Estradiol vaginal cream side effects: A detailed guide

Medically reviewed by Patricia Weiser, PharmD on March 17, 2023.

Specifically, the Food and Drug Administration (FDA) has approved estradiol vaginal cream to treat symptoms due to the thinning of the vaginal lining that may occur after menopause. These include vaginal dryness, burning, itching, spotting, discharge, frequent or painful urination, increased urinary tract infections (UTIs), or pain with sex.

This article describes possible side effects of estradiol vaginal cream. You’ll also find information on cost savings and coupon options for estradiol.

Estradiol vaginal cream is a generic version of the brand-name drug Estrace. Estradiol also comes in forms that you’ll swallow or apply to the skin or inject. It comes in injectable forms and other vaginal forms, too. But these forms aren’t described in this article. To learn more about these forms, talk with your doctor.

Boxed warnings

Estradiol has boxed warnings about the risk of certain cancers and risk of dementia (problems with thinking, memory, and communication). It also has a boxed warning about the risk of serious cardiovascular (heart and blood vessel) events. Boxed warnings are serious warnings from the Food and Drug Administration (FDA).

For details, see the “Side effects of estradiol in detail” section below.

More common side effects of estradiol

Estradiol vaginal cream may cause mild or serious side effects. Below are some of the more common side effects of this medication.

Commonly reported side effects of estradiol include:

• nausea and vomiting
• headache
• abdominal cramps or bloating
• fluid buildup
• irritation, itching, and burning of the vulva and vagina*
• breast pain*

* To learn more about this side effect, see the “Side effects of estradiol in detail” section below.

Mild side effects of estradiol

Estradiol may cause certain mild side effects. Usually, mild side effects are temporary and can be easily managed. Tell your doctor or pharmacist if you have side effects that don’t go away or become bothersome.

Mild side effects of estradiol that have been reported include:

• abdominal cramps or bloating
• nausea and vomiting
• headache
• fluid buildup
• hair loss
• irritation, itching, and burning of the vulva and vagina*
• other vaginal side effects, such as irregular bleeding, spotting, changes in vaginal discharge, or yeast infection*
• breast pain*
• mild allergic reaction†

* To learn more about this side effect, see the “Side effects of estradiol in detail” section below.
† An allergic reaction is possible with estradiol vaginal cream. But it’s unclear whether it occurred in the drug’s studies.

Estradiol vaginal cream may cause more mild side effects than those listed above. For details, see the drug’s prescribing information.

Serious side effects of estradiol

Estradiol may cause certain serious side effects, but they’re not common. If you have any serious side effects from estradiol vaginal cream, call your doctor right away. But if you think you’re having a medical emergency or your side effects feel life threatening, take immediate action. Call 911, or a local emergency number, or go to the nearest emergency room.

After the Food and Drug Administration (FDA) approves a drug, it tracks and reviews side effects of the medication. Visit MedWatch’s website if you’d like to notify the FDA about a side effect you’ve had with estradiol vaginal cream.

Serious side effects of estradiol that have been reported include:

• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• uterine fibroids (growths in the uterus) that get larger in size
• certain breast changes*
• risk of certain cancers†
• risk of dementia†
• risk of serious cardiovascular events†
• severe allergic reaction*‡

* To learn more about this side effect, see the “Side effects of estradiol in detail” section below.
† Estradiol vaginal cream has a boxed warning for this side effect. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “Side effects of estradiol in detail” section below.
‡ An allergic reaction is possible with estradiol vaginal cream. But it’s unclear whether it occurred in the drug’s studies.

Common questions about side effects of estradiol

Here are answers to some common questions about side effects of estradiol vaginal cream. If you have other questions, talk with your doctor or pharmacist.

Can estradiol vaginal cream cause weight gain?

It’s possible for estradiol vaginal cream to cause weight gain. But weight gain wasn’t a commonly reported side effect in the drug’s studies. People taking estrogens, such as estradiol, reported both weight gain and weight loss in studies.

Fluid buildup is also a possible side effect of estradiol vaginal cream. And it may cause some weight gain.

If you notice changes in your weight while using estradiol vaginal cream, talk with your doctor.

Is fatigue a side effect of estradiol?

Fatigue (low energy) is not a likely side effect of estradiol vaginal cream. It wasn’t a reported side effect in studies of the drug.

Still, fatigue and drowsiness are possible symptoms of an overdose of estrogen. Be sure to take the amount of estradiol vaginal cream your doctor prescribes. If you think you’ve used too much estradiol vaginal cream, call your doctor or pharmacist right away. You could also speak with someone at America’s Poison Centers by calling 800-222-1222. You can also use its online resource.

