Estriol (E3)

What It Is

Estriol (E3) is the weakest and gentlest form of estrogen in the human body. While estradiol (E2) is the powerhouse and estrone (E1) is the steady post-menopausal workhorse, estriol is the gentle, protective form that dominates during pregnancy and is sometimes used in hormone therapy for its milder effects.

Why it's called E3:

• The "E" stands for estrogen
• The "3" refers to its chemical structure (it has three hydroxyl groups, compared to estradiol's two and estrone's one)
• It's one of three estrogens in the estrogen family: Estradiol (E2), Estrone (E1), and Estriol (E3)

Where it's produced:

During pregnancy:

• Placenta → primary source (produces massive amounts of estriol, especially in the third trimester)
• Fetal liver → contributes to estriol production (DHEA from fetal adrenals is converted to estriol in placenta)
• Estriol levels during pregnancy → rise from about 2 ng/mL in early pregnancy to 20-30 ng/mL in late pregnancy (this is 1000-10,000 times higher than non-pregnant levels)

During non-pregnant adult life:

• Ovaries → minimal production (trace amounts)
• Liver → converts estradiol and estrone to estriol during metabolism
• Peripheral tissues → small amounts produced during estrogen metabolism
• Gut bacteria → can convert estrone and estradiol metabolites to estriol

After menopause:

• Estriol production is minimal → primarily from metabolism of estradiol and estrone
• Not a significant source of estrogenic activity after menopause (unless supplemented)

Key insight:

Estriol is the "pregnancy estrogen." It's not a major player in non-pregnant women, but it becomes the dominant estrogen during pregnancy (even higher than estradiol). Its role is to support pregnancy, fetal development, and prepare the body for childbirth and breastfeeding.

What makes estriol different from other estrogens:

Estriol (E3) vs. Estradiol (E2):

• E3 is about 80 times weaker than E2 → binds much less strongly to estrogen receptors, creates very gentle effects
• E2 is dominant during reproductive years → ovaries produce high levels
• E3 is dominant only during pregnancy → placenta produces massive amounts
• E3 has a shorter half-life → leaves the body faster than E2 (within hours vs. 12-24 hours for E2)
• E3 is considered more "selective" → preferentially binds to ER-beta receptors (which may be more protective) over ER-alpha (which is more proliferative)

Estriol (E3) vs. Estrone (E1):

• E3 is about 8 times weaker than E1 → E1 is already weaker than E2, and E3 is even weaker
• E1 becomes dominant after menopause → produced by fat tissue and adrenals
• E3 is not a significant post-menopausal estrogen → unless supplemented
• E3 has different metabolic pathways → doesn't convert to E1 or E2 (it's a "metabolic end product")

Why estriol is called the "protective" or "gentle" estrogen:

Receptor selectivity:

• Estriol preferentially binds to ER-beta receptors → these receptors are more abundant in brain, bones, blood vessels, bladder, and are considered more "protective"
• ER-alpha receptors (more abundant in uterus, breast tissue) → more proliferative (stimulate cell growth)
• ER-beta receptors → may have anti-inflammatory, neuroprotective, anti-proliferative effects
• This means estriol provides estrogenic benefits (especially in brain, bones, bladder) with less stimulation of breast and uterine tissue → potentially lower cancer risk

Weak potency:

• Because estriol is so weak, it provides gentle estrogenic activity without the intensity of estradiol
• This can be beneficial for women who want symptom relief without strong estrogen effects
• However, the weakness also means higher doses are needed to achieve symptom relief comparable to estradiol

Primary functions of estriol:

During pregnancy:

• Supports uterine blood flow → increases blood supply to uterus and placenta
• Prepares cervix for birth → softens and ripens cervix
• Supports fetal development → works with other hormones to support pregnancy
• Protects mother's brain → some research suggests estriol has neuroprotective effects during pregnancy
• Supports breast development → prepares breasts for milk production

During non-pregnant reproductive years and menopause (when supplemented):

• Vaginal and urinary health → estriol is highly effective for genitourinary symptoms (dryness, painful sex, urinary urgency/frequency)
• Mild bone support → provides some bone protection, though less than estradiol
• Brain and cognitive support → may support memory, mood, neuroprotection (via ER-beta receptors)
• Skin health → supports collagen, moisture, elasticity (though less potently than estradiol)
• Mild cardiovascular support → some protective effects on blood vessels
• Does not significantly stimulate breast or uterine tissue → potentially safer for women with breast cancer risk (though this is debated)

Why It Matters During Perimenopause/Menopause

Estriol is not a major player during perimenopause and menopause—unless you supplement it.

