What is an aromatase inhibitor?

Aromatase inhibitors are chemicals that block the activity of aromatase, the enzyme that catalyzes the reaction of aromatization. This reaction is crucial for the synthesis of the sex hormone estrogen, particularly prominent in female bodies. Subsequently, aromatase inhibition can suppress estrogen production. 

The human body does not naturally produce substances specifically for aromatase inhibition. However, some natural hormones, such as melatonin, a sleep-regulating hormone produced by the pineal gland in the brain, and certain types of sex hormones like androgens, as well as vitamin D may have mild or moderate inhibitory effects. For example, melatonin can potentially reduce aromatase activity in cancerous glioma cells originating from the supportive glial cells of the brain and spinal cord. It can also decrease the enzyme’s overall expression by downregulating its mRNA levels.¹ 

Some plant-based foods and mushrooms contain bioactive compounds such as flavonoids and polyphenols that exhibit aromatase-inhibiting activity. Yet, for health conditions that can be treated or controlled through aromatase inhibition, synthetic aromatase inhibitors are used more often due to their clinically proven efficiency and consistent results. 

Most of these drugs are divided into two main groups: nonsteroidal inhibitors and steroidal inhibitors. 

Steroidal aromatase inhibitors feature a structure similar to steroids, which are organic compounds consisting of four fused rings. These drugs are designed to mimic the natural substrate of the aromatization reaction catalyzed by aromatase. Such medications aim to permanently inactivate the enzyme by forming stable complexes with it. Exemestane is a common example of a steroidal aromatase inhibitor. 

Non-steroidal aromatase inhibitors do not share a similar structure with steroids and are not intended to mimic the natural substrate. While they also create complexes with aromatase by binding to this enzyme, this process is reversible, meaning such inhibitors can be displaced by natural substrates. Examples of non-steroidal aromatase inhibitors include letrozole and anastrozole.² 

Health conditions treated or controlled with aromatase inhibitor drugs 

Aromatase inhibition plays a crucial role in the treatment of certain types of breast cancer, particularly hormone receptor-positive (HR+) cancer. In estrogen receptor-positive (ER+) breast cancer, estrogen binds to cancerous cells that have estrogen receptors, which can potentially stimulate tumor growth. Blocking aromatase activity can prevent cancer proliferation by suppressing estrogen production.³ 

Aromatase inhibition also helps to treat or manage several non-cancerous health conditions, including: 

• Gynecomastia in males caused by hormonal imbalances; 

• Infertility associated with polycystic ovary syndrome (PCOS); 

• Infertility and painful symptoms associated with endometriosis; 

• Precocious puberty in girls with McCune-Albright syndrome; 

• Hormone modulation in transgender hormone therapy. 

Estrogen also plays a crucial role in regulating bone growth. It participates in the process of growth plate fusion in bones, marking the end of growth. Elevated levels of estrogen in both females and males can lead to premature closure of the growth plates, resulting in short stature. The inhibition of estrogen production can delay fusion and prolong the period of bone growth.⁴ 

Aromatase inhibitor side effects 

By blocking aromatase activity and thus preventing estrogen production, aromatase inhibitor drugs can trigger menopausal symptoms such as night sweats, hot flashes, and vaginal dryness. Bone health issues, particularly the loss of bone density, which is also common in postmenopausal women, are also frequently experienced. Additionally, patients tend to develop muscle pain, known as myalgia, and joint pain or arthralgia. 

In rarer cases, aromatase inhibition can lead to cardiovascular issues, elevated cholesterol levels, and mood changes, including mood swings or depression. Carpal tunnel syndrome, which involves compression of the median nerve in the wrist, is also one of the less frequent side effects of aromatase inhibition. 

The prolonged use of aromatase inhibitors, which are sometimes prescribed for up to 10 years to prevent breast cancer recurrence, may significantly increase the risk of cardiovascular issues and severe osteoporosis. 

The choice of optimal aromatase inhibitor treatment 

Since aromatase inhibitors can impact both the mental and physical well-being of patients, selecting a medication with the least intense side effects is ideal. Although the three FDA-approved drugs for HR+ breast cancer—anastrozole, letrozole, and exemestane—show similar effectiveness and side effects, their different mechanisms of action as steroidal or nonsteroidal inhibitors offer unique advantages and disadvantages that should be considered. 

Exemestane, for instance, binds irreversibly to the enzyme, potentially providing longer-lasting effects and a lower risk of developing resistance compared to letrozole and anastrozole. However, it may also cause androgenic side effects, such as changes in lipid profiles and increased hair growth. 

The choice of the best aromatase inhibitor is subjective and should involve monitoring a patient’s individual tolerance to side effects and their potential for developing resistance. In some cases, switching between medications can also be beneficial. 

References: 

1. Gonzalez A et al. “Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells.” British Journal of Cancer. 2007. 97:755-760.
   https://www.nature.com/articles/6603935.pdf
2. Miller WR. “Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?” The Oncologist. 2008. 13(8): 829-837.
   https://academic.oup.com/oncolo/article/13/8/829/6397451 
3. “Aromatase Inhibitors.” Cleveland Clinic. 
   https://my.clevelandclinic.org/health/treatments/24685-aromatase-inhibitors  
4. Iavarno S. “Aromatase Inhibitors (AIs)”. Everyday Health.
   https://www.everydayhealth.com/drug-classes/aromatase-inhibitors/