Why may a patient experience bleeding while taking Estrofem (estradiol) during an artificial menstrual cycle, having initiated it on day 2 of her menstrual period?

From the Guidelines

Breakthrough bleeding during an artificial cycle with Estrofem is common and usually not a reason to stop treatment. If a patient starts Estrofem on day 2 of her period, some bleeding may continue for a few days as the endometrium transitions from shedding to rebuilding under estrogen influence. This is expected and typically resolves within 3-5 days, as noted in studies discussing common side effects of combined hormonal contraceptives, such as unscheduled spotting or bleeding, especially during the first 3–6 months of use 1.

Key Considerations

• The standard protocol involves taking Estrofem (usually 2mg daily) for the first 12-14 days, then adding progesterone while continuing Estrofem for another 10-14 days.
• If bleeding is light to moderate and occurs early in the cycle, continue the medication as prescribed, as these bleeding irregularities are generally not harmful and usually improve with persistent use of the hormonal method 1.
• However, if bleeding is heavy, persists beyond 5-7 days, or occurs later in the cycle (especially after progesterone is added), medical evaluation is warranted as it could indicate inadequate dosing, endometrial pathology, or structural abnormalities.

Management of Breakthrough Bleeding

• Adjusting the Estrofem dose (potentially increasing to 4-6mg daily) may be necessary in subsequent cycles if breakthrough bleeding continues to be problematic, aiming to achieve adequate endometrial development without disruption from unscheduled bleeding.
• Counseling should emphasize the importance of correct use and timing, and enhanced counseling about expected bleeding patterns can reduce method discontinuation, as shown in clinical trials 1.

Conclusion on Estrofem Use

Given the information and the goal to prioritize morbidity, mortality, and quality of life, the decision to stop Estrofem should be based on the severity and timing of the bleeding, as well as the patient's overall health status, rather than the presence of breakthrough bleeding alone.

From the FDA Drug Label

Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus.

The patient may bleed on Estrofem during an artificial cycle because estrogens increase the risk of unusual vaginal bleeding.

• The FDA drug label recommends reporting any unusual vaginal bleeding right away while taking estrogens.
• The cause of the bleeding should be evaluated by a doctor to rule out malignancy.
• Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. It is recommended to stop Estrofem and consult a doctor if unusual vaginal bleeding occurs 2, 2, 2.

From the Research

Bleeding Patterns on Estrofem during Artificial Cycle

• Estrofem is a type of hormone replacement therapy (HRT) that contains estrogen, which can affect bleeding patterns in women 3.
• Artificial cycles, also known as artificial menstrual cycles, are created using HRT to mimic a natural menstrual cycle, and bleeding patterns can vary depending on the type and dosage of HRT used 4, 5.
• A study on a novel combined oral contraceptive containing estetrol/drospirenone found that scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants, with a median duration of 4 to 5 days 5.
• Unscheduled bleeding/spotting decreased over time, from 27.1% in Cycle 1 to ≤17.5% from Cycle 5 onwards, and most unscheduled bleeding/spotting episodes were spotting-only 5.

Factors Affecting Bleeding Patterns

• Noncompliance with HRT regimen, such as missing one or more active pills, can result in a higher occurrence of unscheduled bleeding/spotting and absence of scheduled bleeding/spotting 5.
• Body mass index (BMI) can also affect bleeding patterns, with participants having a BMI ≥30 kg/m2 reporting more absence of scheduled bleeding/spotting 5.
• Switching from one HRT regimen to another or starting a new regimen can also impact bleeding patterns, although one study found similar frequencies of unscheduled bleeding/spotting and absence of scheduled bleeding/spotting between switchers and starters 5.

Clinical Considerations

• Women with a history of obstetric or neonatal complications may need to be closely monitored while on HRT, as some studies suggest an increased risk of complications with artificial cycles 6.
• The type and dosage of HRT used can also impact the risk of complications, such as thrombosis or breast cancer, and clinical consideration is required for women at high risk for these conditions 7.
• Healthcare providers should educate patients on the expected bleeding patterns and potential risks associated with HRT use, to improve user acceptability and continuation of treatment 5.