During reproductive years:

• Estriol is produced in trace amounts (typically <2-3 pg/mL)
• It's a metabolic byproduct of estradiol and estrone breakdown
• It has minimal biological activity at these low levels

During perimenopause:

• Estriol levels remain very low (since it's not produced by ovaries in significant amounts)
• Estriol does not fluctuate like estradiol and progesterone do
• It's not responsible for perimenopausal symptoms (those are due to estradiol and progesterone changes)

During menopause:

• Estriol remains very low (often <1-2 pg/mL)
• It's not a significant source of estrogenic activity after menopause (unlike estrone, which becomes dominant)
• However, estriol can be supplemented as part of bioidentical hormone therapy (BHRT)

Why estriol supplementation is used in menopause:

1. Vaginal and urinary symptoms:

• Estriol is highly effective for genitourinary syndrome of menopause (vaginal dryness, painful sex, urinary urgency, recurrent UTIs)
• Local vaginal estriol (cream, tablet, pessary) provides symptom relief with minimal systemic absorption → very safe
• Why estriol is preferred for vaginal use: It's gentle, effective, and has minimal systemic effects (doesn't significantly raise blood estrogen levels)

2. Bioidentical hormone therapy (BHRT):

• Some practitioners use "Biest" or "Triest" formulations:
  • Biest = 80% estriol + 20% estradiol (or other ratios)
  • Triest = 80% estriol + 10% estradiol + 10% estrone (or other ratios)
• Rationale: Combining estriol with estradiol may provide symptom relief with potentially lower cancer risk (since estriol is gentler and more ER-beta selective)
• Evidence is limited: There are no large, long-term studies proving Biest/Triest is safer or more effective than estradiol alone
• Some women prefer it for philosophical reasons ("more natural," "more like pregnancy") or because they feel better on it

3. Potential breast cancer risk reduction:

• Hypothesis: Estriol's ER-beta selectivity and weak potency may make it safer for breast tissue
• Some animal studies suggest estriol may even be protective against breast cancer (by occupying estrogen receptors without strongly stimulating cell growth)
• Human evidence is very limited → no large randomized controlled trials
• Current consensus: Estriol is not proven to be safer than estradiol for breast cancer risk, but it may be an option for women who want gentler estrogen therapy

4. Neuroprotection:

• Estriol's ER-beta activity may provide brain protection with less proliferative risk
• Some small studies suggest estriol may improve cognitive function in post-menopausal women
• More research needed

The estriol controversy:

Proponents say:

• Estriol is "natural" (it's what the body makes during pregnancy)
• It's gentler and safer than estradiol (less proliferative)
• It's effective for vaginal/urinary symptoms with minimal systemic effects
• It may reduce breast cancer risk (compared to estradiol)

Skeptics say:

• There's no large-scale evidence that estriol is safer than estradiol
• Estriol is so weak that you need much higher doses to get symptom relief (and at high doses, is it really "safer"?)
• Vaginal estradiol is just as effective and well-studied as vaginal estriol
• The "bioidentical" label can be misleading (estriol is often compounded, which has quality control issues)
• Estriol is not FDA-approved for systemic use in the US (though vaginal estriol is available in some countries and can be compounded)

Bottom line:

• Vaginal estriol is well-accepted and effective for genitourinary symptoms
• Systemic estriol (Biest/Triest) is more controversial → some practitioners love it, others stick with estradiol
• Evidence is limited → choose based on symptoms, preferences, clinician expertise, and individual response

How It Works

Mechanism of action:

Estriol works the same way as estradiol and estrone—by binding to estrogen receptors (ER-alpha and ER-beta) throughout the body and brain. When estriol binds to a receptor, it triggers changes in gene expression.

