Definition

Chemotherapy-induced Amenorrhea (CIA) is the cessation of menstruation within one year after starting chemotherapy and continuing for 12 months or more. CIA is a long-term side effect of chemotherapy for breast cancer that can affect future reproductive function. Amenorrhea itself refers to the absence of menstruation.

Breast cancer is a cancer commonly found worldwide. Chemotherapy can significantly improve survival rates in early-stage breast cancer patients. However, chemotherapy can cause many side effects, such as CIA.

About 25% of breast cancer diagnoses occur in premenopausal women, and around 15% occur in women under 45. The early diagnosis of CIA is more common now due to the increasing number of breast cancer survivors with the advancement of therapies.

Causes

Various chemotherapy drugs can cause CIA, categorized by their risk levels:

• High Risk: cyclophosphamide, ifosfamide, busulfan, chlorambucil, melphalan, mechlorethamine, procarbazine
• Moderate Risk:
• Platinum compounds: cisplatin, carboplatin
• Anthracycline antibiotics: doxorubicin
• Taxoids: paclitaxel, docetaxel
• Low Risk:
• Vinca alkaloids: vincristine, vinblastine
• Anthracycline antibiotics: bleomycin
• Antimetabolites: methotrexate, 5-fluorouracil, mercaptopurine

The addition of tamoxifen therapy after chemotherapy can significantly increase the risk of CIA. Tamoxifen is believed to affect estrogen production in a part of the brain called the hypothalamus. The earlier chemotherapy is used for breast cancer, the more complex the long-term side effects of the therapy.

Menstruation and fertility in women depend on the number and quality of egg follicles in the ovaries. At birth, the ovaries contain a finite number of inactive follicles that decrease with age. Therefore, a woman's egg follicles capable of being fertilized decrease throughout her life.

Chemotherapy can accelerate the aging and death of egg cells. During chemotherapy, anti-Mullerian hormone levels in the blood decrease, reflecting the number of eggs that can be released by the ovaries for fertilization.

Risk Factor

Several studies indicate that CIA occurrence correlates with factors such as the type of chemotherapy used, the duration and dose of chemotherapy, the age of the patient, pregnancy history, and hormonal therapy presence.

The risk of amenorrhea due to chemotherapy with multiple drug regimens ranges from 21% to 71% in young women and 49% to 100% in women over 40. Older women are generally at higher risk for CIA due to the decreased number of active egg follicles in the ovaries with age.

Women who had their first menstruation at age >13 have a doubled risk of CIA.

CIA incidence significantly increases in patients undergoing hormonal therapy, such as tamoxifen, and those with estrogen receptor (ER)-positive tumors.

One study shows that patients with a high body mass index (overweight) are more likely to experience persistent CIA, although this remains controversial.

Chemotherapy can cause damage to the bone marrow, where blood cells, including white blood cells, are produced. It can lead to leukopenia (decreased white blood cells), especially in older patients (over 40). Leukopenia after the first chemotherapy cycle is associated with an increased risk of CIA, indicating that leukopenia can be an early predictor of chemotherapy-induced fertility issues.

Symptoms

• Cessation of menstruation for at least 3 months or more
• Nipple discharge, possibly due to increased prolactin levels, indicating a hormonal system disorder involving the brain and ovaries. Prolactin is produced in the pituitary gland in the brain.

Read more about the excessive condition of the prolactine hormone called prolactinemia in the following Ai Care article Prolactinemia - Definition, Disease, Symptoms, Laksana Management.

• Weight changes
• General body weakness
• Growth of fine hair on the face, chest, and limbs due to increased androgen levels

Diagnosis

Diagnosing CIA requires examining the number of egg follicles in the ovaries and hormone levels related to menstruation and menopause. CIA involves ovarian failure indicated by menstruation cessation for at least 3 months, a doubling of follicle-stimulating hormone (FSH) levels (>40 IU/L), and decreased estradiol (<10pg/mL) in women under 40. Two FSH measurements with a 4-week interval showing levels above 40 mIU/mL are needed to diagnose ovarian failure.

In summary, the changes indicating CIA include:

• Changes in the menstrual cycle
• Ultrasound findings such as:
• Abnormal egg follicle count
• Changes in ovarian volume
• Laboratory results showing:
• Increased FSH
• Decreased estradiol
• Increased LH
• Decreased inhibin B
• Decreased anti-Mullerian hormone
• Increased prolactin
• Increased androgens

Measuring anti-Mullerian hormone and inhibin-B levels can predict CIA by estimating ovarian reproductive potential and the risk of ovarian failure.

Complications

CIA can cause early menopause, affecting fertility and quality of life.

Early menopause increases the risk of osteoporosis, cardiovascular diseases, and other issues.

Prevention

To maintain fertility, avoid reduced quality of life and sexual dysfunction, and preserve bone and heart health, preventing ovarian dysfunction after chemotherapy is crucial.

Some studies suggest that administering GnRH (gonadotropin-releasing hormone) agonists can help reduce CIA risk. This medication may increase menstruation and ovulation rates, improving pregnancy rates.

However, this remains controversial, as other studies show different results regarding its effectiveness. More research is needed on using this drug to prevent CIA.

Another prevention option is fertility preservation through assisted reproductive therapy.

When to See a Doctor?

If you are undergoing chemotherapy or have completed it and experience menstrual disturbances, particularly amenorrhea (no menstruation for 3 consecutive cycles), consult a doctor for further management.

It is important, especially for women under 45 who have not yet undergone menopause and still wish to conceive. Since chemotherapy can also cause premature menopause and fertility issues that can seriously affect your quality of life, it is crucial for a doctor to investigate your risk factors for CIA to provide the appropriate therapeutic regimen.

Looking for more information about other diseases? Click here!