the absence of contraindications, 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. (Level I)
  • Unless contraindicated, 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. (Level II)
  • Decisions regarding initiation and discontinuation of hormone therapy should be made primarily on the basis of extra skeletal benefits (ie, reduction of VMS) and risks. (Level III)

JOINT PAIN

  • Women in the WHI and other studies have less joint pain or stiffness with hormone therapy compared with placebo. (Level I)
  • There is a need for further understanding of estrogen’s potential effect on joint health. (Level III)

SARCOPENIA

  • Development of frailty with aging is a health risk. (Level I)
  • Sarcopenia and osteoporosis are related to aging, estrogen depletion, and the menopause transition. (Level II)
  • Intervention to improve bioenergetics and prevent loss of muscle mass, strength, and performance is needed. (Level III)
  • Preclinical studies suggest a possible benefit of ET when combined with exercise to prevent the loss of muscle mass, strength, and performance, but this has not been shown in clinical trials. (Level II)

GALLBLADDER AND LIVER

  • Risk of gallstones, cholecystitis, and cholecystectomy is increased with ET and EPT. (Level I)
  • 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. (Level II)
  • 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. (Level II)

DIABETES MELLITUS, METABOLIC SYNDROME, ND BODY COMPOSITION

  • Hormone therapy significantly reduces the diagnosis of new-onset type 2 DM, but it is not government approved for this indication. (Level I)
  • Hormone therapy is not contraindicated in otherwise healthy women with preexisting type 2 DM and may be beneficial in terms of glycemic control when used for menopause symptom management. (Level II)
  • Although hormone therapy may help attenuate abdominal adipose accumulation and weight gain associated with the menopause transition, the effect is small. (Level II)

COGNITION

  • In the absence of more definitive findings, hormone therapy is not recommended at any age to prevent or treat a decline in cognitive function or dementia. (Level I)
  • Initiating hormone therapy in women aged older than 65 years increased 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. (Level I)
  • The effect of hormone therapy may be modified by baseline cognitive function, with more favorable effects in women with normal cognitive function before hormone therapy initiation. (Level II)
  • Estrogen therapy may have cognitive benefits when initiated immediately after hysterectomy with bilateral oophorectomy, but hormone therapy in the early natural post menopause period has neutral effects on cognitive function. (Level II)

DEPRESSION

  • There is some evidence that ET has antidepressant effects of similar magnitude to that observed with antidepressant agents when administered to depressed perimenopausal women with or without concomitant VMS. (Level II)
  • Estrogen therapy is ineffective as a treatment for depressive disorders in postmenopausal women. Such evidence suggests a possible window of opportunity for the effective use of ET for the management of depressive disorders during the perimenopause. (Level II)
  • There is some evidence that ET enhances mood and improves well-being in nondepressed perimenopausal women. (Level II)
  • Transdermal estradiol with intermittent MP may prevent the onset of depressive symptoms in euthymic perimenopausal women, but the evidence is not sufficient to recommend estrogen-based therapies for preventing depression in asymptomatic perimenopausal or postmenopausal women, and the risks and benefits must be weighed. (Level II)
  • Estrogen-based therapies may augment clinical response to antidepressants in midlife and older women, preferably when also indicated for other menopause symptoms such as VMS. (Level III)
  • 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. (Level II)
  • Estrogen is not government approved to treat mood disturbance. (Level I)

CARDIOVASCULAR DISEASE AND ALL-CAUSE MORTALITY

  • For healthy symptomatic women aged younger than 60 years or within 10 years of menopause onset, the favorable effects of hormone therapy on CHD and all-cause mortality should be considered against potential rare increases in risks of breast cancer, VTE, and stroke. (Level I)
  • Hormone therapy is not government approved for primary or secondary cardio protection. (Level I)
  • Personal and familial risk of CVD, stroke, VTE, and breast cancer should be considered when initiating hormone therapy. (Level III)
  • 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. (Level I)
  • Initiation of hormone therapy in recently postmenopausal women reduced or had no effect on subclinical atherosclerosis progression and coronary artery calcification in randomized, controlled trials. (Level I)
  • Observational data and meta-analyses show reduced risk of CHD in women who initiate hormone therapy when aged younger than 60 years or within 10 years of menopause onset. Meta-analyses show a null effect of hormone therapy on CHD after excluding open-label trials. (Level II)
  • 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. (Level I)

BREAST CANCER

  • 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). (Level I)
  • 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. (Level III)
  • 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. (Level II)
  • 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. (Level II)
  • A preponderance 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. (Level II)
  • Insufficient data are available to assess the risk of breast cancer with newer therapies such as TSECs, including BZA plus CEE. (Level II)
  • 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 or after bilateral Salpingo Oophorectomy (BSO) for BRCA 1 or 2 genetic variants. (Level II)
  • Systemic hormone therapy is generally not advised for survivors of breast cancer, although hormone therapy use may be considered in women with severe VMS unresponsive to nonhormone options, with shared decision-making in conjunction with their oncologists. (Level III)
  • For survivors of breast cancer with 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. There is increased concern with low-dose vaginal ET for women on AIs. (Level III)
  • Regular breast cancer surveillance is advised for all postmenopausal women per current breast cancer screening guidelines, including those who use hormone therapy. (Level I)

