Continuous combined hormone replacement therapy (HRT)

Continuous Combined Hormone Replacement Therapy (HRT): Tablets, Capsules, and Patches

Continuous combined hormone replacement therapy (HRT) refers to the daily administration of both estrogen and progestogen without a break, primarily indicated for postmenopausal women with an intact uterus to manage vasomotor symptoms, urogenital atrophy, and to prevent osteoporosis, while reducing the risk of endometrial hyperplasia and carcinoma associated with unopposed estrogen therapy.

This formulation is different from cyclical (sequential) HRT, which alternates estrogen daily with progestogen added for part of the month, and is most appropriate for perimenopausal women. Continuous combined HRT is typically prescribed for women who are more than 12 months postmenopausal.

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1. Rationale and Purpose of Continuous Combined HRT

• Estrogen helps relieve menopausal symptoms such as hot flashes, night sweats, and vaginal dryness.

• Progestogen is added to protect the endometrium from hyperplasia and carcinoma due to continuous unopposed estrogen in women with an intact uterus.

• The continuous combined regimen aims to achieve amenorrhea, avoiding monthly bleeding episodes.

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2. Formulations and Routes

A. Oral Tablets and Capsules

• Contain fixed doses of estrogen and progestogen in a single tablet/capsule taken once daily.

B. Transdermal Patches

• Applied to the skin (usually the lower abdomen or buttocks), changed once or twice weekly.

• Provides steady hormone levels, bypasses hepatic first-pass metabolism, and is suitable for women at risk of thromboembolism or gastrointestinal intolerance.

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3. Commonly Used Continuous Combined HRT Products

A. Oral Tablets / Capsules (UK, EU, US brands)

Product Name	Estrogen Component	Progestogen Component
Kliovance	Estradiol 1 mg	Norethisterone acetate 0.5 mg
Climacontin	Estradiol valerate 2 mg	Norgestrel 0.15 mg
Femoston Conti	Estradiol hemihydrate 1 mg	Dydrogesterone 5 mg
Indivina	Estradiol valerate 1 or 2 mg	Medroxyprogesterone acetate 2.5 mg
Activella (US)	Estradiol 1 mg	Norethindrone acetate 0.5 mg
Angeliq	Estradiol 1 mg	Drospirenone 0.5 mg
Duavee (US)	Conjugated estrogens 0.45 mg	Bazedoxifene 20 mg* (SERM, not progestogen)

*Note: Duavee contains a selective estrogen receptor modulator (SERM) rather than a traditional progestogen; it’s used as an endometrial-protective alternative.

B. Transdermal Patches

Product Name	Estrogen Component	Progestogen Component
Evorel Conti	Estradiol 3.2 mg	Norethisterone acetate 11.2 mg (released 50 mcg and 170 mcg/day)
FemSeven Conti	Estradiol 1.5 mg	Levonorgestrel 0.525 mg (delivers 50 mcg and 7 mcg/day)
Climara Pro (US)	Estradiol 0.045 mg/day	Levonorgestrel 0.015 mg/day
Combipatch (US)	Estradiol 0.05 mg/day	Norethindrone acetate 0.14 or 0.25 mg/day

4. Mechanism of Action

• Estradiol (17β-estradiol or other estrogens) binds to estrogen receptors in tissues including the hypothalamus, bones, and genitourinary tract, relieving vasomotor symptoms, preserving bone density, and improving vaginal trophism.

• Progestogens (e.g., norethisterone, dydrogesterone, medroxyprogesterone) act on the endometrium to oppose proliferative effects of estrogen, thereby preventing hyperplasia and cancer.

• In combination, they stabilize the endometrium, promoting endometrial atrophy, ideally resulting in no bleeding.

