Patient Education Materials for Combined Hormone Replacement Therapy (Estradiol, Progesterone, and Testosterone)

What These Medications Are For

You should take combined hormone replacement therapy (HRT) only to relieve moderate-to-severe menopausal symptoms such as hot flashes, night sweats, or vaginal dryness—not to prevent heart disease, osteoporosis, or other chronic conditions. 1

Approved Uses:

Relief of hot flashes and night sweats (vasomotor symptoms) 1
Treatment of vaginal dryness, painful intercourse, and urinary symptoms (genitourinary symptoms) 1
Management of premature menopause (before age 40) or surgical menopause (removal of ovaries before natural menopause) 2, 1

NOT Approved For:

Prevention of heart disease or stroke 2, 1
Prevention of osteoporosis in women without symptoms 2, 1
Prevention of dementia or cognitive decline 1

What Benefits to Expect and When

Symptom Relief Timeline:

Hot flashes and night sweats: You should notice a 75% reduction in frequency and severity within 4-8 weeks of starting therapy at the correct dose 1, 3

Vaginal dryness and painful intercourse: Improvement typically begins within 2-4 weeks, with maximum benefit at 8-12 weeks 2, 1

Sleep quality and mood: Many women report better sleep and mood within 4-6 weeks as hot flashes decrease 4

Additional Benefits (Not Primary Reasons to Take HRT):

Bone protection: HRT reduces fracture risk by 22-27%, but this benefit stops when you discontinue therapy 1

Cardiovascular effects: In women under 60 or within 10 years of menopause, transdermal estradiol may have neutral or slightly protective cardiovascular effects, but HRT should never be started solely for heart protection 2, 1

Risks You Need to Know About

For Every 10,000 Women Taking Combined Estrogen-Progesterone for One Year:

Increased risks:

8 additional cases of invasive breast cancer 2, 1
8 additional strokes 2, 1
8 additional blood clots in the lungs (pulmonary emboli) 2, 1
7 additional heart attacks 2, 1

Decreased risks:

6 fewer cases of colon cancer 2, 1
5 fewer hip fractures 2, 1

Important Risk Factors:

Breast cancer risk:

Does not appear until after 4-5 years of continuous use 1
Risk increases with longer duration of therapy 2, 1
Using micronized progesterone (instead of synthetic progestins) may lower this risk 5, 4
If you have had a hysterectomy and take estrogen alone (no progesterone), breast cancer risk actually decreases slightly 2, 1

Blood clot and stroke risk:

Highest in the first 1-2 years of oral estrogen therapy 1
Transdermal (patch) estradiol does NOT increase stroke or blood clot risk, unlike oral estrogen 2, 1
Risk is much higher if you smoke, are over 60, or are more than 10 years past menopause 1

Endometrial (uterine lining) cancer risk:

Taking estrogen alone (without progesterone) increases uterine cancer risk 2.3 to 9.5-fold after 5-10 years 1
Adding progesterone reduces this risk by 90% 2, 1
If you have had a hysterectomy, you do not need progesterone 1

Common Side Effects and How to Manage Them

Estradiol Side Effects:

Breast tenderness or swelling:

Usually improves after 2-3 months as your body adjusts 6, 7
If persistent, your dose may need to be lowered 1

Nausea or bloating:

More common with oral estrogen; switching to transdermal (patch) often eliminates this 2, 1
Taking oral estrogen with food may help 6

Headaches:

May improve by switching from oral to transdermal estrogen 2, 1
If migraines worsen, contact your provider immediately 2

Skin irritation from patches:

Rotate patch application sites 2
Apply to clean, dry skin on abdomen, buttocks, or upper thigh (avoid breasts) 2
If severe irritation occurs, consider switching to gel or oral formulation 1

Progesterone Side Effects:

Drowsiness or sedation:

Take progesterone at bedtime to use this effect to improve sleep 1, 5
This side effect often decreases after 4-6 weeks 5

Mood changes or irritability:

More common with synthetic progestins (like medroxyprogesterone acetate) 5
Micronized progesterone has fewer mood side effects 5, 4

Breakthrough bleeding or spotting:

Common in the first 3-6 months as your body adjusts 2, 1
Should decrease over time; if heavy or persistent bleeding occurs, contact your provider 2, 1

Testosterone Side Effects:

Acne or oily skin:

Usually mild and improves with lower doses 2
Standard acne treatments can be used 2

Increased facial or body hair:

Dose-dependent; notify your provider if bothersome 2
May require dose reduction 2

Voice deepening (rare):

Stop testosterone immediately and contact your provider if this occurs 2

When to Stop and Call Your Doctor Immediately

Stop HRT and Seek Emergency Care If You Experience:

Sudden severe chest pain or pressure 2, 1
Sudden shortness of breath or difficulty breathing 2, 1
Sudden severe headache, vision changes, or difficulty speaking 2, 1
Sudden severe leg pain, swelling, warmth, or redness (signs of blood clot) 2, 1
Coughing up blood 2, 1
Yellowing of skin or eyes (jaundice) 2, 1

Call Your Provider Within 24 Hours If You Experience:

