Does Estrogen Feed mCRPC?
No, estrogen does not feed metastatic castration-resistant prostate cancer (mCRPC); in fact, estrogen therapy has been used as a treatment option for mCRPC, though it is not a first-line therapy in modern practice. 1
Understanding the Androgen Receptor Paradox in CRPC
The fundamental biology of CRPC reveals that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression—not estrogen. 1 This persistent AR activity occurs through:
- Upregulation of enzymes involved in androgen synthesis within the tumor microenvironment 2
- Overexpression of the androgen receptor itself 2
- Emergence of mutant ARs with promiscuous recognition of various steroidal ligands 2
Historical and Current Role of Estrogen in mCRPC Treatment
Estrogen has actually been employed as a therapeutic agent rather than a disease promoter in CRPC:
- Secondary hormonal manipulation options for mCRPC include estrogens (such as diethylstilbestrol/DES) as one of several treatment choices when disease progresses on initial androgen deprivation therapy 1
- Estrogen therapy can induce PSA declines in patients with CRPC, with studies showing 39% of patients experiencing >50% PSA decline with estrogen-containing compounds 3
- The mechanism appears to involve suppression of adrenal androgens (particularly DHEA-S decline) rather than direct tumor stimulation 3
Why Estrogen Fell Out of Favor (Not Because It Feeds Cancer)
Estrogen therapy declined in use not because it promoted cancer progression, but due to:
- Cardiovascular complications including thromboembolic events 4
- Poorer overall survival related to cardiovascular toxicity, not cancer progression 4
- Availability of safer alternatives with the advent of LHRH agonists/antagonists and novel AR-targeted therapies 1
Modern Treatment Paradigm for mCRPC
Current standard treatments for mCRPC all target the androgen axis, not estrogen:
- Abiraterone (androgen synthesis inhibitor) 1
- Enzalutamide, apalutamide, darolutamide (AR antagonists) 1
- Docetaxel and cabazitaxel (chemotherapy) 1, 2, 5
- Sipuleucel-T (immunotherapy) 1, 5
- Radium-223 (bone-targeted radiopharmaceutical) 1
All FDA-approved agents demonstrate survival benefits by targeting pathways other than estrogen stimulation. 1
Critical Clinical Pitfall to Avoid
Do not discontinue androgen deprivation therapy even when mCRPC develops—maintaining castrate testosterone levels (<50 ng/dL) remains essential throughout all subsequent treatments. 1, 6 The disease is termed "castration-resistant" because it progresses despite castrate testosterone, not because testosterone or estrogen levels rise to stimulate growth. 1, 7
Evidence on Hormone Changes During Estrogen Treatment
When estrogen therapy is administered to mCRPC patients:
- Testosterone levels decline further (P < .001) 3
- DHEA levels decrease (P < .001) 3
- Sex hormone-binding globulin increases dramatically (>5-fold) 3
- PSA responses correlate with DHEA-S decline, not estrogen elevation 3
This hormonal profile demonstrates estrogen works by suppressing residual androgens, not by providing an alternative growth stimulus. 3