Fatigue can also be a symptom of blood clots or other serious heart-related* side effects. If you have fatigue or weakness combined with chest or leg pains, call your doctor right away. These symptoms can occur with or without trouble breathing.

If you have any of the above symptoms, call 911 or a local emergency number immediately. You can also go to the closest emergency room.

* Estradiol vaginal cream has a boxed warning for the risk of serious cardiovascular (heart and blood vessel) events. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “Side effects of estradiol in detail” section below.

Does estradiol cause long-term side effects?

It’s possible to have long-term effects from some of the serious but less common side effects of estradiol. These serious side effects include certain cancers, dementia, and heart-related side effects, such as heart attack, stroke, and blood clots. Estradiol vaginal cream has a boxed warning about these risks. For details, see the “Side effects of estradiol in detail” section below.

If you’re concerned about the long-term effects of estradiol, talk with your doctor for more information.

Coupon for estradiol

Visit this page to access Optum Perks coupons and get price estimates for estradiol when you use the coupons. These coupons can provide significant savings on your prescription costs.

Note: Optum Perks coupons cannot be used with insurance copays or benefits.

Side effects of estradiol in detail

Below you’ll find details on some of the side effects of estradiol vaginal cream.

Black box warnings

Estradiol vaginal cream comes with several boxed warnings.

Risk of certain cancers

Estradiol vaginal cream has a boxed warning for the risk of certain cancers. Boxed warnings are serious warnings from the Food and Drug Administration (FDA). They alert doctors and patients about drug effects that may be dangerous.

Estradiol is a type of estrogen hormone that can increase the risk of certain types of cancer. These cancers and their symptoms include:

• Endometrial cancer (a type of cancer in the uterus). Symptoms in females* after menopause can include:
  • vaginal bleeding that continues or keeps coming back
  • spotting or bleeding without a known cause
• Breast cancer. Symptoms can include:
  • breast swelling
  • nipple discharge
  • a lump in the breast
  • thickening of the skin of the nipple or breast
• Ovarian cancer. Symptoms can include:†
  • pain in the abdomen or pelvis
  • bloating or trouble eating

* Sex and gender exist on spectrums. In this article, we use the term “female” to refer to a person’s sex assigned at birth.
† These and other symptoms are different from the usual discomfort from your period or digestion. And they may not be present in early stage ovarian cancer.

Ways to manage

Talk with your doctor if you’ve ever had any of the above cancers before starting treatment with estradiol vaginal cream. Your doctor can also discuss factors that can increase the risk of certain types of cancer while taking an estrogen. They can determine whether the drug is right for you.

If your doctor prescribes estradiol, talk with them about ways you can lower your risk of cancer. They may recommend you perform a self-exam of your breasts to monitor for any changes. If you notice any changes in your breasts or have symptoms of the above cancers, tell your doctor. They may have you come in for an exam to determine the cause of your symptoms.

This article provides some information on ways to lower your risk of endometrial cancer. And you can learn how to help lower your risk of developing ovarian cancer in this article.

Risk of dementia

Estradiol vaginal cream has a boxed warning for the risk of dementia (problems with thinking, memory, and communication). Boxed warnings are serious warnings from the Food and Drug Administration (FDA). They alert doctors and patients about drug effects that may be dangerous.

Symptoms of dementia include difficulty with:

• memory
• language
• focus
• communication
• reasoning
• performing familiar tasks
• multitasking

Using estrogen, such as estradiol, may increase the risk of serious dementia in females* who have undergone menopause. This risk applies to females over the age of 65 years. It’s unknown whether this risk applies to females less than 65 years of age who have undergone menopause.

In studies, some females were diagnosed with dementia 4 to 5 years after starting estradiol treatment.

* Sex and gender exist on spectrums. In this article, we use the term “female” to refer to a person’s sex assigned at birth.

Ways to manage

Due to the risk of dementia,your doctor will likely prescribe the lowest dose of estradiol vaginal cream that meets your treatment goals. And they’ll likely recommend using it for the shortest length of time necessary.

Dementia may take a while to develop. So, it’s important to be familiar with its symptoms. Talk with your doctor if you have any changes in your memory or other symptoms that aren’t a usual part of aging.

If you have dementia, your doctor might recommend the following tips:

• establishing a scheduled daily routine
• taking your time with tasks
• reducing distractions to help improve focus
• involving family members in your care for support

Talk with your doctor about the risk of dementia while using estradiol vaginal cream. They can give you more information about the condition.

