EndoAxis Clinical Team
What is CYP3A4?
CYP3A4 (Cytochrome P450 3A4) is one of the most abundant and clinically significant liver enzymes involved in Phase I detoxification.
It metabolizes:
~50% of pharmaceutical drugs, Endogenous hormones, especially steroid hormones (cortisol, estrogen, testosterone) & Xenobiotics (environmental toxins, pollutants, etc.)
It’s expressed primarily in the liver and intestines, and its activity can be modulated by: Genetics, inflammation, nutritional status, drugs/herbs (inducers and inhibitors)
Cortisol’s Relationship with CYP3A4
Cortisol is both a substrate and a modulator of CYP3A4. Here’s how they tango:
- Cortisol undergoes hepatic metabolism via multiple CYP enzymes, including CYP3A4.
- Cortisol can induce expression of CYP3A4 (more expression = more activity)
- When CYP3A4 activity is high, cortisol clearance increases, potentially reducing circulating cortisol levels.
- When CYP3A4 is inhibited, cortisol clearance slows, potentially elevating cortisol levels systemically.
Why this matters for females
Estrogen is also a CYP3A4 substrate, and here’s where things get spicy:
- CYP3A4 metabolizes estrone to 16-OH E1
- 16-OH E1 can bind to intracellular estrogen receptors, increasing cellular proliferation and estrogen excess symptoms.
- Cortisol can compete with CYP3A4 for hydroxylation, increasing circulating estrogens
Possible worsening of:
- PMS
- fibroids
- PCOS
- endometriosis symptoms
Why this matters for males
Testosterone → Estradiol conversion happens via aromatase (not CYP3A4 directly), but:
- CYP3A4 helps metabolize estradiol downstream.
- If CYP3A4 is sluggish, estradiol can build up → leading to symptoms like:
- Fat gain around chest/hips
- Emotional sensitivity
- Low motivation/drive
- Elevated 16-OH E1 in men can increase prostate hypertrophy
So ironically, high stress can lead to both low T and relatively high E in males -an imbalance often missed.
IMPACT: How Stress + CYP3A4 Impact Hormones in Men & Women
CYP3A4 is the liver’s main detox enzyme for steroid hormones like cortisol and estrogen.
When stress hits and cortisol rises, this enzyme gets hijacked – creating a hormone traffic jam with gender-specific fallout.
Clinically Relevant Takeaways
Stress & high cortisol can increase CYP3A4 expression and compete with liver clearance. Estrogen dominance symptoms may flare under chronic stress for this reason. If a patient is on a CYP3A4-inhibiting medication, they may experience hormone overload symptoms (mood swings, bloating, insomnia, etc.). Nutraceuticals that modulate CYP3A4 (milk thistle, quercetin, berberine) should be used with awareness of their effect on hormone metabolism.
Key Takeaways
When stress pushes cortisol to the front of the metabolic line, estrogen in women and testosterone in men get stuck waiting — or get flushed out too fast. The result? Hormonal imbalances that feel like burnout, PMS, or low drive… even when labs look “normal.”
In these scenarios, as practitioners, we are likely more apt to reach for detoxification support, when we really need to prioritize the stress response. EndoAxis knows that each body is different and that each body is dynamic. In understanding this complex interplay, we have created the “Optimize” line to support appropriate and balanced HPA function.
