When the media talks about hormone therapy, “estrogen” is often treated as a single hormone. In reality, estrogen therapy comes in several forms, each with its own unique role. Two of the most commonly prescribed bioidentical estrogens are estradiol (E2) and estriol (E3). Understanding how these two bioidentical hormones differ can help explain why providers may choose one, the other, or a combination of both.
Estriol vs Estradiol
Estradiol is the overachiever that gets most of the attention. It’s potent, widely studied, and responsible for many estrogenic hallmark effects throughout the body. Estriol, meanwhile, stays out of the spotlight with its gentler and more localized effects. And yet, it plays an important therapeutic role particularly in vaginal and urogenital health that can often be overlooked.
An estrogen’s strength is mostly determined by how tightly it can bind to a receptor. Estriol and estradiol exhibit distinct binding affinities to the two primary types of estrogen receptors. Estrogen receptor alpha (ERɑ) and estrogen receptor beta (ERβ) are widely distributed across various tissues but at different levels of expression.
Estradiol (E2) is the primary estrogen during a woman’s reproductive years, while estriol (E3) is the predominant estrogen during pregnancy. Estradiol has the strongest binding affinity for both receptors, with the capacity to produce powerful, systemic effects. In contrast, estriol creates weaker bonds (favoring ERβ slightly), disassociating quickly thereby eliciting shorter-lived effects.
Estradiol: The Most Widely Used Form of Estrogen
Estradiol tends to get all the glory and recognition as it is the most widely used and included form of estrogen in medical guidelines. It’s no surprise why—as the most potent and powerful form of estrogen, it’s known to strongly activate estrogen receptors with well-researched effects on the heart, bone, reproductive function, and metabolic health. Often prescribed to address menopausal symptoms, like hot flashes and night sweats, as well as benefit mood stability and sleep quality, it’s the cornerstone of systemic bioidentical hormone replacement therapy (BHRT).
But with great power comes great responsibility. Estradiol therapy may promote proliferative effects in certain estrogen-sensitive tissues, such as the endometrium, prompting appropriate use of progesterone therapy to mitigate this biological activity in patients with a uterus.
Estriol: Ideal for Localized Vaginal and Urogenital Use
When local tissue is exposed to a concentrated amount of estriol, the hormone can continuously occupy and activate the receptors, which compensates for its rapid disassociation. This explains why estriol is uniquely suited for vaginal and urogenital targets and has demonstrated meaningful local estrogenic effects with sustained exposure.
Case in point: Genitourinary Syndrome of Menopause (GSM), an all-encompassing term for the external genital, sexual, and urological problems affecting women in perimenopause and beyond, often warrants local intervention. Triggered by hormonal imbalances, estrogen’s drastic drop sets off a cascade of undesirable symptoms.
Prior to menopause, vaginal flora (lactobacilli) break down glycogen from vaginal epithelial cells into glucose, which can then be metabolized into lactic acid—acid that helps maintain a low vaginal pH. But as vaginal tissue thins due to lack of estrogen, depleting glycogen stores causes good bacteria to suffer and pH to climb, promoting growth of harmful bacteria. These microbiota and vaginal pH changes contribute to postmenopausal susceptibility to infection, particularly to urinary tract infections (UTIs).
In a recent randomized, double-blind, placebo-controlled trial, over 100 postmenopausal women with a history of recurrent urinary tract infections were randomly assigned ultra-low-dose 0.005% estriol vaginal gel or placebo for 24 weeks. Applied daily for the first 3 weeks, then twice weekly thereafter, results reflect estriol’s potential to restore vaginal flora and pH.
The women in the study using estriol gel had 26% fewer UTIs compared to placebo and experienced an 8% reduction in vaginal pH. Most of the women in the estriol gel group suffered no UTIs at all (87% in fact), while the remaining 13% only had one.
Addressing GSM at the Source
For postmenopausal women with GSM, estrogen deprivation can additionally lead to decreases in skin elasticity, blood flow, and secretions. These shifts cause the vaginal lining to become fragile and flattened as the tissue breaks down, exacerbating irritation and dryness as well as intensifying sexual discomfort.
HRT for menopause like vaginal estriol creams can strengthen the vaginal mucosa and improve secretions to help alleviate vulvovaginal symptoms such as tissue thinning, itching, painful intercourse (dyspareunia), and dryness.
In another randomized, double-blind, placebo-controlled trial, 61 postmenopausal women with hormone-receptor-positive early breast cancer receiving nonsteroidal aromatase inhibitors were randomly assigned ultra-low-dose 0.005% estriol vaginal gel or placebo for 12 weeks. The gel was applied daily for the first 3 weeks, then twice weekly thereafter.