However, estriol binds much more weakly than estradiol:

• Very low binding affinity → estriol doesn't "stick" to estrogen receptors as tightly as estradiol (about 1/80th the affinity)
• Weaker activation → even when bound, estriol doesn't activate the receptor as strongly as estradiol
• Shorter duration → estriol has a short half-life (a few hours) compared to estradiol (12-24 hours) → it's cleared from the body quickly
• Result: Estriol creates very gentle, short-lived effects → must be dosed more frequently (often twice daily) for sustained activity

Estriol's receptor preferences:

ER-beta selectivity:

• Estriol preferentially binds to ER-beta receptors (though it's not exclusively ER-beta selective)
• ER-beta is primary in: brain, bones, blood vessels, bladder, ovaries, prostate tissue
• ER-beta effects: neuroprotection, anti-inflammation, cardiovascular protection, bladder health
• This is why estriol is considered "protective" → it activates receptors associated with health benefits without strongly activating proliferative receptors (ER-alpha in breast and uterus)

ER-alpha binding (weaker):

• Estriol binds to ER-alpha (in uterus, breast tissue) but much more weakly than estradiol
• Lower proliferative activity → less stimulation of breast and uterine tissue (potentially lower cancer risk)
• However, at high doses, estriol can still stimulate these tissues → the "safety" is dose-dependent

What this means:

Estriol provides selective estrogenic activity—more activity in brain, bones, bladder, blood vessels (ER-beta) and less in breast and uterus (ER-alpha). This is the theoretical basis for why estriol might be safer, though human evidence is limited.

Estriol metabolism:

Estriol is a metabolic end product—meaning it doesn't convert to estradiol or estrone. It's broken down and excreted.

Metabolic pathway:

• Estriol is primarily metabolized in the liver (like other estrogens)
• It's conjugated (attached to glucuronide or sulfate molecules) to make it water-soluble
• It's excreted via urine and bile (into gut, then stool)
• Gut bacteria can deconjugate estriol → some is reabsorbed (enterohepatic recirculation), but most is excreted

Estriol does not significantly convert to other estrogens:

• Unlike estrone and estradiol (which can convert back and forth), estriol is a "dead end" metabolically
• This means estriol supplementation doesn't significantly raise estradiol or estrone levels
• This is part of the appeal → estriol provides estrogenic activity without adding to the pool of more potent estrogens

Estriol's relationship with other hormones:

Estriol + Estradiol:

• No significant conversion between the two
• If using Biest (estriol + estradiol), they act independently → estradiol provides potent estrogenic activity, estriol adds gentler, ER-beta-selective activity
• Estriol may modulate estradiol's effects → by occupying some estrogen receptors with weak activity, estriol may reduce estradiol's proliferative effects (this is theoretical)

Estriol + Estrone:

• No significant conversion between the two
• Independent actions

Estriol + Progesterone:

• If you have a uterus and are using systemic estriol (Biest/Triest), you still need progesterone to protect the uterine lining
• Even though estriol is weak, unopposed estriol can stimulate uterine lining (especially at high doses)
• Vaginal estriol does not require progesterone (systemic absorption is minimal)

Estriol + Testosterone:

• No direct interaction
• Both support sexual function → estriol supports vaginal tissue health, testosterone supports libido and arousal

What It Looks Like

When Optimal (Healthy Estriol Levels)

During pregnancy:

This is when estriol is naturally high and doing its job:

Physical:

• Healthy pregnancy progression → adequate blood flow to uterus and placenta
• Cervical ripening → cervix softens in preparation for birth
• Breast development → breasts prepare for milk production
• Skin changes → "pregnancy glow" (partly due to increased blood flow, partly due to estriol and other hormones)

Cognitive:

• "Mommy brain" but also neuroprotection → some research suggests estriol protects maternal brain during pregnancy

Emotional:

• Varied → estriol is one of many hormones during pregnancy affecting mood

During menopause (if supplementing estriol):

Physical:

• Vaginal and urinary health → moist, elastic vaginal tissue; reduced urinary urgency/frequency; fewer UTIs
• Mild bone support → some bone density protection (though less than estradiol)
• Skin health → improved moisture, elasticity, collagen (though less than estradiol)
• No significant breast or uterine stimulation (at typical doses) → potentially safer

Cognitive:

• Mild cognitive support → improved memory, focus (though effects are subtle)
• Mood stability → gentle mood support

Emotional:

• Calm, stable → estriol doesn't create the intensity or fluctuation of estradiol

Key insight:

"Optimal estriol" in menopause means gentle, targeted symptom relief (especially vaginal/urinary) without the intensity of estradiol. It's a "soft landing" for women who want estrogen support but prefer gentler effects.

