Meta Information
ID:17-alpha-estradiol
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/cyp3a4-strong-inhibitors
Target name:
Strong CYP3A4 Inhibitors
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) block CYP3A4, a significant (secondary) metabolic pathway for steroid hormones, which can lead to higher and less predictable levels of this experimental compound.
Actionable advice:
Strong CYP3A4 inhibitor medications should not be used while taking 17-alpha-estradiol.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol
Label source:
PubMed: Lee AJ et al., Endocrinology / J. (2003) - article title; establishes CYP3A4 contributes to 17beta-estradiol hydroxylation, so CYP3A4 modulators alter estradiol levels (PMID 11555828)
Action type:
avoid
Target id:
/class/broad-spectrum-inducers
Target name:
Broad-Spectrum Metabolic Enzyme Inducers
Severity:
major
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These substances (e.g., rifampin, carbamazepine, phenytoin) dramatically speed up the metabolism of 17-alpha-estradiol in the liver, which would likely render it ineffective.
Actionable advice:
Strong enzyme inducers should not be used, as they will significantly lower the effectiveness of 17-alpha-estradiol.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin,
rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.
Label source:
FDA label: Carbamazepine [class-derived from: Carbamazepine]
Action type:
avoid
Target id:
/intervention/saint-johns-wort
Target name:
Saint John's Wort
Severity:
major
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
St. John's Wort is a potent inducer of the CYP3A4 enzyme, which will significantly accelerate the breakdown of 17-alpha-estradiol and severely reduce its potential efficacy.
Actionable advice:
St. John's Wort should not be taken while using 17-alpha-estradiol.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives.
Label source:
PubMed: The interaction between St John's wort and an oral contraceptive. (PMID 14663455)
Action type:
avoid
Target id:
/dietary/grapefruit-pomelo
Target name:
Grapefruit or Grapefruit Juice
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
72
Hours after target:
4
Description:
Grapefruit contains compounds that irreversibly inhibit the CYP3A4 enzyme in the gut, which can dangerously increase the absorption and systemic levels of 17-alpha-estradiol.
Actionable advice:
Completely avoid grapefruit and its juice for at least 3 days before and during the entire period of use.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol
Label source:
PubMed: Lee AJ et al., Endocrinology / J. (2003) - article title; establishes CYP3A4 contributes to 17beta-estradiol hydroxylation, so CYP3A4 modulators alter estradiol levels (PMID 11555828)
Action type:
avoid
Target id:
/condition/history-hormone-sensitive-cancer
Target name:
History of Hormone-Sensitive Cancer
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Despite low affinity for classical estrogen receptors, any potential for off-target hormonal activity makes its use in individuals with a history of cancers (e.g., breast, uterine, prostate) an unacceptable risk.
Actionable advice:
Absolutely contraindicated in individuals with a personal history of hormone-sensitive cancers.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The nuclear 17 alpha-E-receptor complex was determined to be biologically active by its ability to stimulate an increase in the progesterone receptor content and to reverse antiestrogen inhibition of cellular proliferation and DNA polymerase activity.
Label source:
PubMed: Edwards DP & McGuire WL, Endocrinology (1980) - 17alpha-estradiol is a biologically active estrogen in human breast cancer (MCF-7) cells (PMID 7408775)
Action type:
avoid
Target id:
/condition/history-of-vte
Target name:
History of Venous Thromboembolism (VTE)
Severity:
major
Interaction type:
adverse
Nature:
relative
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Conventional estrogens increase the risk of blood clots. The clot risk of 17-alpha-estradiol - a weak, largely non-feminizing estrogen - is unknown, so caution is prudent in individuals with a history of DVT or pulmonary embolism.
Actionable advice:
This should be avoided or used with caution in individuals with a personal history of blood clots; the venous-clot risk of this weak, largely non-feminizing estrogen is not established.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
avoid
Target id:
/condition/hepatic-impairment
Target name:
Hepatic Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
17-alpha-estradiol is expected to be extensively metabolized by the liver. Impaired liver function could lead to accumulation and unpredictable toxicity.
Actionable advice:
Use should be avoided in individuals with moderate to severe liver disease.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Hepatic impairment or disease Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Undiagnosed abnormal genital bleeding
Label source:
FDA label: Estradiol (Lyllana)
Action type:
avoid
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The effects of 17-alpha-estradiol on fetal development are unknown. All experimental hormonal compounds are strictly contraindicated during pregnancy.
Actionable advice:
Absolutely contraindicated during pregnancy.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
avoid
Target id:
/condition/lactation
Target name:
Breastfeeding (Lactation)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
It is not known if 17-alpha-estradiol is excreted in breast milk or what its effects on a nursing infant would be. Use is contraindicated.
Actionable advice:
Absolutely contraindicated while breastfeeding.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
avoid
Target id:
/class/estrogens
Target name:
Estrogens and Progestins (Hormonal Therapy & Contraceptives)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining 17-alpha-estradiol with other estrogenic compounds leads to an unknown and potentially harmful additive hormonal effect, even if their primary mechanisms differ.
