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

Bleeding during an artificial cycle with Estrofem is expected when starting on day 2 of the menstrual period due to the overlap between natural menstruation and the beginning of hormonal therapy. This phenomenon occurs because Estrofem, which contains estradiol, takes several days to effectively suppress ongoing menstruation by increasing estrogen levels to build the endometrial lining 1. The initial bleeding typically represents the tail end of the natural period that was already in progress when treatment began. Key considerations for managing this situation include:

• Evaluating for underlying gynecological problems if bleeding persists, such as interactions with other medications, STDs, pregnancy, or new pathologic uterine conditions like polyps or fibroids 1.
• Considering short-term treatment options during days of bleeding, including NSAIDs for 5–7 days or hormonal treatment with low-dose COCs or estrogen for 10–20 days, if medically eligible 1.
• Counseling on alternative methods if irregular bleeding persists and is found unacceptable by the woman, and offering another method if desired 1. It is essential for patients to continue taking Estrofem as prescribed despite this initial bleeding, as interrupting the medication can disrupt the artificial cycle. The bleeding typically diminishes with subsequent cycles as the body adjusts to the hormonal regimen. If bleeding persists beyond 5-7 days or is unusually heavy, further evaluation for inadequate dosing, poor absorption, or underlying pathology is necessary.

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. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots.

The patient may bleed on Estrofem during an artificial cycle because estrogens can cause irregular vaginal bleeding or spotting, and starting the treatment at day 2 of her period may lead to breakthrough bleeding. Additionally, estrogens can increase the risk of blood clots, which may also contribute to bleeding. It is essential to report any unusual vaginal bleeding to the healthcare provider, as it can be a warning sign of cancer of the uterus 2.

From the Research

Possible Causes of Bleeding on Estrofem

• The exact mechanism of endometrial bleeding during hormone therapy is unknown, but several potential pathophysiologic mechanisms have been proposed, including changes in the ratio of vascular endothelial growth factor to Thrombospondin-1, alterations in metalloproteinases and tissue inhibitor of metalloproteinases (TIMP), changes in tissue factor, and increased endometrial leukocytes 3.
• The use of estrogen with a progestin, such as in Estrofem, can result in regular endometrial bleeding at a scheduled time, but the mechanism involved in this regimen is not fully understood 3.
• Menorrhagia, or heavy menstrual bleeding, can be caused by various factors, including uterine abnormalities such as fibroids and endometrial polyps, as well as hormonal disorders and impaired hemostasis 4, 5, 6.

Diagnostic and Treatment Options

• Diagnostic options for menorrhagia include pelvic examination, vaginal sonography, and endometrial biopsy, while treatment options include non-steroidal anti-inflammatory drugs, tranexamic acid, hormonal intrauterine systems, and surgical interventions such as endometrial ablation or hysterectomy 4, 5, 7.
• For patients with endometrial polyps, hysteroscopy is a highly effective diagnostic and treatment tool, allowing for both histological diagnosis and effective treatment 7.
• Medical treatments for menometrorrhagia include combined oral contraception, progestins, and levonorgestrel-releasing intrauterine systems, as well as newer options such as selective progesterone receptor modulators (SPRMs) 6.

Estrofem and Bleeding

• Starting Estrofem at day 2 of a period may not necessarily prevent bleeding, as the mechanism of endometrial bleeding during hormone therapy is complex and not fully understood 3.
• Patients on Estrofem may still experience bleeding due to various factors, including uterine abnormalities, hormonal disorders, and impaired hemostasis, and should be evaluated and monitored for endometrial safety 3, 4, 5, 6.