Understanding Divigel Side Effects

Divigel (Estradiol gel 0.1%) is a prescription topical estrogen used to treat moderate to severe hot flashes caused by menopause. Like all medications, it can cause side effects. Most are mild and temporary, but some require immediate medical attention.

This guide covers what to expect when you start Divigel, which side effects are normal, and the warning signs you shouldn't ignore.

Common Side Effects of Divigel

The most frequently reported side effects in clinical trials include:

• Nasopharyngitis (runny or stuffy nose) — This was one of the most commonly reported side effects in studies. It usually resolves on its own.
• Upper respiratory tract infection — Cold-like symptoms that are generally mild.
• Vaginal yeast infection — Estrogen can change vaginal pH, making yeast infections more likely. Over-the-counter antifungal treatments usually help.
• Headache — Common in the first few weeks. Tends to improve as your body adjusts.
• Breast tenderness — Your breasts may feel sore or swollen, especially at the start of treatment.
• Irregular bleeding (metrorrhagia) — Spotting or unexpected vaginal bleeding may occur, particularly in the first few months.
• Application site reactions — Redness, itching, or irritation where you apply the gel on your thigh.

Most of these side effects are mild and improve within the first 1 to 3 months of use. If they persist or bother you, talk to your doctor — adjusting the dose may help.

Serious Side Effects: When to Call Your Doctor

While rare, some side effects of Divigel are serious and need immediate medical attention. Call your doctor or go to the emergency room if you experience:

Signs of a Blood Clot

• Sudden swelling, pain, or warmth in one leg (possible deep vein thrombosis)
• Sudden shortness of breath or chest pain (possible pulmonary embolism)
• Sudden severe headache, confusion, vision changes, or trouble speaking (possible stroke)

Heart-Related Symptoms

• Chest pain or pressure
• Pain spreading to your arm, jaw, or back
• Sudden dizziness or fainting

Signs of an Allergic Reaction

• Hives, rash, or severe itching
• Swelling of the face, lips, tongue, or throat
• Difficulty breathing

Other Serious Symptoms

• Unusual vaginal bleeding (especially heavy or prolonged)
• Yellowing of the skin or eyes (jaundice) — may indicate liver problems
• Severe stomach pain
• Breast lumps
• Changes in vision or speech
• Severe mood changes or depression

What Changed with the Boxed Warning

You may have heard that estrogen products carry a "black box" warning. In February 2025, the FDA removed the boxed warning from Divigel following a comprehensive scientific literature review. The risks previously listed in the boxed warning — including cardiovascular disorders, endometrial cancer, and breast cancer — are now described in the Warnings and Precautions section of the label.

This doesn't mean these risks disappeared. It means the FDA determined that the original warning overstated the risk relative to current evidence. Your doctor can help you weigh the benefits and risks based on your personal health history.

Managing Common Side Effects

Headaches

Stay hydrated, get enough sleep, and consider taking Divigel at the same time each day. If headaches persist beyond a few weeks, ask your doctor about a dose adjustment.

Breast Tenderness

Wearing a supportive bra and reducing caffeine may help. This usually improves after 2 to 3 months on Divigel.

Application Site Irritation

Make sure your skin is clean and dry before applying Divigel. Alternate between your right and left upper thigh each day, as directed. Avoid applying to irritated or broken skin. If irritation persists, talk to your doctor.

Irregular Bleeding

Spotting is common in the first few months. However, if bleeding is heavy, prolonged, or occurs after the first 3 to 6 months of treatment, tell your doctor. Women with a uterus should be taking a progestogen alongside Estradiol to reduce the risk of endometrial cancer.

Yeast Infections

Over-the-counter antifungal treatments usually work. If infections recur frequently, your doctor may recommend a preventive approach.

Side Effects vs. Symptoms of Menopause

It can be hard to tell whether a symptom is from Divigel or from menopause itself. For example:

• Mood changes — Can be caused by fluctuating hormones or by starting HRT
• Sleep problems — Menopause commonly disrupts sleep, but Divigel may also contribute initially
• Weight changes — Menopause is associated with weight gain, though estrogen therapy is not a primary cause

Keeping a symptom diary can help you and your doctor sort out what's related to the medication and what isn't.

Long-Term Risks to Discuss with Your Doctor

If you use Divigel for an extended period, discuss these risks with your provider:

• Endometrial cancer — If you have a uterus, using Estradiol without a progestogen increases this risk. Most doctors prescribe a progestogen alongside Divigel.
• Breast cancer — The risk is primarily associated with combined estrogen-progestin therapy over long periods. Estrogen-only therapy appears to carry lower risk.
• Blood clots and stroke — Transdermal estrogen like Divigel may carry a lower clot risk compared to oral estrogen, though the risk is not zero.
• Gallbladder disease — Estrogen therapy can increase the risk of gallbladder problems.

Your doctor should regularly review whether Divigel is still appropriate for you, typically at least once a year.

How Divigel Compares to Other Estrogen Products

One advantage of Divigel is that it's a transdermal (through-the-skin) product. Research suggests that transdermal estrogen may carry a lower risk of blood clots compared to oral Estradiol. This is because it avoids first-pass metabolism through the liver.

If side effects from Divigel are bothering you, your doctor may suggest alternatives like Estradiol patches, EstroGel, or oral Estradiol. Each has its own side effect profile.

The Bottom Line

Most women who take Divigel experience only mild side effects that improve over time. Serious side effects are rare but important to recognize. The key is to stay in close contact with your doctor, especially during the first few months of treatment.

If you're considering starting Divigel, learn more in our complete guide to Divigel uses and dosage. Already have a prescription? Use Medfinder to find Divigel in stock near you.