Estriol gel significantly improved vaginal symptoms, tissue health, vaginal maturation index and pH, enhancing sexual function in the process.
What About the Black Box Warning?
If you somehow missed the recent plot twist, FDA proposed several safety-related labeling changes to the black box warnings associated with estrogen therapies back in 2025. Today, the misleading boxed warnings for breast cancer, cardiovascular disease, stroke, and probable dementia are history. The FDA also went as far as to eliminate messaging that urged clinicians to use the lowest effective dose for the shortest duration. Although the risks that shaped hormone therapy discussions for decades have been right-sized, public concern lingers.
It’s hard to let go of limiting beliefs. And for patients who are hesitant to initiate BHRT or have a history of hormone-sensitive conditions, maintaining minimal systemic hormone exposure is important.
A recent systematic review of postmenopausal women revealed that vaginal estriol therapy shows no meaningful impact on systemic hormone levels. Estrone, estradiol, testosterone, progesterone, and sex hormone binding globulin (SHBG) were unaltered. Of course, the idea that estriol could be converted back to more potent estrogens is not possible, and all minor, transient increases in estriol were normalized within hours or days.
Of note, synthetic conjugated equine estrogen (CEE) therapy appears to paint a different picture. Unlike CEE, BHRT with estriol and estradiol are thought to elicit physiological responses similar to those of the body’s endogenous hormones, because they are structurally identical to the hormones produced naturally.
What Is Biest?
Plot twist: this isn’t really a story of estriol vs estradiol. Individualized BHRT allows providers to harness the benefits of both in a single formulation. Compounded biest (estriol/estradiol) is a combination of bioidentical estriol and estradiol. Typically prescribed at an 80:20 ratio of estriol (E3) to estradiol (E2), the combination is thought to mimic the body’s natural environment, giving both forms an opportunity to therapeutically shine.
When estriol is given in conjunction with estradiol, it serves as a counterbalance. It competes with estradiol for receptor binding and is thought to modulate the effects of the stronger estrogens. Competitive inhibition of estrone (E1) and estradiol (E2) binding to ERɑ is thought to mitigate tissue proliferation risks. In a sense, estriol acts as an estrogen and an anti-estrogen. And its slight preference for ERβ only serves to inhibit cell proliferation further. By customizing the ratio and strength of estriol to estradiol, providers can formulate bioidentical biest compounds to meet individual need.
Ultimately, estrogen selection is less about potency and more about purpose. Whether prioritizing systemic symptoms, local tissue, or a balance of both, personalized BHRT equips prescribers to take advantage of customizable dosage forms and delivery methods that play to estriol and estradiol’s strengths.
References
- Ali ES, Mangold C, Peiris AN. Estriol: emerging clinical benefits. Menopause. 2017 Sep;24(9):1081-1085.
- Biundo B. Establishing a Rationale for Compounding Hormone Replacement Therapy. Int J Pharm Compd. 2024 Jan-Feb;28(1):22-27.
- Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne). 2022 Aug 18;13:839005.
- Hirschberg AL, Sánchez-Rovira P, Presa-Lorite J, Campos-Delgado M, Gil-Gil M, Lidbrink E, Suárez-Almarza J, Nieto-Magro C. Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial. Menopause. 2020 May;27(5):526-534.
- Kolokythas A, Betschart C, Wunder D, Janka H, Stute P. Impact of vaginal estriol on serum hormone levels: a systematic review. Climacteric. 2024 Apr;27(2):137-153.
- Muiños Fernández N, Martínez Salamanca JI, Pardo González de Quevedo JI, Diz Morales MP, Palomo Alameda L, Duce Tello S, González Béjar M, Rabanal Carrera A, Rosado Martín J, Noguera Vera L, Doyle Sanchez A, Rodríguez Mariblanca A, García Aguilar E. Efficacy and safety of an ultra-low-dose 0.005 % estriol vaginal gel in the prevention of urinary tract infections in postmenopausal women with genitourinary syndrome of menopause: A randomized double-blind placebo-controlled trial. Maturitas. 2024 Dec;190:108128.
- Paoletti JE. The Physiologic Role and Use of Estriol. Int J Pharm Compd. 2024 Jan-Feb;28(1):16-21.
- Sriprasert I, Hodis HN, Mack WJ, Rosser M, Evans ML, Xu X, Wright JD. Elimination of the Black Box Warning on Menopausal Hormone Therapy. Obstet Gynecol. 2026 May 1;147(5):642-646.
Reach Out to Belmar Pharmacy for Additional Information
If you are a prescriber and are interested in prescribing these medications, please complete this form and a Belmar Solutions Engineer will reach out to you.