Heavy vaginal bleeding (soaking through a pad every 1-2 hours) 2, 1
New breast lump or significant breast changes 2, 1
Severe abdominal pain 1
Persistent severe headaches 2, 1
New or worsening depression or mood changes 5, 4

How Long You Should Take HRT

Use the lowest effective dose for the shortest time necessary to control your symptoms. 2, 1

General Duration Guidelines:

For natural menopause symptoms:

Most women need HRT for 2-5 years 1
Your provider should reassess necessity every year 2, 1
Attempt to reduce dose or stop therapy once symptoms are controlled 1

For premature menopause (before age 40) or surgical menopause:

Continue HRT at least until age 51 (average age of natural menopause), then reassess 1
Longer duration is appropriate because you are replacing hormones lost prematurely 2, 1

For testosterone therapy:

Evaluate effectiveness after 3-6 months 2
Consider limiting to 24 months due to limited long-term safety data 2

Age-Specific Considerations:

If you are under 60 or within 10 years of menopause:

HRT has the most favorable risk-benefit profile 1
Standard doses are appropriate for symptom control 1

If you are over 60 or more than 10 years past menopause:

Use the absolute lowest dose possible 1
Strongly consider discontinuation due to increased stroke and blood clot risks 1
Do not start HRT for the first time after age 65 1

Monitoring and Follow-Up Care

Annual Visits Should Include:

Review of ongoing symptoms and medication adherence 2, 1
Assessment for new contraindications (breast lumps, blood clots, stroke, heart disease) 1
Blood pressure measurement (HRT can raise blood pressure in some women) 2
Discussion of whether you still need HRT or can reduce the dose 2, 1

Routine Screening (Not HRT-Specific):

Annual mammogram per standard guidelines (HRT does not change screening recommendations) 1
Pelvic exam and Pap smear per standard guidelines 1
Bone density testing if indicated by other risk factors 1

Laboratory Testing:

Hormone levels (estradiol, FSH, testosterone) do NOT need to be routinely monitored. 1

Dosing is based on symptom control, not blood levels 1
Testing may be done if symptoms are not controlled or side effects occur 2

Endometrial Monitoring (If You Have a Uterus):

No routine ultrasound or biopsy is needed if you are taking progesterone correctly 2, 1
Report any heavy, prolonged, or irregular bleeding to your provider 2, 1

Absolute Contraindications (You Should NOT Take HRT If You Have):

Current or past breast cancer 2, 1
Current or past blood clot in legs or lungs 2, 1
Current or past stroke 2, 1
Current or past heart attack or coronary artery disease 2, 1
Active liver disease 2, 1
Unexplained vaginal bleeding 1
Known or suspected estrogen-dependent cancer 1
Antiphospholipid syndrome or positive antiphospholipid antibodies 2, 1
Known thrombophilic disorder (inherited clotting disorder) 1
Pregnancy (you must use non-hormonal contraception if still at risk of pregnancy) 1

Relative Contraindications (Use with Caution):

History of gallbladder disease (oral estrogen increases risk; transdermal is preferred) 2, 1
Smoking over age 35 (significantly increases stroke and blood clot risk) 2, 1
Migraine headaches (may worsen with HRT; transdermal estrogen is preferred) 2, 1
Hypertension (transdermal estrogen is preferred; blood pressure must be monitored) 2, 1

Choosing the Right Formulation

Estradiol Options:

Transdermal (patch) estradiol is strongly preferred over oral estrogen because:

Does NOT increase stroke risk (oral estrogen increases stroke risk by 28-39%) 2, 1
Does NOT increase blood clot risk (oral estrogen increases risk 2-4 fold) 1
Bypasses liver metabolism, reducing cardiovascular and gallbladder risks 2, 1
Provides more stable hormone levels 2, 1

Standard starting dose: 50 mcg patch applied twice weekly 2, 1

Oral estradiol alternatives:

May be used if patches cause severe skin irritation 1
Typical dose: 1-2 mg daily 1
Carries higher cardiovascular and clot risks than transdermal 1

Progesterone Options (Required If You Have a Uterus):

Micronized progesterone is strongly preferred over synthetic progestins because:

Lower breast cancer risk compared to synthetic progestins 5, 4
Lower blood clot risk compared to synthetic progestins 5
Fewer mood side effects 5, 4
Provides adequate endometrial protection 1, 5

Standard dose: 200 mg taken orally at bedtime 1, 5

Dosing schedules:

Continuous daily (preferred for postmenopausal women to avoid monthly bleeding) 1
Cyclic 12-14 days per month (may be used in perimenopause) 2, 1

Alternative synthetic progestins:

Medroxyprogesterone acetate 2.5 mg daily or 10 mg for 12-14 days per month 1
Higher breast cancer and blood clot risk than micronized progesterone 5

Testosterone Options:

Indications for adding testosterone:

Persistent low libido despite adequate estrogen replacement 2
Severe fatigue not explained by other causes 2
Loss of muscle mass or strength 2

Formulations:

Transdermal testosterone cream or gel (compounded or FDA-approved) 2
Typical dose: 0.5-2 mg daily 2