Actionable advice:
Any other form of estrogen or hormone replacement therapy should not be used concurrently.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Competition for [3H]17 beta-estradiol ([3H]17 beta-E) binding shows that 17 alpha-E binds to receptor with high affinity and has a dissociation constant (Kd) estimated to be 0.7 nM.
Label source:
PubMed: Edwards DP & McGuire WL, Endocrinology (1980) - 17alpha-estradiol binds the estrogen receptor with high affinity (PMID 7408775)
Action type:
avoid
Target id:
/class/serms
Target name:
Selective Estrogen Receptor Modulators (SERMs)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The interaction between 17-alpha-estradiol and SERMs (e.g., tamoxifen, raloxifene) is unknown and could lead to unpredictable and potentially adverse outcomes on estrogen-sensitive tissues.
Actionable advice:
SERMs should not be used concurrently with 17-alpha-estradiol.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Exact phrase from label:
Competition for [3H]17 beta-estradiol ([3H]17 beta-E) binding shows that 17 alpha-E binds to receptor with high affinity and has a dissociation constant (Kd) estimated to be 0.7 nM.
Label source:
PubMed: Edwards DP & McGuire WL, Endocrinology (1980) - 17alpha-estradiol binds the estrogen receptor with high affinity (PMID 7408775)
Action type:
avoid
Target id:
/class/cyp3a4-moderate-inhibitors
Target name:
Moderate CYP3A4 Inhibitors
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Moderate CYP3A4 inhibitors can increase levels of 17-alpha-estradiol by slowing its breakdown in the liver, raising the risk of unknown side effects from this experimental compound.
Actionable advice:
This is best used with extreme caution and under medical supervision, and avoiding it if possible may be worth considering.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol
Label source:
PubMed: Lee AJ et al., Endocrinology / J. (2003) - article title; establishes CYP3A4 contributes to 17beta-estradiol hydroxylation, so CYP3A4 modulators alter estradiol levels (PMID 11555828)
Action type:
informational_none
Target id:
/class/cyp1a2-inhibitors
Target name:
CYP1A2 Inhibitors
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
CYP1A2 is the principal enzyme that metabolizes estradiol; strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) can slow the breakdown of 17-alpha-estradiol and raise its levels unpredictably.
Actionable advice:
Strong CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin should be avoided or used cautiously.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol
Label source:
PubMed: Lee AJ et al. (2003) - article title; CYP1A2 is a principal enzyme in 17beta-estradiol hydroxylation (PMID 11555828)
Action type:
avoid
Target id:
/dietary/meal
Target name:
Any Meal
Severity:
moderate
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
As a lipophilic steroid hormone, taking 17-alpha-estradiol with food, particularly containing some fat, may enhance and standardize its absorption, leading to more consistent blood levels.
Actionable advice:
It is best taken with a meal to ensure consistent absorption and minimize variability.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
informational_none
Target id:
/biomarker/estradiol
Target name:
Estradiol Blood Test
Severity:
moderate
Interaction type:
assay_interference
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
17-alpha-estradiol is a stereoisomer of 17-beta-estradiol and can cross-react with estradiol immunoassays. Cross-reactivity is assay-dependent and is low in specific monoclonal assays (~0.1%), but older or less specific assays may overestimate estradiol.
Actionable advice:
If measuring estradiol while using this compound, prefer a specific LC-MS/MS method and tell the lab, since immunoassay cross-reactivity (though usually small) is possible.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
a monoclonal antibody is used that binds estradiol with high affinity (Ka = 10(10) L/mol), and does not bind other steroids tested, the highest cross reactivity observed being 0.1% for estradiol-17 alpha.
Label source:
PubMed: De Boever J et al., Clin Chem (1986) - 17alpha-estradiol cross-reacts only ~0.1% in a monoclonal estradiol immunoassay (PMID 3489572)
Action type:
monitor
Target id:
/intervention/quercetin
Target name:
Quercetin
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
4
Description:
Quercetin is a mild inhibitor of CYP3A4 and other metabolic enzymes, which could theoretically increase levels of 17-alpha-estradiol if taken at the same time.
Actionable advice:
Doses of quercetin and 17-alpha-estradiol are best separated by at least 4 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome preparation from human liver.
Label source:
PubMed: European journal of drug metabolism and pharmacokinetics (1995)
Source url:
Exact phrase from label:
These flavonoids interact with the metabolism of drugs such as 17 beta-estradiol and other steroids that are extensively metabolised through the P-450NF (P-450 IIIA4) enzyme or closely related P-450 systems.
Label source:
PubMed: Maturitas (1994)
Source url:
Exact phrase from label:
Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 1.97 μM.
Label source:
PubMed: Archives of pharmacal research (2011)
Action type:
separate
Target id:
/intervention/curcumin-and-piperine
Target name:
Curcumin and Piperine
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
4
Description:
Piperine, often combined with curcumin for absorption, is a known inhibitor of CYP3A4, which could slow the metabolism of 17-alpha-estradiol and increase its concentration.
Actionable advice:
Doses of curcumin/piperine and 17-alpha-estradiol are best separated by at least 4 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4
Label source:
PubMed: Bhardwaj RK et al., J Pharmacol Exp Ther (2002) - article title; piperine inhibits CYP3A4 (PMID 12130727)
Action type:
separate