A steroidal aromatase inhibitor is a medication designed to lower estrogen levels by interfering with the body’s ability to produce it. These drugs belong to a broader class of agents known as aromatase inhibitors, which function by targeting a specific protein. Their structural design is fundamental to their classification and dictates how they interact with their target, aiming to reduce circulating estrogen without directly affecting how it interacts with cells.
The Mechanism of Action
To understand how a steroidal aromatase inhibitor works, it is necessary to understand the function of the aromatase enzyme. Aromatase is a protein complex that plays a final part in the body’s production of estrogens. It facilitates the conversion of androgens, a group of hormones that includes testosterone, into estrogens through a process called aromatization. In postmenopausal women, this conversion primarily occurs in tissues outside the ovaries, such as fat and muscle tissue.
A steroidal aromatase inhibitor, such as exemestane, possesses a chemical framework that is very similar to the body’s natural androgens. Because of this structural resemblance, the inhibitor can fit into the same spot on the aromatase enzyme that the androgen substrate normally would. This action is competitive, meaning the drug vies with the natural substrate for access to the enzyme’s active site.
Once the steroidal inhibitor binds to the aromatase enzyme, it forms a permanent, covalent bond. This binding event is irreversible and effectively deactivates the enzyme, which is why steroidal inhibitors are often referred to as “suicide inhibitors.” This irreversible action ensures a long-lasting suppression of estrogen synthesis, as the body must produce new enzyme molecules to restore its estrogen-producing capability.
Clinical Applications
The primary use for steroidal aromatase inhibitors is in the treatment of hormone receptor-positive (HR+) breast cancer in postmenopausal women. In this type of cancer, estrogen molecules can bind to receptors on cancer cells, signaling them to grow and divide. By lowering the body’s estrogen levels, these inhibitors starve the cancer cells of the signals they need to proliferate, making them a standard part of adjuvant therapy after surgery to reduce the risk of cancer recurrence.
These medications are specifically indicated for postmenopausal women because their main source of estrogen comes from the aromatization of androgens in peripheral tissues. In premenopausal women, the ovaries are the main producers of estrogen, and inhibiting aromatase alone is not sufficient. It can trigger a feedback loop that increases other hormones and stimulates the ovaries to produce even more estrogen, so these drugs are generally not used unless ovarian function is also suppressed.
Beyond breast cancer treatment, steroidal aromatase inhibitors have been explored for some off-label uses. One such application is in the management of gynecomastia, the enlargement of breast tissue in males, caused by an imbalance of hormones. They are also sometimes used with testosterone replacement therapy in men to prevent the conversion of supplemented testosterone into estrogen.
Common Side Effects
The side effects associated with steroidal aromatase inhibitors are a direct result of the reduction in estrogen levels throughout the body. Since estrogen has roles in many different tissues, its depletion can lead to a range of symptoms, many of which resemble those experienced during menopause.
One of the most frequently reported categories of side effects involves the musculoskeletal system. Patients often experience joint pain (arthralgia) and muscle pain (myalgia). This discomfort can affect various parts of the body, including the hands, wrists, feet, and back. Because estrogen helps maintain bone density, its suppression increases the risk of bone loss, potentially leading to osteoporosis and a higher likelihood of fractures.
Hot flashes and night sweats are frequently reported by women taking these medications. Vaginal dryness, which can lead to discomfort or pain during intercourse, is another common issue. Fatigue and hair thinning are also potential side effects that can impact a patient’s quality of life while on this therapy.
Distinctions from Non-Steroidal Aromatase Inhibitors
The key distinction between steroidal and non-steroidal aromatase inhibitors lies in their chemical structure and interaction with the enzyme. Steroidal inhibitors like exemestane have a structure similar to androgens and bind irreversibly, permanently deactivating the enzyme. This irreversible action is why they are classified as Type I or “suicide inhibitors.”
In contrast, non-steroidal aromatase inhibitors, such as anastrozole and letrozole, are classified as Type II inhibitors. These drugs do not share the steroid-like structure and bind to the enzyme in a reversible manner. Their binding is non-covalent, meaning they competitively block the active site but can detach, leaving the enzyme intact to resume function if the inhibitor is cleared from the body.
This difference in binding mechanism can have clinical implications. If a patient’s cancer develops resistance to a non-steroidal inhibitor, a physician might switch them to a steroidal one. There is a lack of complete cross-resistance between the two classes, meaning a tumor that no longer responds to a reversible inhibitor may still be sensitive to an irreversible one. This provides a sequential treatment option for managing advanced breast cancer.