Meta Information
ID:progesterone
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:
/circadian/sleep
Target name:
Going to Sleep
Severity:
major
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
0
Description:
Progesterone's primary metabolite, allopregnanolone, has potent sedative effects. Taking the dose at bedtime utilizes this effect to improve sleep quality and avoids significant daytime drowsiness.
Actionable advice:
A progesterone dose should be taken within 2 hours of bedtime to aid sleep and avoid daytime impairment.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
drowsiness and fatigue
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
separate
Target id:
/dietary/meal
Target name:
Any Caloric Meal
Severity:
major
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Taking oral micronized progesterone with food, particularly a meal containing fat, can more than double its absorption from the gut, leading to more effective and consistent blood levels.
Actionable advice:
Oral progesterone should be taken with a meal, ideally the evening meal, for consistent absorption.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Administration with food
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
informational_none
Target id:
/class/cyp3a4-strong-inhibitors
Target name:
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Grapefruit)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These substances block the primary enzyme (CYP3A4) that breaks down progesterone, leading to significantly higher levels in the body and an increased risk of side effects like drowsiness and dizziness.
Actionable advice:
Strong CYP3A4 inhibitors should not be used with progesterone; it is important to consult a clinician for alternatives.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
avoid
Target id:
/class/broad-spectrum-inducers
Target name:
Metabolic Enzyme Inducers (e.g., Rifampin, Carbamazepine)
Severity:
major
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These medications speed up the liver enzymes (like CYP3A4) that metabolize progesterone, causing it to be cleared from the body too quickly and severely reducing its effectiveness.
Actionable advice:
Co-administration should be avoided, as progesterone efficacy will be severely compromised.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Inducers of CYP3A4, such as St. John's wort
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
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 significantly accelerates the breakdown of progesterone, rendering it much less effective.
Actionable advice:
St. John's Wort should not be taken while using progesterone.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
St. John's wort (Hypericum perforatum) preparations
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
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:
The liver is the primary site of progesterone metabolism; severe liver disease impairs its clearance, leading to dangerously high levels and is a contraindication for use.
Actionable advice:
Progesterone should not be used in 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:
Estrogens may be poorly metabolized in women with impaired liver function
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
avoid
Target id:
/condition/hormone-sensitive-cancer
Target name:
History of Hormone-Sensitive Cancer (e.g., Breast Cancer)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone can potentially stimulate the growth of certain hormone-sensitive cancers. Its use is contraindicated in individuals with a personal history of these conditions.
Actionable advice:
Progesterone is contraindicated if you have a history of breast cancer or other hormone-sensitive malignancies.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Breast cancer or history of breast cancer
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
avoid
Target id:
/condition/thromboembolic-disorder
Target name:
History of Thromboembolic Disorders (Blood Clots)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Hormonal therapies can influence blood clotting factors. Progesterone is contraindicated in individuals with an active or past history of blood clots (DVT, PE), stroke, or heart attack.
Actionable advice:
Progesterone should not be used with a history of blood clots, stroke, or heart attack.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Active arterial thromboembolic disease
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
avoid
Target id:
/condition/undiagnosed-vaginal-bleeding
Target name:
Undiagnosed Abnormal Vaginal Bleeding
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Abnormal vaginal bleeding must be investigated to rule out serious underlying conditions, such as cancer, before initiating progesterone therapy.
Actionable advice:
Progesterone is contraindicated until the cause of any abnormal vaginal bleeding has been diagnosed.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Undiagnosed abnormal genital bleeding
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
avoid
Target id:
/class/estrogens
Target name:
Estrogen Therapy (in women with a uterus)
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
In women with an intact uterus, unopposed estrogen therapy increases the risk of endometrial hyperplasia and cancer. Progesterone is required to oppose this effect and protect the uterine lining.
Actionable advice:
Progesterone must be co-administered with estrogen if you have a uterus to prevent endometrial cancer.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
estrogen plus progestin therapy
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
informational_none
Target id:
/class/cns-depressants
Target name:
CNS Depressants (e.g., Alcohol, Benzodiazepines, Opioids)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone can cause drowsiness and dizziness; combining it with other substances that depress the central nervous system can lead to excessive sedation and impaired coordination.
Actionable advice:
Extreme caution is warranted, and combining progesterone with alcohol or other sedative medications is best avoided.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
PROMETRIUM Capsules may cause transient dizziness and drowsiness and should be used with caution
Label source:
FDA label: Progesterone (Prometrium)
Action type:
avoid
Target id:
/class/antidiabetic-medications
Target name:
Diabetes Medications
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone may slightly decrease glucose tolerance and increase insulin resistance in some individuals, potentially reducing the effectiveness of diabetes medications.
Actionable advice:
Blood glucose levels are best monitored closely when starting or changing the dose of progesterone.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use,
Label source:
FDA label: Progesterone (Prometrium)
Action type:
monitor
Target id:
/condition/depression
Target name:
Major Depressive Disorder
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone and its metabolites can influence mood and neurotransmitter systems, potentially exacerbating symptoms in individuals with a history of depression.
Actionable advice:
Mood should be monitored closely, and it is important to report any worsening of depressive symptoms to a clinician.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
depression, pruritus, breast pain
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
monitor
Target id:
/class/cyp2c19-inhibitors
Target name:
CYP2C19 Inhibitors (e.g., Omeprazole, Fluconazole)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These drugs can inhibit a secondary enzyme (CYP2C19) involved in progesterone breakdown, potentially increasing its levels and the risk of side effects.
Actionable advice:
This is best used with caution, and it is a good idea to monitor for increased side effects like drowsiness when taken with a CYP2C19 inhibitor.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Ketoconazole is a known inhibitor of cytochrome P450 3A4
Label source:
FDA label: Progesterone (Prometrium)
Action type:
monitor
Target id:
/condition/lactation
Target name:
Breastfeeding (Lactation)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone is excreted in breast milk, and its effects on a nursing infant are not fully established. Caution is advised.
Actionable advice:
It is important to consult a healthcare provider before using progesterone while breastfeeding.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Lactation: Estrogen administration to lactating women has been
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
informational_none
Target id:
/biomarker/thyroid-panel
Target name:
Thyroid Function Tests
Severity:
minor
Interaction type:
assay_interference
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone can increase levels of thyroid-binding globulin (TBG), which may lead to an increase in total T4 and T3 measurements, though free hormone levels and TSH usually remain normal.
Actionable advice:
It is generally best to let a clinician know about progesterone use when interpreting thyroid tests, focusing on Free T4, Free T3, and TSH.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
thyroid-binding globulin
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
monitor
Target id:
/biomarker/lipid-panel
Target name:
Lipid Panel
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Progesterone can have variable effects on lipid profiles, sometimes slightly increasing LDL and decreasing HDL cholesterol in some individuals.
Actionable advice:
Periodically monitor your lipid panel when on long-term progesterone therapy.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
increased triglycerides
Label source:
FDA label: Conjugated estrogens/medroxyprogesterone acetate (PREMPRO/PREMPHASE)
Action type:
monitor