Estradiol valerate: estrogen ester prodrug for HRT and contraception

Estradiol valerate is the valeric acid ester of 17 beta estradiol, the most important female sex hormone. As an orally active prodrug it is rapidly cleaved by non-specific esterases into free estradiol and valeric acid. The natural drug estradiol thus reaches the circulation without the synthetic modification used for ethinylestradiol.

Well-known products include estradiol depot injections (Progynon Depot), oral hormone replacement therapy (Estrofem, Klimonorm, Cyclo Progynova in combination with norgestrel or levonorgestrel) and the oral contraceptive Qlaira combined with dienogest. Pharmacologically, estradiol valerate is identical to estradiol but is better suited for oral and intramuscular administration.

Mechanism of action

After ester cleavage estradiol binds to the intracellular estrogen receptors ER alpha and ER beta. The hormone-receptor complex translocates into the nucleus, binds to specific Estrogen Response Elements of DNA and regulates the transcription of numerous target genes.

Important target tissues include:

• Endometrium and vagina (proliferation, thinning of cervical mucus)
• Breast tissue (growth of ductal and stromal components)
• Hypothalamus and pituitary (negative feedback on FSH and LH)
• Bone (inhibition of osteoclasts, bone protection)
• Skin, CNS, vessels, liver (lipoproteins, coagulation factors)

Compared with ethinylestradiol, estradiol has a more favourable profile on lipids, hepatic synthesis and thromboembolic risk because it is not ethinylated and is metabolised faster by the liver.

Indications

• Hormone replacement therapy (HRT) at menopause: hot flushes, sleep disturbance, vaginal atrophy, loss of libido, depressive symptoms in peri- and postmenopause
• Prevention of postmenopausal osteoporosis: in women with high fracture risk if other therapies are unsuitable
• Hypogonadism, primary ovarian insufficiency: substitution in young women with estrogen deficiency
• Oral contraception: in fixed combination with dienogest (Qlaira) as a multiphase pill
• Gender-affirming hormone therapy: in trans women as part of feminisation

Dosing and administration

Oral HRT: 1 to 2 mg estradiol valerate daily, usually continuous or cyclic in combination with a progestogen in non-hysterectomised women.

Depot injection: 5 to 10 mg intramuscularly every 3 to 4 weeks, mainly in hypogonadism or in patients who do not tolerate oral therapy.

Oral contraception (Qlaira): dynamic multiphase dosing of 3 mg, 2 mg or 1 mg estradiol valerate combined with dienogest, taken over 26 days followed by 2 placebo days.

Oral intake is independent of meals, ideally at the same time each day. For contraception, regular intake is essential, as missed pills can compromise contraceptive protection.

Side effects

Common: breast tenderness, spotting, nausea, headache, migraine, fluid retention, mood swings, acne, libido changes.

Uncommon: hypertension, cholestasis, cholelithiasis, weight gain, endometrial hyperplasia without progestogen protection, vaginal mycosis, leg cramps.

Rare and very rare: deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, breast cancer, endometrial cancer (without progestogen), ovarian cancer, liver tumours, erythema nodosum, chorea, worsening of asthma, otosclerosis, hereditary angioedema flare.

Risk assessment:

• Absolute VTE and stroke risk is small but rises with age, obesity, smoking, hypertension and thrombophilia
• Breast cancer risk increases with duration; after 5 years it becomes the dominant risk factor
• Transdermal estradiol products have a more favourable VTE profile than oral preparations

Interactions

• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort, some HIV agents): reduced estrogen levels, possible therapy failure or breakthrough bleeding
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin): increased levels
• Levothyroxine: higher requirement as estrogens raise thyroid binding globulin
• Anticoagulants: estrogens may weaken vitamin K antagonists
• Tamoxifen, aromatase inhibitors: attenuated antihormonal action
• Lamotrigine: reduced levels via glucuronidation, seizure risk

Special considerations

Pregnancy: contraindicated, as is suspected pregnancy.

Breastfeeding: estrogens pass into milk and may reduce milk production, hence not recommended.

Endometrial protection: women with an intact uterus must take an additional progestogen at least 12 days per month (or continuously) to reduce the risk of endometrial hyperplasia and endometrial cancer.

Pre-HRT assessment:

• Mammography per local recommendations (at least baseline)
• Blood pressure, lipid panel, blood glucose
• Family history (VTE, breast cancer)
• Gynaecological examination with cancer screening
• Counselling on risk, benefit and duration

Duration of therapy: the lowest effective dose for the shortest possible duration is the standard. For vasomotor symptoms a discussion of stopping is often raised after 2 to 5 years.

Contraindications: known or suspected breast cancer, estrogen-dependent tumours, vaginal bleeding of unknown cause, acute or past VTE, acute liver disease, hereditary angioedema.

Related substances

• Ethinylestradiol, classic synthetic estrogen in combined oral contraceptives
• Dienogest, progestogen with antiandrogenic profile
• Dutasterid, 5-alpha reductase inhibitor
• Letrozol, aromatase inhibitor in breast cancer
• Raloxifen, SERM for postmenopausal osteoporosis

Frequently asked questions

Sources

• EMA European Medicines Agency
• BfArM Federal Institute for Drugs and Medical Devices
• AWMF guideline peri- and postmenopause
• Gelbe Liste estradiol valerate monograph