Risk of serious cardiovascular events

Estradiol vaginal cream has a boxed warning for the risk of serious cardiovascular (heart and blood vessel) events. Boxed warnings are serious warnings from the Food and Drug Administration (FDA). They alert doctors and patients about drug effects that may be dangerous.

Using estrogen, such as estradiol, may increase the risk of serious cardiovascular events in females* who have undergone menopause. These events include heart attack, stroke, and blood clots.

Symptoms of serious cardiovascular events may include:

• chest pain
• pain that radiates into your arms, legs, jaw, or neck
• numbness or tingling in your face, arms, or legs
• loss of balance or coordination
• pain, swelling, or warmth in the leg
• trouble breathing
• disorientation (unable to think clearly and identify your surroundings) 
• lightheadedness, dizziness, or fainting

* Sex and gender exist on spectrums. In this article, we use the term “female” to refer to a person’s sex assigned at birth.

Ways to manage

If you think you’re having a medical emergency or your side effects feel life threatening, take immediate action. Call 911, or a local emergency number, or go to the nearest emergency room.

Before you start using estradiol vaginal cream, talk with your doctor about the symptoms of heart attack, stroke, and blood clots.

Due to the risk of cardiovascular effects, your doctor will likely prescribe the lowest dose of estradiol vaginal cream for the shortest duration of time that meets your treatment goals.

Vaginal side effects

Vaginal side effects may occur during treatment with estradiol vaginal cream. This side effect was common in studies of estrogen treatment. (Estradiol is a type of estrogen.)

Side effects can include irritation, itching, and burning of the vulva and vagina. Other vaginal side effects,* such as irregular bleeding, spotting, changes in vaginal discharge, or yeast infection, can occur.

Ways to manage

Vaginal side effects are usually mild and temporary. But if you develop vaginal side effects that don’t go away or are unusual, talk with your doctor.

If you have an infection, your doctor may recommend treating it. Keep in mind that some side effects, such as unusual vaginal bleeding, may be a sign of endometrial cancer.* So it’s important to tell your doctor if you have unusual vaginal bleeding that doesn’t go away.

* Estradiol vaginal cream has a boxed warning for this side effect. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see “Boxed warnings” above.

Certain breast changes or pain

Estradiol vaginal cream can cause side effects that affect the breasts. These side effects may include:

• breast pain or tenderness
• nipple discharge
• swollen breasts
• breast tissue that becomes more dense than usual
• breast cancer*

Breast pain and tenderness were commonly reported in studies of estrogen treatment. (Estradiol is a type of estrogen.) More serious side effects, such as breast cancer were not common.

 * Estradiol vaginal cream has a boxed warning for this side effect. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see “Boxed warnings” above.

Ways to manage

Some side effects, such as breast pain, are usually temporary. If this side effect becomes bothersome, your doctor may recommend certain over-the-counter (OTC) pain relievers to help ease your symptoms.

Your doctor may also recommend you reduce your intake of salt, eliminate caffeine, and wear a supportive bra. These changes can help reduce breast discomfort in some people.

Some side effects, such as a lump in the breast, may be a sign of breast cancer. During your treatment, your doctor may recommend you perform breast self-exams. If you notice a new lump or concerning changes to your breasts while using estradiol vaginal cream, talk with your doctor right away.

Allergic reaction

For some people, estradiol vaginal cream can cause an allergic reaction. But it’s not clear whether this side effect occurred in the drug’s studies.

Symptoms can be mild or serious, and they may include:

• itchiness
• skin rash
• swelling under the skin, usually affecting eyelids, lips, hands, or feet
• swelling of the mouth, tongue, or throat, which can make it hard to breathe
• flushing (temporary warmth, redness, or deepening of skin color)

Ways to manage

For mild allergic reaction symptoms, such as a mild rash, call your doctor right away. They may recommend treatments to help manage your symptoms. They’ll also let you know whether you should keep using the medication.

For severe allergic reaction symptoms, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms require immediate medical care because they can become life threatening. If you’ve had a serious allergic reaction to estradiol vaginal cream, your doctor may recommend taking a different medication instead.

Warnings for estradiol

Below are some factors you may want to discuss with your doctor before using estradiol vaginal cream.

Boxed warnings

This drug has boxed warnings about the risk of certain cancers and risk of dementia. It also has a boxed warning about the risk of serious cardiovascular (heart and blood vessel) events. Boxed warnings are serious warnings from the Food and Drug Administration (FDA).

