What You Need to Know About Estradiol/Norethindrone Side Effects

Estradiol/Norethindrone is a combination hormone replacement therapy (HRT) used to treat menopause symptoms like hot flashes, night sweats, and vaginal dryness. It's also prescribed to prevent postmenopausal osteoporosis. Brand names include Activella, Amabelz, Lopreeza, Mimvey, and CombiPatch (the transdermal patch).

Like all medications, Estradiol/Norethindrone can cause side effects. Most are mild and improve as your body adjusts, but some are serious and require immediate medical attention. This guide covers what to expect and when to call your doctor.

What Is Estradiol/Norethindrone?

Estradiol/Norethindrone combines two hormones: Estradiol (a form of estrogen) and Norethindrone Acetate (a progestin). Estradiol replaces the estrogen your body stops making after menopause. Norethindrone is added to protect your uterus — without it, estrogen alone can cause the uterine lining to overgrow, which increases the risk of endometrial cancer. To learn more about how this medication works, see our guide on Estradiol/Norethindrone mechanism of action.

Common Side Effects

These side effects are reported frequently in clinical trials and FDA labeling. They're usually mild and often improve within the first few weeks or months of treatment:

• Headache — One of the most commonly reported side effects
• Breast pain or tenderness — May decrease over time as your body adjusts
• Nausea — Taking the tablet with food can help
• Bloating and abdominal cramps — Common in the first few months
• Back pain
• Vaginal bleeding or spotting — Breakthrough bleeding is common in the first 3 to 6 months. It usually decreases over time
• Weight changes — Some women gain a few pounds; others notice no change
• Mood changes — Including irritability, anxiety, or depressed mood
• Hair loss — Usually mild and temporary

If any of these side effects persist beyond the first few months or become bothersome, talk to your doctor. A dose adjustment or switch to a different formulation (such as the CombiPatch transdermal patch) may help.

Serious Side Effects

Estradiol/Norethindrone carries an FDA boxed warning — the most serious type of safety warning. The boxed warning states that estrogen plus progestin therapy increases the risk of:

• Blood clots — Including deep vein thrombosis (DVT) and pulmonary embolism (PE). Symptoms include sudden leg pain or swelling, chest pain, or difficulty breathing.
• Stroke — Sudden numbness, confusion, trouble speaking, severe headache, or vision changes.
• Heart attack — Chest pain or pressure, shortness of breath, pain in the arm or jaw.
• Breast cancer — The Women's Health Initiative (WHI) study found an increased risk of invasive breast cancer with long-term estrogen plus progestin use.
• Probable dementia — In women 65 years and older, estrogen plus progestin therapy may increase the risk of dementia.

Other serious side effects include:

• Gallbladder disease
• Liver problems — Symptoms include yellowing of the skin or eyes, dark urine, and severe abdominal pain
• Severe allergic reactions — Hives, swelling of the face or throat, difficulty breathing
• Vision changes — Retinal vascular thrombosis (sudden loss of vision or blurred vision in one eye)
• Endometrial cancer — Although the progestin in this combination is designed to reduce this risk, report any unusual vaginal bleeding to your doctor

When to Call Your Doctor Immediately

Seek emergency medical help if you experience:

1. Sudden severe headache or migraine
2. Chest pain or shortness of breath
3. Sudden leg pain, swelling, or warmth
4. Sudden vision changes or loss of vision
5. Signs of stroke (face drooping, arm weakness, speech difficulty)
6. Severe abdominal pain
7. Yellowing of the skin or eyes

Specific Populations at Higher Risk

Certain groups may have a higher risk of side effects from Estradiol/Norethindrone:

• Women 65 and older — Higher risk of dementia and stroke with HRT
• Women with a history of blood clots — Should not take this medication
• Women with a history of breast cancer — This medication is contraindicated
• Women with liver disease — May not be able to metabolize the hormones properly
• Women with high triglycerides — Oral estrogen can raise triglyceride levels, increasing the risk of pancreatitis. The transdermal patch (CombiPatch) may be a better option.
• Smokers — Smoking increases the risk of blood clots and cardiovascular events while on hormone therapy
• Women who are pregnant or breastfeeding — This medication is not indicated during pregnancy or lactation

For a full list of who should not take this medication, see our guide on what is Estradiol/Norethindrone.

How to Manage Side Effects

Here are some practical tips for managing the most common side effects:

• For nausea: Take your tablet with food or at bedtime
• For breast tenderness: Wear a supportive bra, and give it 2 to 3 months — tenderness often resolves on its own
• For bloating: Reduce salt intake, stay hydrated, and exercise regularly
• For breakthrough bleeding: This is common in the first 3 to 6 months. If it continues beyond 6 months, talk to your doctor
• For headaches: Stay hydrated, manage stress, and keep a headache diary to identify patterns. If headaches are severe or new, contact your doctor
• For mood changes: Regular exercise, adequate sleep, and stress management can help. If mood changes are significant, your doctor may adjust your dose

Always talk to your doctor before stopping Estradiol/Norethindrone. Abruptly stopping HRT can cause a return of menopause symptoms.

Final Thoughts

Most women tolerate Estradiol/Norethindrone well, and common side effects like headache, breast tenderness, and spotting often improve within the first few months. However, because this medication carries a boxed warning about cardiovascular risks and breast cancer, it's important to use the lowest effective dose for the shortest time needed.

If you're currently taking Estradiol/Norethindrone and need help finding it at a pharmacy near you, Medfinder can help you check availability. And if you're concerned about drug interactions, we have a guide for that too.