ENDOMETRIAL CANCER

  • Unopposed systemic ET in a postmenopausal woman with an intact uterus increases the risk of endometrial cancer, so adequate progestogen is recommended. (Level I)
  • 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. (Level II)
  • 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 nonhormone therapies are ineffective. (Level II)
  • Systemic hormone therapy is not advised with high-grade, advanced-stage endometrial cancers or with endometrial stromal sarcomas or leiomyosarcomas. (Level II)

OVARIAN CANCER

  • Use of oral contraceptives is associated with a significant reduction in ovarian cancer risk. (Level I)
  • 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 EPT in the WHI. (Level II)
  • In women with a history of ovarian cancer, benefits of hormone therapy use generally outweighs risks, especially with bothersome VMS or 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. (Level II)
  • Short-term hormone therapy use appears safe in women with BRCA1 and BRCA2 genetic variants who undergo risk-reducing BSO before the average age of menopause. (Level II)

COLORECTAL CANCER

  • Observational studies suggest a reduced incidence of colorectal cancer in current hormone therapy users, with reduced mortality. (Level II)
  • 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. (Level I)

LUNG CANCER

  • There appears to be an overall neutral effect of hormone therapy on lung cancer incidence and survival. (Level II)
  • Smoking cessation should be encouraged, with increased lung cancer surveillance for older smokers, including current or past users of hormone therapy. (Level I)

DURATION OF USE, INITIATION AFTER GE 60 YEARS, AND DISCONTINUATION OF HORMONE THERAPY

  • The safety profile of hormone therapy is most favorable when initiated in healthy women aged younger than 60 years or within 10 years of menopause onset, so initiation of hormone therapy by menopausal women aged older than 60 years requires careful consideration of individual benefits and risks. (Level I)
  • Long-term use of hormone therapy, including for women aged older than 60 years, may be considered in healthy women at low risk of CVD and breast cancer with persistent VMS or at elevated risk of fracture for whom other therapies are not appropriate. (Level III)
  • Factors that should be considered include severity of symptoms, effectiveness of alternative nonhormone interventions, and underlying risk for osteoporosis, CHD, cerebrovascular accident, VTE, and breast cancer. (Level III)
  • Hormone therapy does not need to be routinely discontinued in women aged older than 60 or 65 years. (Level III)
  • Mitigation of risk through use of the lowest effective dose and potentially with a nonoral route of administration becomes increasingly important as women age and with longer duration of therapy. (Level III)
  • Longer durations or extended use beyond age 65 should include periodic reevaluation of comorbidities with consideration of periodic trials of lowering or discontinuing hormone therapy. (Level III)
  • For women with GSM, low-dose vaginal ET may be considered for use at any age and for extended duration, if needed. (Level III)
  • In the absence of contraindications, a woman should determine her preferred hormone therapy formulation, dose, and duration of use, with ongoing assessment and shared decision-making with her healthcare professional. (Level III)

CONCLUSIONS

  • Hormone therapy is the most effective treatment for VMS and GSM and has been shown to prevent bone loss and fracture.
  • Risks of hormone therapy differ for women, depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is needed. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation.
  • For women aged younger than 60 years or within 10 years of menopause onset and without contraindications, the benefit-risk ratio appears favorable for treatment of bothersome VMS and for the prevention of bone loss and reduction of fracture. Based on the WHI RCTs, longer duration may be more favorable for ET than for EPT.
  • For women who initiate hormone therapy more than 10 or 20 years from menopause onset or when aged 60 years or older, the benefit-risk ratio appears less favorable than for younger women because of greater absolute risks of CHD, stroke, VTE, and dementia.
  • For GSM symptoms not relieved with nonhormone therapies, low-dose vaginal ET or other government-approved therapies (eg, vaginal DHEA or oral ospemifene) are recommended.

Recommendation Grading

Overview

Title

Hormone Therapy Position Statement 2022

Authoring Organization

North American Menopause Society

Publication Month/Year

June 30, 2022

Last Updated Month/Year

April 1, 2024

Supplemental Implementation Tools

Document Type

Consensus

Country of Publication

US

Document Objectives

An Advisory Panel of clinicians and researchers expert in the field of women’s health and menopause was recruited by NAMS to review the 2017 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Advisory Panel’s recommendations were reviewed and approved by the NAMS Board of Trustees.

Inclusion Criteria

Female, Adult, Older adult

Health Care Settings

Ambulatory

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Management

Diseases/Conditions (MeSH)

D008593 - Menopause, D014666 - Vasomotor System, D020249 - Hormone Replacement Therapy

Keywords

menopause, hormone therapy, vasomotor symptoms, Genitourinary syndrome of menopause

Source Citation

Faubion, Stephanie S. MD, MBA, FACP, NCMP; Crandall, Carolyn J. MD, MS, MACP, NCMP, FASBMR; Davis, Lori DNP, FNP-C, NCMP; El Khoudary, Samar R. PhD, MPH, FAHA; Hodis, Howard N. MD; Lobo, Roger A. MD; Maki, Pauline M. PhD; Manson, JoAnn E. MD, DrPH, MACP, NCMP; Pinkerton, JoAnn V. MD, FACOG, NCMP; Santoro, Nanette F. MD; Shifren, Jan L. MD, NCMP; Shufelt, Chrisandra L. MD, MS, FACP, NCMP; Thurston, Rebecca C. PhD, FABMR, FAPS; Wolfman, Wendy MD, FRCSC, FACOG The 2022 hormone therapy position statement of The North American Menopause Society, Menopause: July 2022 - Volume 29 - Issue 7 - p 767-794
doi: 10.1097/GME.0000000000002028