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CYP21A2 Enzyme, Fertility, & Stress

Written by Biljana Novkovic, PhD | Last updated:

CYP21A2 is an important enzyme that controls steroid hormone levels. It produces the hormones cortisol and aldosterone, while it decreases testosterone levels. Mutations that decrease the activity of the enzyme are fairly common, and many people are carriers. They are associated with more masculine physical traits in women and lower fertility in both sexes. However, these people also have a lower risk of developing mood and stress-related disorders. Read on to find out more about this enzyme and its variants.

What is CYP21A2?

This enzyme is also known as 21-hydroxylase. It is one of the cytochrome P450 monooxygenase enzymes (CYPs) [1].

Many CYP enzymes eliminate toxins and drugs from the human body. However, some, like CYP21A2, are not involved in the detox process. Instead, they produce steroid hormones.

Read more about the CYP enzymes here.

CYP21A2 Function

This enzyme is responsible for cortisol production [2].

Cortisol is produced in response to stress. It increases energy but suppresses the immune system.

CYP21A2 also helps produce aldosterone [2].

Aldosterone helps our bodies conserve sodium and maintain blood pressure.

Finally, CYP21A2 also decreases androstenedione and testosterone levels [3].

CYP21A2 Location

This enzyme is found in the adrenal glands [2].

CYP21A2 Gene Polymorphism

The CYP21A2 gene has over 35 variants [4]. More are discovered by the day.

There are some people who don’t have this gene or those who have more than two gene copies [5].

Most of the mutations decrease the activity of this enzyme. Lower enzyme activity, in turn, decreases aldosterone and cortisol levels but increases testosterone [6].

Complete Enzyme Deficiency

In most of the cases, a complete lack of the enzyme causes congenital adrenal hyperplasia [5]. Common symptoms of this dissease are:

  • virilizing effects. Women develop male-pattern hair growth and other masculine traits [6].
  • salt-wasting (low blood sodium due to aldosterone deficiency) [7].
  • oligomenorrhea or amenorrhea (infrequent or absent menstruation) [6].
  • polycystic ovaries [6].
  • ambiguous genitalia in girls [7].

Mutations that cause a total lack of enzyme function are rare (1 in about 15,000).

Mild Enzyme Deficiency

Mutations that cause mild enzyme deficiency are much more common.

They occur in 1 in 100 subjects. They can be even more frequent in some populations, such as Eastern European Jews (1 in 27) [7].

These people retain ∼20-60% enzyme activity [7].

Symptoms include:

  • Excessive body hair, infrequent menstrual periods, and impaired fertility in women [7].
  • Short stature and low fertility in adult men, due to the excess of androgens [7].

Why are CYP21A2 mutations so frequent?

Mutations in this gene may confer an advantage, as a result of the higher activity of the hypothalamic-pituitary-adrenal axis (HPA axis) [8]. This axis controls many processes, including the response to stress, mood and emotions.

Mutation carriers have a lower risk of developing mood and stress-related disorders. They are less often diagnosed with psychiatric disorders. Also, they are less vulnerable to mentally stressful situations (over 600 patients) [8].

Decreasing CYP21A2

These decrease CYP21A2:

  • 1α,25-dihydroxyvitamin D(3), derived from vitamin D [9].

About the Author

Biljana Novkovic

Biljana Novkovic

Biljana received her PhD from Hokkaido University.
Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science and health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.


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