CYP17A1: Steroid Hormone Production and Metabolism

Key Takeaways:
~ The formation of steroid hormones, such as testosterone and estrogen, depends on CYP17A1.
~ Genetic variants (SNPs) in the CYP17A1 gene can impact hormone levels.
~ Knowing your genetic variants can help you understand your risk for hormone-related conditions.

What is CYP17A1?

The CYP17A1 gene encodes an enzyme essential for the formation of steroid hormones, such as the precursor to testosterone and estrogen.

Cholesterol is the precursor of sex hormones. Cholesterol is converted into pregnenolone, which can then be converted to 17OH-pregnenolone or progesterone by the CYP17A1 enzyme. Cholesterol can also be converted to cortisol.

Located primarily in the gonads and adrenal glands, CYP17A1 is responsible for catalyzing two key reactions in steroidogenesis: 17α-hydroxylation and 17,20-lyase activity.

Here is an overview of the pathways that are impacted by CYP17A1.

Cholesterol steroid pathway. CYP17A1 plays key roles in creation of DHEA, Testosterone, and Estrogens

The 17α-hydroxylase activity of CYP17A1 is responsible for the conversion of pregnenolone and progesterone to their derivatives. These intermediates serve as precursors for the synthesis of cortisol and other glucocorticoids.

On the other hand, the 17,20-lyase activity of CYP17A1 is involved in the production of androgens, such as dehydroepiandrosterone (DHEA) and androstenedione. These androgens act as precursors for the synthesis of testosterone and estrogens.

The activity of CYP17A1 is tightly regulated and plays a critical role in several physiological processes, including sexual development, fertility, and the maintenance of hormonal balance.

Genetic variations in the CYP17A1 gene can influence its function, leading to altered hormone production.

Interactions with environmental factors:

In animal studies, glyphosate decreases testosterone by decreasing CYP17A1 in Leydig cells, which are the primary site of testosterone production.[ref]

However, this may not hold true for all herbicides formulated with glyphosate. The various different ingredients in commercially available herbicides interact with glyphosate, and one herbicide formulation increased CYP17A1 in rats.[ref]

Steroid hormone levels are extremely important during the development of a fetus, and exposure to toxicants during development may have effects that aren’t fully understood until puberty.

A mother’s CYP17A1 genotype may also be important, as estrogen levels impact the growth of the fetus. One study found an interaction between exposure to organochlorine pesticides, the normal CYP17A1 variant, and a lower birth weight.[ref] In this case, the variant allele increases CYP17A1 activity and the wildtype or typical CYP17A1 allele is associated with lower activity.

Rare mutations in CYP17A1:

To determine the function of a gene, scientists often create animal models with nonfunctioning or ‘knock out’ genes. This helps researchers understand the effects of the gene.

In mice, a genetic deficiency of CYP17A1 causes all mice (including those with a Y chromosome) to appear female. They were also all infertile and had abnormal genitalia and reproductive organs.

In the CYP17A1 knockout mice with XY chromosomes there was a complete lack of testosterone, and in the KO mice with XX chromosomes, there was an accumulation of progesterone.[ref]

Similarly, rare mutations in CYP17A1 in humans cause 17α-hydroxylase deficiency.  This condition occurs in about 1 in 1,000,000 individuals. A case series describing 8 of these rare individuals shows that there is a range of severity due to CYP17A1 mutations. In general, genetically male (XY) individuals will have more female appearing external genetalia. Both males and females with 17α-deficiency have delayed puberty, are infertile, and often have hypertension at a young age.[ref]

Heart Disease:

While much of the research on CYP17A1 has focused on hormone-related cancers or developmental problems, estrogen and steroid hormones also affect the heart. In women, higher levels of estrogen are thought to protect against heart disease, while the opposite may be true for men.[ref] In the genotype report, you’ll see that several of the CYP17AA1 variants are linked to heart-related changes.

Prostate cancer:

CYP17A1 and the conversion of androgens may be important  in prostate cancer. A CYP17A1 inhibitor (abiraterone) was approved by the FDA a few years ago for the treatment of late-stage prostate cancer treatment [ref].