When Low (Estriol Deficiency)

Estriol deficiency in non-pregnant adults is not a clinical concern because estriol is not a major hormone outside of pregnancy.

However, low estriol during pregnancy can indicate problems:

During pregnancy:

• Low estriol in maternal serum or urine → may indicate fetal distress, placental insufficiency, or chromosomal abnormalities (like Down syndrome)
• Unconjugated estriol (uE3) is part of prenatal screening (quad screen, triple screen) to assess fetal health
• Low estriol requires follow-up → ultrasound, amniocentesis, or other testing

During menopause (if not supplementing):

• Low estriol is normal and expected → it's not a deficiency state
• Symptoms are due to low estradiol, not low estriol → hot flashes, night sweats, brain fog, mood changes are due to estradiol loss
• Vaginal/urinary symptoms are due to low estrogen overall (primarily estradiol) → these can be treated with estriol supplementation

When High (Estriol Excess)

Estriol excess in non-pregnant adults is only relevant if supplementing estriol:

If using high-dose estriol (Biest/Triest):

Physical:

• Breast tenderness → even though estriol is weak, high doses can stimulate breast tissue
• Uterine stimulation → high-dose estriol can thicken uterine lining (endometrial hyperplasia) if unopposed by progesterone
• Bloating, water retention → estriol affects fluid balance (though less than estradiol)
• Nausea → some women experience nausea with estriol (especially oral)

Emotional:

• Mood changes → high estriol can affect mood, though less dramatically than estradiol

What to do if estriol feels too high:

• Reduce dose → work with prescriber to find lowest effective dose
• Consider switching to estradiol → may provide better symptom relief at lower doses (since it's more potent)
• If you have a uterus, ensure adequate progesterone → protects uterine lining

During pregnancy:

Very high estriol is normal in late pregnancy (20-30 ng/mL or higher). This is not a concern—it's physiological.

Phase Impact

Baseline (Regular Cycle, Pre-Perimenopause): Estriol is present in trace amounts (<2-3 pg/mL). It's a metabolic byproduct of estradiol and estrone. No significant biological activity at these levels. Not a factor in menstrual cycle symptoms or function.

Electric Cougar (Early Perimenopause): Estriol remains at trace levels. Does not fluctuate with estradiol and progesterone. Not a factor in perimenopausal symptoms (those are due to estradiol/progesterone changes). Women are not aware of estriol during this phase.

Wild Tide (Mid-Perimenopause): Estriol remains at trace levels. No role in the erratic symptoms of this phase. Estradiol and progesterone are the "main characters"—estriol is a background player with no speaking role.

Henapause (Late Perimenopause, 7-11 Months Without Period): Estriol remains at trace levels. Not a factor in intensifying symptoms. However, if a woman chooses to start vaginal estriol at this stage, it can be highly effective for vaginal dryness and urinary symptoms.

The Pause (Menopause, 12+ Months Without Period): Estriol remains at very low levels (<1-2 pg/mL) unless supplemented. If using vaginal estriol, symptoms like vaginal dryness, painful sex, and urinary urgency improve significantly. If using systemic estriol (Biest/Triest), it provides gentle estrogenic support.

Phoenix Phase (Early Post-Menopause, 2-10 Years After Last Period): Estriol remains at very low levels unless supplemented. Vaginal estriol continues to be effective for genitourinary symptoms. Systemic estriol (if used) provides ongoing gentle support for bones, brain, skin, cardiovascular health.

Golden Sovereignty (Established Post-Menopause, 7+ Years After Last Period): Estriol remains at very low levels unless supplemented. Long-term vaginal estriol use is safe and effective for genitourinary symptoms. Long-term systemic estriol use (Biest/Triest) is less studied, but some women continue it for years with good results.