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5. Indications

• Moderate to severe vasomotor symptoms (e.g., hot flashes)

• Urogenital atrophy: vaginal dryness, dyspareunia, urinary urgency

• Prevention of postmenopausal osteoporosis (when other non-hormonal therapies are not suitable)

• Women >12 months postmenopausal with an intact uterus who desire no withdrawal bleeding

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6. Dosing and Administration

Oral Tablets / Capsules

• Once daily, taken at the same time each day

• Not to be split or chewed

Transdermal Patches

• Applied to clean, dry, non-irritated skin

• Avoid breast area

• Evorel Conti: replace twice weekly

• Climara Pro / Combipatch: replace once or twice weekly depending on brand

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7. Benefits

• Eliminates vasomotor symptoms (hot flushes, night sweats)

• No monthly bleeding

• Improves urogenital health

• Prevents bone loss and osteoporosis

• Improves quality of life

• May offer cardiovascular protection if started early post-menopause

• Patches have lower risk of thromboembolic events and bypass hepatic metabolism

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8. Adverse Effects

Estrogen-Related

• Breast tenderness

• Nausea

• Headache

• Fluid retention

• Leg cramps

Progestogen-Related

• Mood changes

• Breast tenderness

• Acne (especially with androgenic progestogens like norethisterone)

• Bloating

• Fatigue

Other

• Breakthrough bleeding or spotting (especially in the first 3–6 months)

• Weight gain (not significant in trials)

• Skin irritation with patches

• Gallbladder disease (increased risk with oral estrogens)

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9. Contraindications

• Known, suspected or past breast cancer

• Endometrial cancer or undiagnosed vaginal bleeding

• Active or history of thromboembolism (DVT, PE)

• Arterial thrombotic disease (e.g., myocardial infarction, stroke)

• Severe hepatic impairment

• Porphyria cutanea tarda

• Known hypersensitivity to active substances or excipients

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10. Warnings and Precautions

• Stroke and cardiovascular risk: increased with oral HRT, especially if started late (>10 years after menopause)

• Breast cancer: risk increases with duration; lower with transdermal regimens

• Venous thromboembolism (VTE): higher with oral estrogen; patches preferred in women with risk factors

• Endometrial safety: protected with adequate progestogen

• Dementia: some evidence of increased risk if started >65 years old

Women should be counseled individually on risk-benefit ratio based on personal and family history.

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11. Monitoring and Follow-Up

• Annual review: to reassess need, effectiveness, and risk factors

• Breast exams: self-exam monthly, clinician annually

• Mammography: regular as per national guidelines

• Pelvic exam: if abnormal bleeding or pain occurs

• Monitor:

  • Blood pressure

  • Weight

  • Menstrual patterns

  • Mood and cognitive changes

  • Lipids if required (mostly with oral estrogens)

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12. Drug Interactions

• Enzyme inducers (e.g., rifampin, carbamazepine, phenytoin): may reduce estrogen and progestogen levels → decreased efficacy

• Anticoagulants: may be antagonized by estrogens

• Corticosteroids: oral estrogens may increase corticosteroid levels

• Levothyroxine: estrogen may increase thyroxine-binding globulin, requiring dose adjustment

No significant interactions reported with transdermal HRT.

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13. Fertility and Discontinuation

• Not a contraceptive: not for perimenopausal women requiring contraception

• Average duration of use: 2–5 years, based on symptom control

• Discontinuation:

  • Gradual tapering preferred by some to avoid symptom rebound

  • Abrupt discontinuation also acceptable; recurrence of symptoms is possible

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14. Alternatives to Continuous Combined HRT

• Sequential HRT: For perimenopausal women

• Tibolone: Synthetic steroid with estrogenic, progestogenic, and androgenic effects

• SERMs (e.g., raloxifene): For osteoporosis, not for vasomotor symptoms

• Non-hormonal therapies:

  • SSRIs/SNRIs (e.g., paroxetine, venlafaxine)

  • Gabapentin

  • Clonidine

• Local estrogen: for vaginal atrophy only

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15. Advantages of Transdermal over Oral

• Lower VTE risk

• Bypasses liver metabolism

• Less impact on triglycerides and CRP

• Better tolerated in women with gallbladder disease or gastrointestinal intolerance