Breast Cancer:

Research shows that exposure to PFAA (perfluoroalkyl acids) increases the relative risk of breast cancer. However, the increased risk may only apply to people with certain genotypes. A recent study found that a CYP17A1 rs743572 variant (below in the genotype report), which is associated with higher enzyme function, was associated with a decreased risk of breast cancer at higher PFAA exposure levels.[ref]

Similarly, higher levels of BPA are associated with an increased relative risk of breast cancer. Among women with the CYP17A1 rs743572 variant, which leads to higher function, there was no increased risk of breast cancer from BPA. Women with the lower CYP17A1 variants had a 2.5-fold increased relative risk of breast cancer with higher BPA exposure.[ref]


CYP17A1 Genotype Report:

Check your genetic data for rs743572 -34T/C (23andMe v4; AncestryDNA):

  • A/A: typical
  • A/G: somewhat higher CYP17A1 function
  • G/G: higher CYP17A1 function (possibly higher sex hormone levels); increased risk of prostate cancer in African American men[ref]; increased risk of PCOS[ref]; increased risk of acne vulgaris[ref] decreased risk of breast cancer in certain situations[ref][ref]

Members: Your genotype for rs743572 is .

Check your genetic data for rs4919687 (23andMe v4; AncestryDNA):

  • A/A: increased risk of coronary heart disease[ref]
  • A/G: increased risk of coronary heart disease
  • G/G: typical

Members: Your genotype for rs4919687 is .

Check your genetic data for rs6162 (23andMe v4, v5):

  • G/G: increased relative risk of higher PSA levels (prostate cancer risk)[ref]
  • A/G: increased relative risk of higher PSA levels (prostate cancer risk)
  • A/A: typical

Members: Your genotype for rs6162 is .

Check your genetic data for rs11191548 (23andMe v4, v5; AncestryDNA):

  • C/C: lower serum cholesterol (Chinese ancestry)[ref] decreased risk of high blood pressure [ref][ref][ref]
  • C/T: decreased risk of high blood pressure
  • T/T: typical (most common genotype)

Members: Your genotype for rs11191548 is .

 

Rare mutations in CYP17A1:

The following are rare mutations that lead to CYP17A1 deficiency. Errors are possible in Ancestry, 23andMe, etc. Always double check a rare mutation with a clinical test before taking any medical actions.

Check your genetic data for rs104894154 (23andMe v4 i5001477; AncestryDNA)

  • C/C: typical
  • C/T: carrier of a CYP17A1 deficiency mutation[ref]
  • T/T: Complete combined 17-alpha-hydroxylase/17,20-lyase deficiency (extremely rare, known from childhood)

Members: Your genotype for rs104894154 is or i5001477 is .

Check your genetic data for rs104894153 (23andMe v4 i5001478; AncestryDNA)

  • C/C: typical
  • C/T: carrier of a CYP17A1 deficiency mutation[ref]
  • T/T: Complete combined 17-alpha-hydroxylase/17,20-lyase deficiency (extremely rare, known from childhood)

Members: Your genotype for rs104894153 is or i5001478 is .

Check your genetic data for rs104894148 (23andMe v4 i5001486; AncestryDNA)

  • T/T: typical
  • A/T: carrier of a CYP17A1 deficiency mutation[ref]
  • A/A: Complete combined 17-alpha-hydroxylase/17,20-lyase deficiency (extremely rare, known from childhood)

Members: Your genotype for rs104894148 is or i5001486 is .
** given in plus orientation to match 23andMe or AncestryDNA data

Check your genetic data for rs61754278 (23andMe v4, v5; AncestryDNA)

  • C/C: typical
  • C/T: carrier of a CYP17A1 deficiency mutation[ref]
  • T/T: Complete combined 17-alpha-hydroxylase/17,20-lyase deficiency (extremely rare, known from childhood)

Members: Your genotype for rs61754278 is .

 


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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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