Aromatase is an enzyme responsible for the production of estrogen, starting from androgens.
There are two main types of aromatase inhibitors
- Type I – similar to androstenedione (an androgen hormone) also present in women. Exemestane is a 3rd generation aromatase inhibitors of Type I. Type I means that it is an analogues of the androgen androstenedione. It is steroidal and share the same structure with it.
- Type II – do not resemble androstenedione and are non-steroidal inactivators. They include Anastrozole and Letrozole.
Aromatase belongs to the CYP450 family. They synthesize estrogen from androstenedione and testosterone produced by the adrenal glands. Androstenedione is the precursor of estrone, whilst testosterone is the precursor of 17-β-estradiol.
In postmenopausal women, the above estrogen conversion is the main source of circulating estrogen. Conversely, the gonads (ovary) are the main source in premenopausal women.
Thus, another strategy for treating hormone dependent breast cancer is to inhibit aromatase, thus reducing estrogen source. Aromatase is mainly expressed in placental and ovarian cells. However, they are also present in the brain, adipose tissues and muscles. Thus, the aromatase inhibition in postmenopausal women causes a deep depletion in estrogen.
Exemestane irreversibly inhibit aromatase. Conversely, nonsteroidal hormones ( Anastrozole and Letrozole) are reversible competitive inhibitors that bind to a group present on the aromatase. Since they are competitive and reversible, it is important for the drug to be continuously present.