Testing & Optimization

When to Test

Testing estriol levels is rarely necessary in non-pregnant adults, except in specific situations:

When estriol testing makes sense:

During pregnancy:

• Prenatal screening → unconjugated estriol (uE3) is part of quad screen/triple screen to assess fetal health
• If low estriol is detected → follow-up with ultrasound, amniocentesis, or other testing to rule out chromosomal abnormalities or placental issues

During menopause (if using estriol supplementation):

• If using Biest/Triest → some practitioners test estriol levels to ensure they're in therapeutic range (though this is not standard practice)
• If symptoms persist despite estriol therapy → testing may show that estriol levels are too low → need higher dose or switch to estradiol
• If side effects occur → testing may show estriol levels are too high → need lower dose

Estriol is not routinely tested in menopause because:

• It's naturally very low in non-pregnant adults (this is normal, not a deficiency)
• Symptoms are due to low estradiol, not low estriol
• If you're not supplementing estriol, there's no reason to test it

What tests measure:

• Serum estriol (blood test) → measures estriol in blood (results in pg/mL or ng/mL)
• Urine estriol → measures estriol in urine (24-hour collection or spot urine)
• Unconjugated estriol (uE3) → specific test used in prenatal screening

Typical reference ranges:

• Non-pregnant, pre-menopausal: <2-3 pg/mL
• Post-menopausal (not supplementing): <1-2 pg/mL
• Pregnant (third trimester): 2-30+ ng/mL (1000-10,000 times higher than non-pregnant)
• On estriol therapy: Varies depending on dose and formulation (no established "optimal" range)

Optimization Strategies

Since estriol is not naturally produced in significant amounts outside of pregnancy, "optimization" means supplementation:

1. Vaginal Estriol (for genitourinary symptoms)

This is the most well-established use of estriol in menopause:

What it treats:

• Vaginal dryness, irritation, atrophy
• Painful sex (dyspareunia)
• Urinary urgency, frequency, incontinence
• Recurrent urinary tract infections (UTIs)
• Vaginal pH changes (less acidic → more prone to infections)

Formulations:

• Estriol cream (0.03-0.5 mg per application) → applied vaginally with applicator
• Estriol pessaries/tablets (0.03-2 mg) → inserted vaginally
• Estriol ovules (similar to pessaries)

Dosing:

• Initial treatment: Daily for 2-4 weeks (to restore tissue health)
• Maintenance: 2-3 times per week (to sustain tissue health)
• Some women need daily long-term → individualize based on symptoms

Safety:

• Vaginal estriol has minimal systemic absorption → blood estrogen levels remain very low
• Does not require progesterone (even if you have a uterus) → systemic absorption is too low to stimulate uterine lining
• Safe for long-term use → no time limit
• May be safer than vaginal estradiol for women with breast cancer history (though this is debated; both are generally considered safe for vaginal use)

Effectiveness:

• Highly effective → 80-90% of women report significant improvement in vaginal and urinary symptoms
• Comparable to vaginal estradiol → both work well; choice is based on availability, cost, and personal preference

2. Systemic Estriol (Biest/Triest for systemic symptoms)

This is more controversial and less studied than vaginal estriol:

What it's used for:

• Hot flashes, night sweats
• Mood, cognitive, sleep issues
• Bone health
• Skin, joint health
• Cardiovascular health
• Alternative to estradiol for women who want gentler estrogen therapy

Formulations:

• Biest (bi-estrogen): typically 80% estriol + 20% estradiol (though ratios vary; some use 50:50 or other combinations)
• Triest (tri-estrogen): typically 80% estriol + 10% estradiol + 10% estrone
• Estriol alone (less common; usually combined with estradiol for better symptom relief)
• Delivery: cream, gel, capsule, sublingual troches (usually compounded, not FDA-approved in US)

Dosing:

• Varies widely depending on formulation and ratio
• Example Biest dose: 1-5 mg total (0.8-4 mg estriol + 0.2-1 mg estradiol), applied once or twice daily
• Requires individualization → start low, titrate based on symptoms and labs

Effectiveness:

• Some women report excellent results → symptom relief with gentler effects than estradiol alone
• Some women find it less effective than estradiol → need to switch to estradiol or increase estradiol percentage
• Limited research → no large randomized controlled trials comparing Biest to estradiol

