Hormone Replacement Therapy (HRT) is a vital tool for managing symptoms of hormonal imbalances, such as menopause, low testosterone, or gender-affirming care. However, how your body metabolizes and responds to hormones can vary significantly based on your genetic makeup. By analyzing specific genetic variants, called Single Nucleotide Polymorphisms (SNPs), you can better understand your unique metabolism of hormone therapy and optimize its efficacy and safety.

In this post, we’ll explore the connection between DNA and HRT metabolism, key genes and SNPs to consider, and how genetic testing can inform personalized hormone therapy.

How DNA Affects HRT Metabolism

Your body metabolizes hormones like estrogen, progesterone, and testosterone through enzymatic pathways in the liver, kidneys, and other tissues. Genetic variations can influence how efficiently these pathways function, impacting:

• Hormone bioavailability.
• Conversion to active or inactive forms.
• Potential side effects or adverse reactions.

By identifying specific SNPs, you can assess potential risks, including poor metabolism, overactive hormone breakdown, or an increased likelihood of side effects.

Key Genes and SNPs for HRT Metabolism

Below are the primary genes and SNPs to investigate when evaluating your genetic predisposition to hormone metabolism:

1. CYP450 Family (Cytochrome P450 Enzymes)

The CYP450 enzymes play a critical role in hormone metabolism, particularly in the liver.

• CYP1A1 (rs1048943):

  • Metabolizes estrogens into hydroxylated forms.
  • Variants can increase oxidative stress, influencing estrogen-related cancer risks.

• CYP1B1 (rs1056836):

  • Involved in estrogen metabolism.
  • Certain variants may increase the production of 4-hydroxyestrone, a potentially harmful estrogen metabolite linked to cancer.

• CYP3A4 (rs2740574):

  • Responsible for metabolizing testosterone and estradiol.
  • Variants can lead to slower hormone metabolism, increasing circulating hormone levels.

• CYP2C19 (rs4244285):

  • Impacts progesterone and testosterone metabolism.
  • Poor metabolizers may have altered hormone efficacy.

2. COMT (Catechol-O-Methyltransferase)

• COMT (rs4680):
  • Regulates the breakdown of catechol estrogens (e.g., 2-hydroxyestrone).
  • The Val/Met variant can slow estrogen clearance, increasing the risk of estrogen-related conditions.

3. GST (Glutathione S-Transferase)

• GSTT1 and GSTM1 (Copy Number Variants):
  • Affect detoxification of estrogen metabolites.
  • Deletions in these genes can impair the body’s ability to clear reactive estrogen metabolites, increasing oxidative stress.

4. SULT1A1 (Sulfotransferase 1A1)

• SULT1A1 (rs9282861):
  • Sulfonates estrogens for excretion.
  • Variants can reduce enzyme activity, leading to hormone buildup and increased side effects.

5. UGT (UDP-Glucuronosyltransferase)

• UGT2B17 (Copy Number Variation):
  • Glucuronidates testosterone for excretion.
  • Deletions or reduced function can increase circulating testosterone, impacting therapy outcomes.

6. ESR (Estrogen Receptors)

• ESR1 (rs2234693 and rs9340799):

  • Polymorphisms in the estrogen receptor alpha gene can influence sensitivity to estrogen therapy.

• ESR2 (rs4986938):

  • Variants in the estrogen receptor beta gene may impact bone health and cardiovascular response to HRT.

Why These SNPs Matter

Poor Metabolizers

• Individuals with impaired CYP2C19 or CYP3A4, function may metabolize hormones slowly, leading to excessive hormone levels, increasing side effects such as bloating, headaches, or mood changes.

Fast Metabolizers

• Enhanced CYP1A1 or CYP3A4 activity can lead to rapid clearance of hormones, reducing their effectiveness and requiring dosage adjustments.

Estrogen Metabolite Imbalance

• SNPs in COMT or GST or MTHFR genes can alter the balance between protective and harmful estrogen metabolites, potentially increasing the risk of estrogen-related cancers.

How to Use Genetic Information for HRT

1. Genetic Testing

• Companies like 23andMe or specialized labs offer SNP testing that can provide insights into your hormone metabolism.

2. Personalized HRT Dosing

• At Bloom we adjust hormone types, routes (e.g., oral, transdermal), and dosages based on your genetic profile and offer lifestyle recommendations and supplements to help support the proper function of impaired genes.

3. Monitor Biomarkers

• Combine genetic insights with regular lab tests for hormone levels, liver function, and inflammatory markers (e.g., CRP, homocysteine.
• The DUTCH test is critically important to assess how hormones are being metabolized and utilized in your body.  If metabolites are going down the “bad” pathway it can contribute to cancer.  However, we can push them down “good” pathway using simple inexpensive supplements and lifestyle choices.

Conclusion

Understanding your genetic makeup through SNP testing can provide valuable insights into how your body processes hormone replacement therapy. By focusing on key genes like CYP450, COMT, GST, and others, you can personalize your HRT to minimize risks and maximize benefits. Consult with a healthcare provider experienced in genetics and hormone therapy to integrate these insights into your treatment plan.

With the right knowledge, you can optimize your HRT experience and support your long-term health.