What are the guidelines for initiating and monitoring Hormone Replacement Therapy (HRT) in patients?

Hormone Replacement Therapy (HRT) Initiation and Monitoring

Indications for HRT

HRT is indicated for treatment of estrogen deficiency symptoms in women with premature ovarian insufficiency (POI) and for relief of bothersome menopausal symptoms in postmenopausal women, but should not be initiated for primary or secondary prevention of cardiovascular disease. 1, 2

• HRT effectively treats vasomotor symptoms (hot flashes, night sweats), genitourinary syndrome of menopause, and provides bone protection in women with POI 1, 3
• Women with POI should be informed that HRT may have a role in primary prevention of cardiovascular disease and bone protection, with a different risk-benefit profile than HRT in naturally menopausal women 1, 3
• For naturally menopausal women, HRT should be used at the lowest effective dose for the shortest possible time when prescribed for symptom relief 2, 4

Pre-Treatment Assessment

Before initiating HRT, evaluate the following risk factors:

• Cardiovascular risk: History of coronary heart disease, stroke, hypertension, diabetes, hypercholesterolemia 1, 5
• Thrombotic risk: Personal or family history of venous thromboembolism 1, 5
• Breast cancer risk: Personal or family history, BRCA mutations 1, 2
• Endometrial cancer risk: Uterine status (intact vs hysterectomy) 1
• Other contraindications: Active breast cancer, undiagnosed vaginal bleeding, active liver disease 1

Estrogen Selection and Route of Administration

17β-estradiol administered transdermally is the preferred first-line approach, particularly for women with cardiovascular risk factors or hypertension. 1, 3

Estrogen Formulation Priority:

1. First choice: 17β-estradiol (transdermal patches or vaginal gel) 1, 3
2. Second choice: Oral micronized 17β-estradiol 1
3. Avoid: Ethinylestradiol or conjugated equine estrogens 1

Rationale for Transdermal Route:

• Avoids hepatic first-pass metabolism, reducing impact on coagulation factors 1, 4
• Preferred in women with hypertension 1
• Better safety profile for cardiovascular and thrombotic risk 1, 4
• Superior for cancer survivors at increased cardiovascular risk 1

Dosing:

• Standard adult dose: 50-100 mcg/day transdermally (may increase to 200 mcg/day if needed) 1
• Initial dose in older women: Start at half the normal dose and titrate based on tolerability 6
• Adolescents with POI: Begin with low-dose estrogen (6.25 mcg/day transdermal or 0.25 mg/day oral) and gradually increase over 2-3 years 1

Progestogen Selection for Endometrial Protection

All women with an intact uterus must receive progestogen in combination with estrogen to protect the endometrium. 1

Progestogen Options (in order of preference):

1. First choice: Micronized progesterone (MP) 100-200 mg orally daily for 12-14 days every 28 days 1

   • Preferred due to physiological and safe profile 1
   • Devoid of antiapoptotic properties on breast cells compared to synthetic progestogens 4

2. Alternatives (if MP contraindicated or poorly tolerated):

   • Medroxyprogesterone acetate (MPA) 5-10 mg daily for 12-14 days every 28 days 1
   • Norethisterone 5 mg daily for 12-14 days every 28 days 1

3. Transdermal progestin: Sequential combined patches available in some countries 1

Timing of Progestogen Initiation:

• In adolescents with induced puberty: Begin cyclical progestogens after at least 2 years of estrogen or when breakthrough bleeding occurs 1
• Confirm adequate endometrial thickness via ultrasound before prescribing progestogen 1

Special Populations and Considerations

Women with Hypertension:

• Hypertension is not a contraindication to HRT in women with POI 1
• Transdermal estradiol is the preferred delivery method 1

Women with Migraine:

• Migraine is not a contraindication to HRT in women with POI 1
• Consider changing dose, route, or regimen if migraine worsens during HRT 1

Women with BRCA Mutations:

• HRT is a treatment option for women with BRCA1/2 mutations without personal history of breast cancer after prophylactic bilateral salpingo-oophorectomy 1

Breast Cancer Survivors:

• HRT is generally contraindicated in breast cancer survivors 1

Women with Endometriosis:

• Combined estrogen/progestogen therapy can be effective for vasomotor symptoms and may reduce risk of disease reactivation after oophorectomy 1

Contraception Needs:

• If contraception is required in post-pubertal patients, combined oral contraceptives (COCs) may be considered as first choice 1
• If contraception not required, transdermal 17β-estradiol remains first choice 1

Monitoring Protocol

Once established on therapy, women with POI using HRT should have a clinical review annually, with particular attention to compliance. 1, 3

Annual Review Should Include:

• Assessment of symptom control and treatment satisfaction 1
• Evaluation of compliance with prescribed regimen 1, 3
• Review of any new contraindications or risk factors 2
• Cardiovascular health assessment 2
• Bone health monitoring in at-risk patients 2

Routine Testing:

• No routine monitoring tests are required but may be prompted by specific symptoms or concerns 1
• Ovarian function cannot be reliably assessed during HRT 3
• FSH and estradiol levels are not useful for monitoring during HRT 3

Specific Monitoring Considerations:

• Monitor for sustained edema, gastrointestinal bleeding, or worsening renal function if patient develops new conditions 1
• Bone mineral density assessment may be warranted in women at risk for osteoporosis after discontinuation 2

Risk Communication

Risks in Women with POI (Before Age of Natural Menopause):

• Breast cancer: HRT has not been found to increase risk before the age of natural menopause 1, 3
• Cardiovascular disease: May provide protective benefits in this population 1, 3
• Thromboembolism: Small increased risk, minimized with transdermal route 4

Risks in Naturally Menopausal Women:

• Breast cancer: Small increased risk with long-term estrogen-progestin use (approximately 8 additional cases per 10,000 women per year) 1, 2
• Stroke: Small increased risk that persists over years (approximately 8 additional cases per 10,000 women per year) 1, 4
• Venous thromboembolism: Increased risk, especially in first 1-2 years (approximately 8 additional cases per 10,000 women per year) 1, 5
• Coronary heart disease: May increase risk, especially if initiated years after menopause (approximately 7 additional events per 10,000 women per year) 1

Benefits:

• Reduction in hip fractures (approximately 5 fewer per 10,000 women per year) 1
• Reduction in colorectal cancer with estrogen-progestin therapy (approximately 6 fewer cases per 10,000 women per year) 1

Common Pitfalls to Avoid

• Do not use HRT solely for prevention of chronic conditions like osteoporosis or cardiovascular disease without considering alternative therapies 2
• Do not prescribe unopposed estrogen in women with intact uterus due to endometrial cancer risk 1
• Do not continue HRT during bedrest or hospitalization due to increased thrombotic risk 1
• Do not use ethinylestradiol or conjugated equine estrogens when 17β-estradiol is available 1
• Do not initiate HRT for secondary prevention of cardiovascular events in women with established coronary disease 1, 2