Safety:

• Not proven to be safer than estradiol → no large studies showing lower breast cancer risk or other risks
• Theoretically may be safer due to ER-beta selectivity and weaker potency, but this is unproven
• Still requires progesterone if you have a uterus → even gentle estrogen can stimulate uterine lining
• Quality control concerns → Biest/Triest are usually compounded (not FDA-regulated) → variability in quality, potency, purity

Risks:

• Same risks as estradiol (blood clots, stroke, breast cancer) cannot be ruled out → assume similar risk profile until proven otherwise
• Compounding variability → dose may not be consistent batch to batch

Who might prefer Biest/Triest:

• Women who want "bioidentical" hormones (though estradiol is also bioidentical if FDA-approved)
• Women who want gentler estrogen effects
• Women with breast cancer risk factors who are nervous about estradiol (though evidence for safety is lacking)
• Women who tried estradiol and didn't feel well on it (sometimes switching to Biest helps)

Who should stick with estradiol:

• Women who want FDA-approved, well-studied hormones
• Women who need more potent symptom relief (estradiol is more effective per mg)
• Women who want consistent dosing and quality control

3. Lifestyle Strategies (not specific to estriol, but support overall estrogen balance)

Since estriol is not naturally produced in significant amounts, lifestyle doesn't directly "optimize" estriol. However, these strategies support overall estrogen health:

• Healthy body composition → supports estrone production (from fat tissue), which provides baseline estrogenic activity
• Stress management → supports adrenal health (adrenals produce androgens that convert to estrone)
• Gut health → healthy gut bacteria support estrogen metabolism and excretion
• Liver health → liver metabolizes all estrogens, including estriol
• Avoid xenoestrogens → environmental estrogens (plastics, pesticides) can disrupt estrogen balance

4. Combining Estriol with Estradiol

Some practitioners recommend adding estriol to estradiol therapy (rather than replacing estradiol with Biest):

Rationale:

• Get the potency of estradiol for symptom relief
• Add the ER-beta selectivity of estriol for potential neuroprotection, bladder health, and gentler effects
• May reduce estradiol dose needed → if estriol occupies some receptors, you may need less estradiol

Example regimen:

• Vaginal estriol (for genitourinary symptoms) + systemic estradiol (patch or gel for hot flashes, bone health, mood)
• Oral or transdermal Biest (combining estriol and estradiol)

Evidence:

• Limited → no large studies comparing this approach to estradiol alone
• Anecdotal reports are mixed → some women love it, others don't notice a difference

When to Review with Clinician

You should discuss estriol if:

Vaginal or urinary symptoms:

• Vaginal dryness, painful sex → vaginal estriol is highly effective
• Urinary urgency, frequency, incontinence → vaginal estriol can help
• Recurrent UTIs → vaginal estriol reduces UTI risk by restoring healthy vaginal pH and flora

Interest in bioidentical hormone therapy (BHRT):

• Want to explore Biest/Triest → discuss risks, benefits, evidence (or lack thereof) with knowledgeable clinician
• Prefer "gentler" estrogen therapy → estriol may be an option, though estradiol at low doses is also gentle
• Concerned about breast cancer risk → discuss whether estriol is truly safer (evidence is lacking)

Currently using estriol and want to reassess:

• Symptoms persist → may need higher dose, different formulation, or switch to estradiol
• Side effects → may need lower dose or different formulation
• Wondering about long-term safety → discuss risks, benefits, and monitoring

Pregnancy-related:

• Low estriol on prenatal screening → requires follow-up to assess fetal health

Red flags requiring immediate medical attention:

• Vaginal bleeding after menopause (if using systemic estriol and have a uterus without progesterone) → could indicate endometrial hyperplasia or cancer
• Severe pelvic pain, unusual discharge → could indicate infection or other issue
• Chest pain, shortness of breath, leg pain/swelling (if using systemic estriol) → possible blood clot (though risk is thought to be low with estriol, it can't be ruled out)

Related Terms

• estrogen
• estradiol-e2
• estrone-e1
• progesterone
• vaginal-dryness
• painful-sex
• urinary-urgency
• menopause
• perimenopause
• bioidentical-hormone-therapy