For details, see the “Side effects of estradiol in detail” section above.

Other warnings

It may not be safe for you to use estradiol vaginal cream if you have specific health conditions. These are sometimes called drug-condition interactions. Other things may also affect whether estradiol vaginal cream is a safe treatment option for you.

Before using estradiol vaginal cream, tell your doctor about your health and medications you take. Things to consider include those listed below.

High blood pressure. Estrogen may increase blood pressure. If you have high blood pressure, talk with your doctor before starting estradiol vaginal cream. They’ll help determine whether the drug is safe for you. They may also monitor your blood pressure often while you’re using estradiol vaginal cream.

High triglycerides. If you have high triglycerides (a kind of body fat), estradiol may increase your risk of developing higher triglyceride levels. This can lead to pancreatitis and other complications. Before starting estradiol vaginal cream, talk with your doctor to learn if you have high triglycerides.

Liver problems. Estradiol is processed by the liver. If you have certain liver problems, your risk of liver problems due to estradiol treatment may increase. Your risk may also increase if you’ve ever had liver problems with past estrogen use or during pregnancy. Talk with your doctor about your liver function before starting your estradiol treatment.

Certain cancers. Estrogen, such as estradiol, may increase your risk of certain cancers,* including endometrial cancer, ovarian cancer, and breast cancer. Talk with your doctor about your health history and the risks of using estradiol vaginal cream.

Serious heart problems and blood clots. Estrogen, such as estradiol, can increase your risk of serious heart problems.* These can include heart attack, stroke, and blood clots. Talk with your doctor about your health history before you start using estradiol vaginal cream. If you already have serious heart problems, your doctor will likely not prescribe this drug. They may recommend a different treatment option for you.  

Hypothyroidism and hypoparathyroidism. Estradiol may affect thyroid function in people with hypothyroidism. If you’re taking medication to treat hypothyroidism, your doctor may adjust your dosage of thyroid replacement drugs during your estradiol therapy.

If you have hypoparathyroidism and use estradiol vaginal cream, the drug may lower your blood calcium levels. Your doctor may monitor you more closely if you have this condition.

Other conditions. Estradiol may worsen symptoms of other conditions, such as epilepsy, migraine, diabetes, asthma, lupus, and liver hemangiomas. If you have any of these conditions, talk with your doctor. They may monitor you more closely while you’re using estradiol vaginal cream.

Allergic reaction. If you’ve had an allergic reaction to estradiol vaginal cream or any of its ingredients, your doctor will likely not prescribe this medication. Ask them about other treatment options that may be better for you. To learn more about allergic reaction, see the “Side effects of estradiol in detail” section above.

* Estradiol vaginal cream has a boxed warning for this side effect. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “Side effects of estradiol in detail” section above.

Estradiol and pregnancy

Estradiol is not safe to use during pregnancy. Your doctor will likely not prescribe estradiol vaginal cream while you’re pregnant. The drugmaker advises that you should not use estradiol vaginal cream during pregnancy. 

Talk with your doctor for more information about the risks of using estradiol vaginal cream during pregnancy.

Estradiol and breastfeeding

Estradiol is not safe to use while breastfeeding a child. The drug is known to pass into breast milk. Also, the drug may lower the quantity and quality of breast milk. For these reasons, your doctor won’t likely recommend you breastfeed while using estradiol vaginal cream.

To learn about other feeding options for your child, talk with your doctor.

Estradiol and alcohol

There’s no known interaction between estradiol vaginal cream and alcohol. But drinking high amounts of alcohol can increase estrogen levels. This may be related to an increased risk of developing breast cancer. Consuming alcohol while using estradiol may further increase this risk.

If you drink alcohol, talk with your doctor about whether it’s safe to consume it during your treatment with estradiol vaginal cream.

Note: Estradiol has a boxed warning about the risk of certain cancers, including breast cancer. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “Side effects of estradiol in detail” section above.

What to ask your doctor

This article describes common and serious side effects of estradiol vaginal cream. If your doctor prescribes this medication, they can discuss possible side effects with you. Let your doctor know if you have concerns or questions about treatment with this medication.

Here’s a list of some possible questions you may want to ask your doctor:

• Are the side effects of estradiol vaginal cream the same as taking the other forms of estradiol?
• How do the side effects of estradiol vaginal cream and the brand-name version compare?
• How do the side effects of estradiol compare with other estrogens?

Disclaimer: Optum Perks has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.