Important: Testosterone therapy for women has limited long-term safety data and should be evaluated after 3-6 months and possibly limited to 24 months 2

Compounded "Bioidentical" Hormones: What You Need to Know

FDA-approved hormone products are strongly preferred over custom-compounded preparations. 5, 3

Why Avoid Compounded Hormones:

Not standardized (dose varies between batches and pharmacies) 5, 3
Not FDA-approved (safety and efficacy not rigorously tested) 5, 3
Not covered by most insurance 5
More expensive than FDA-approved options 5
Salivary hormone testing used by compounding pharmacies is unreliable and unnecessary 3

FDA-Approved "Bioidentical" Options:

Many FDA-approved hormone products contain bioidentical hormones (chemically identical to human hormones), including:

Transdermal estradiol patches (Climara, Vivelle-Dot, Estraderm) 3
Oral micronized estradiol (Estrace) 3
Oral micronized progesterone (Prometrium) 5, 3
Vaginal estradiol (Vagifem, Estrace cream) 3

These FDA-approved products are safer, more reliable, and equally effective as compounded preparations. 5, 3

Lifestyle Measures to Maximize Benefits and Reduce Risks

To Reduce Cardiovascular Risk:

Stop smoking immediately (single most important intervention to reduce stroke and heart attack risk) 2, 1
Maintain healthy blood pressure (target <130/80 mmHg) 2
Control cholesterol and diabetes if present 2, 1
Maintain healthy weight through diet and exercise 1

To Optimize Bone Health:

Calcium 1,000-1,300 mg daily (from diet and supplements combined) 2, 1
Vitamin D 800-1,000 IU daily 2, 1
Weight-bearing exercise 30 minutes most days of the week 2, 1
Avoid excessive alcohol (no more than 1 drink per day) 1

To Reduce Breast Cancer Risk:

Maintain healthy weight (obesity increases breast cancer risk) 2, 1
Limit alcohol to no more than 1 drink per day 2, 1
Exercise regularly (150 minutes moderate activity per week) 1
Use the lowest effective HRT dose for the shortest time necessary 1

To Manage Hot Flashes Without Increasing HRT Dose:

Keep bedroom cool (65-68°F) and use fans 1
Dress in layers that can be easily removed 1
Avoid triggers: spicy foods, caffeine, alcohol, hot beverages, stress 1
Practice stress reduction techniques (deep breathing, meditation, yoga) 1
Consider cognitive behavioral therapy or clinical hypnosis (proven effective for hot flashes) 1

Questions to Ask Your Provider

"Am I a good candidate for HRT, or do I have any contraindications?" 1
"Should I use transdermal (patch) or oral estrogen, and why?" 2, 1
"Do I need progesterone, and should I use micronized progesterone or a synthetic progestin?" 1, 5
"What is the lowest dose that will control my symptoms?" 1
"How long do you recommend I stay on HRT?" 1
"What specific symptoms or side effects should prompt me to call you or go to the emergency room?" 1
"When should we try to reduce my dose or stop HRT?" 2, 1
"Are there non-hormonal alternatives I should consider?" 1
"How will we monitor for complications?" 2, 1
"What lifestyle changes can I make to reduce my risks while on HRT?" 1

Non-Hormonal Alternatives If HRT Is Not Right for You

For Hot Flashes:

Selective serotonin reuptake inhibitors (SSRIs): paroxetine, venlafaxine 1
Gabapentin 1
Cognitive behavioral therapy 1
Clinical hypnosis 1

For Vaginal Dryness:

Low-dose vaginal estrogen (minimal systemic absorption, can be used even if systemic HRT is contraindicated) 2, 1
Vaginal moisturizers (used regularly, not just before intercourse) 1
Vaginal lubricants (used during intercourse) 1

For Bone Health:

Bisphosphonates (alendronate, risedronate) 1
Denosumab 1
Weight-bearing exercise and calcium/vitamin D supplementation 2, 1

Key Takeaways

HRT is for symptom relief, not disease prevention. Do not take HRT solely to prevent heart disease, osteoporosis, or dementia. 2, 1
Transdermal estradiol is safer than oral estrogen because it does not increase stroke or blood clot risk. 2, 1
If you have a uterus, you must take progesterone with estrogen to prevent uterine cancer. Micronized progesterone is preferred over synthetic progestins. 1, 5
Use the lowest effective dose for the shortest time necessary. Your provider should reassess your need for HRT every year. 2, 1
The risk-benefit profile is most favorable if you are under 60 or within 10 years of menopause. If you are older or further from menopause, risks increase significantly. 1
Stop HRT immediately and seek emergency care if you develop chest pain, shortness of breath, severe headache, leg pain/swelling, or vision changes. 2, 1
Avoid custom-compounded "bioidentical" hormones. FDA-approved products are safer, more reliable, and equally effective. 5, 3
Lifestyle modifications are essential: stop smoking, maintain healthy weight, exercise regularly, and optimize bone health with calcium and vitamin D. 2, 1

What patient education should be provided to individuals receiving combined progesterone, estradiol, and testosterone hormone replacement therapy regarding indications, expected benefits and onset, risks, side effects, mitigation strategies, and monitoring?

Help us tailor your experience