Aromatase Inhibitors

Author: Gianpiero Pescarmona
Date: 15/06/2008

2012-02-20T22:55:00 - Valentina Alliod


Aromatase inhibitors (AIs) are a class of drugs used in hormonotherapy as follow-up treatment after primary treatment (surgery, chemotherapy, radiotherapy) for estrogen-receptor positive breast cancer in postmenopausal women.


AIs are classified as first, second, or third generation according to the specificity and potency with which they inhibit the aromatase enzyme. Third-generation AIs (i.e., anastrozole, letrozole, and exemestane) are the most selective and least toxic AIs known today and can reduce serum estrogen by more than 95%. They are further subclassified as type 1 or type 2 inhibitors, according to the reversibility of their inhibitory activity:
- Type 1 inhibitors: irreversible steroidal inhibitors analogues of androstenedione (exemestane (Aromasin©) forms a covalent and deactivating bond with the aromatase enzyme. So, permanent inactivation persists after discontinuation of the drug until the peripheral tissues synthesize new enzymes.
- Type 2 inhibitors: non-steroidal inhibitors (anastrozole (Arimidex©) and letrozole (Femara©)), inhibits the synthesis of estrogen via reversible competition for the aromatase enzyme.


Aromatase inhibitors are used to treat estrogen-receptor positive breast cancer in postmenopausal women.
Before menopause, most of the bodies estrogen is produced in the ovaries, so the suppression of plasma estrogen can not be maintained because of the feedback on the pituitary gland, which induces aromatase activity releasing FSH. However, after menopause, the main source of estrogen consists in the conversion of androgen, produced by the adrenal cortex, to estrogen by the aromatase enzyme in peripheral tissues (especially adipose tissue, liver, kidney and also CNS). Aromatase inhibitors work by blocking the enzyme aromatase, a cytochrome p450, decreasing in this way the level of circulating estrogen which stimulates the growth of estrogen-receptor positive breast cancer cells.


All of the third-generation oral aromatase inhibitors (letrozole, anastrozole and exemestane) are orally avaiable:
- Anastrozole: 1 mg once daily. Plasma half-life: 41-48 hours. Time to steady-state plasma levels: 7 days.
- Letrozole: 2,5 mg once daily. Plasma half-life: 2-4 days. Time to steady-state plasma levels: 60 days.
- Exemestane: 25 mg once daily. Plasma half-life: 27 hours. Time to steady-state plasma levels: 7 days.


Aromatase, an enzyme of the cytochrome P-450 superfamily and the product of the CYP19 gene, is highly espressed in the placenta, in the granulosa cells of ovarian follicles (where its expression depends on cyclical FSH stimulation) and, at lower levels, in several other tissues, such as subcutaneous fat, liver, muscle, brain, normal breast and breast-cancer tissue. Aromatase enzyme catalyzes the last step of the pathway of estrogen biosynthesis: it removes the methyl group between the A and B rings of the androgen substrate (Δ4-androstenedione converted to estrone or testosterone converted to estradiol), so the A ring becomes aromatic. This reaction requires three hydroxylations, all of which use O2 and NADPH. Estrogens increase proliferation within the breast, especially in breast cancer tissue. Aromatase inhibitors block the aromatase enzyme, decreasing estrogen levels.
Type 1 inhibitors, like exemestane (Aromasin ©), are androgen analogues and bind irreversibly aromatase, so they are also called “suicide inhibitors”. The duration of inhibitory effect is primarily dependent on the rate of de novo synthesis of aromatase.
Type 2 inhibitors, like anastrozole (Arimidex ©) or letrozole (Femara ©), contain a functional group within the ring structure that binds the heme iron of the cytochrome P450, interfering with the hydroxylation reactions.


Side effects are related to low estrogen levels:
- muscoloskeletal diseases:
osteoporosis → estrogen decreases the osteoblastic production of resorptive cytokines (RANK-L, CSF-1,IL-1 and TNF) and at the same time increases the production of antireceptive cytokines (mainly osteoprotegerin). This leads to increased osteoclastic apoptosis and increased osteoblastic activity, favouring bone apposition. Futhermore, estrogen increases the intestinal absorption and the renal re-absorption of calcium. If plasma estrogen levels are low, there is a rise in the serum-parathyroid hormone stimulating the osteoclasts that result in the increased bone loss (3) → calcium and vitamin D supplements can reduce the risk of fracture (4)
arthralgia and joint pain → joint pain is perceived by the nociceptive fibers innervating the articular structures and inflammatory mediators, such as prostaglandins and bradykinin, which activate these nociceptors, augmenting their sensitivity to pain with mechanical stimuli. Estrogen has been associated with anti-nociceptive effects, activating the spinal cord kappa-opioid analgesic system. (5)
→ morning stiffness (6) → probably caused by sleep-related hypoventilation and hypoxemia
- cardiovascular disease (7) → estrogens protect cardiovascular system through three mechanism: enhancement of vasodilator capacity, suppression of vascular inflammation and increase in mitochondrial efficiency. Estrogen increases eNOS activity binding ERα, causing vasodilation. Estrogen also decrease NF-kB, an important transcription factor involved in the activation of infiammatory pathway. Futhermore, estrogen can increase mitochondrial biogenesis and decrease ROS formation. (8)
- cephalgia
Weak androgenic effects (weight gain and acne) and cutaneous vasculitis have been associated with exemestane (9) (10)


  1. Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors, 2003
  2. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer, 2003
  3. Drug-induced osteoporosis: mechanisms and clinical implications, 2010
  4. The Effect of Aromatase Inhibitors on Bone Metabolism, 2009
  5. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer, 2010
  6. Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more?, 2010
  7. Estrogen and progesterone activate spinal kappa-opiate receptor analgesic mechanisms, 1996
  8. Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management, 2011
  9. A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health, 2009
  10. Mechanisms of cerebrovascular protection: oestrogen, inflammation and mitochondria, 2011
  11. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane, 2002
  12. Aromatase inhibitor-induced skin adverse reactions: exemestane-related cutaneous vasculitis, 2011
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