estriol
Regulatory sources consulted
Approved indications
- Symptoms of vaginal atrophy due to estrogen deficiency in postmenopausal women.
- Preoperative and postoperative therapy for vaginal surgery in postmenopausal women.
Contraindications
Absolute
- Current, previous, or suspected breast cancer; estrogen-dependent malignancy; undiagnosed vaginal bleeding; untreated endometrial hyperplasia.
- Current or previous venous thromboembolism, known thrombophilia, or active or recent arterial thromboembolic disease.
- Acute liver disease or history without normalization, porphyria, or hypersensitivity.
Clinical warnings
- Major warning · Use the lowest effective dose for the shortest duration and review at least annually. Evaluate any unexpected vaginal bleeding and cancer, thromboembolism, and liver disease history. — CIMA/AEMPS, ficha técnica 57467
- Major warning · Although systemic absorption with twice-weekly maintenance is low, hormone-therapy class risks must be considered, and thrombosis or jaundice requires discontinuation and assessment. — CIMA/AEMPS, ficha técnica 57467
Drug interactions
- ModerateOther local vaginal treatments and enzyme inducers
Mechanism: Vaginal products may interact locally; inducers may increase estrogen metabolism, although systemic absorption is low.
Recommendation: Review concomitant vaginal treatments and monitor response or bleeding.
CIMA/AEMPS, ficha técnica 57467https://cima.aemps.es/cima/dochtml/ft/57467/FT_57467.html
Adverse events
Common (≥1%)
Breast discomfort or pain, postmenopausal spotting, or vaginal discharge (uncommon) · Application-site irritation or pruritus (uncommon) · Genital burning or vulvovaginal stinging (frequency unknown) · Flu-like symptoms, dysuria, fluid retention, or nausea (frequency unknown)
Rare but serious
Headache, visual disturbances, hypertension, or leg cramps (rare) · Venous or arterial thromboembolism · Endometrial, breast, or ovarian cancer associated with systemic hormone exposure
Pregnancy and lactation
It is indicated only for postmenopausal women. Do not use during pregnancy; discontinue immediately if pregnancy occurs. It is not indicated while breastfeeding; estriol passes into milk and may reduce milk production.
Recent literature (PubMed)
Estrogens (estradiol, estriol, and estrone) are important hormones that directly and indirectly regulate the metabolism and function of bone and skeletal muscle via estrogen receptors. Menopause causes a dramatic reduction in the concentration of estrogen in the body. This contributes to a decline in bone and skeletal muscle function, thereby resulting in osteoporosis and sarcopenia. Menopausal women often experience osteoporosis and muscle wasting, and clinicians recognize estrogen as playing an important role in these conditions, particularly in women. Bone and muscle are closely related endocrine tissues that synthesize and produce various cytokines. These bone- and muscle-derived cytokines, including interleukin-6, irisin, β-aminoisobutyric acid, osteocalcin, fibroblast growth factor-23, and sclerostin, regulate both local and distant tissues, and they mediate the crosstalk between bone and skeletal muscle. This review examines the metabolic effects of estrogen on bone and skeletal muscle and describes cytokine-mediated bone-muscle crosstalk in conditions of estrogen deficiency.
Estrogens regulate important processes in reproductive, skeletal, cardiovascular, and central nervous systems that impact women's overall health. Understanding endogenous and exogenously administered estrogen metabolism is vital to determining therapeutic estrogen levels. The present review provides an overview of estrogen metabolites formed in non-pregnant and pregnant women, and those resulting from exogenous estrogen administration. There are four principal endogenous estrogens: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). E4, which is produced only in pregnancy, has emerged recently as an estrogen with significant therapeutic potential. E1, E2, and E3 undergo extensive metabolism primarily through phase I (hydroxylation, oxidation, reduction) and phase II (primarily conjugation) reactions, whereas E4 undergoes only phase II reactions. Exogenous estrogens commonly used for menopausal treatment and/or contraception, including micronized E2, conjugated equine estrogens, and ethinyl estradiol, also undergo phase I and phase II reactions, but differ widely in the types of metabolites formed. The mechanisms by which estrogen metabolites are formed and their excretion in urine, bile, and feces, are still poorly understood. We highlight areas that require further research to foster a better understanding of how estrogen metabolism impacts dosing of oral estrogens for therapeutic use, as well as the physiological regulation of endogenous estrogens.
To summarize the literature on the rediscovery and clinical exploration of the fourth natural estrogen estetrol (E4), more than 100 years after the discovery of estrone (E1), estradiol (E2), and estriol (E3). Literature review of E4 publications. Preclinical and clinical research and development of E4 revealed that: (1) contrary to the other 3 natural estrogens, E4 has a high oral bioavailability, and (2) oral E4 has limited effect on hemostasis and other liver functions, and is, therefore, expected to be a safer estrogen. Since 2022, E4 combined with drospirenone has been registered worldwide as an oral contraceptive. E4 for menopausal hormone therapy is expected to become available in 2026. Clinical development of the use of E4 for the treatment of advanced breast cancer and advanced prostate cancer is ongoing, and E4 has been proposed as a component of an oral male contraceptive. The recognition of E4 as a useful and safe natural estrogen for human use is expected to change the scene of estrogen treatment in women and men significantly.
This review investigated the impact of probiotics during the menopause transition and explored their potential to enhance the effectiveness of estrogenic substances in perimenopausal or recently postmenopausal women. A thorough literature search of EMBASE, MEDLINE, Cochrane Library, Scopus, and Web of Science was conducted, identifying 39 studies involving 3187 women. Quality assessments were conducted using the relevant Cochrane Risk of Bias tools. The results demonstrated that probiotics had positive effects on menopausal symptoms, urogenital health, bone health, and the efficacy and safety of estriol and isoflavones. Meta analysis of 7 studies comparing probiotics versus placebo demonstrated large effects of probiotics on menopausal symptoms (total score) [standardized mean difference (SMD) = 0.82, 95 % CI -0.52 to -1.09], vasomotor symptoms (SMD = -0.96, 95 % CI -1.25 to -0.68), psychological symptoms (SMD = -0.51, 95 % CI -0.95 to -0.08), vaginal dryness (SMD = 0.95, 95 % CI -1.40 to -0.49), and vaginal microbiome health (Nugent score) (SMD = -0.91, 95 % CI -1.32 to -0.49). Meta-analysis results were nonsignificant for reducing somatic and sexual symptoms. Probiotics hold promise in addressing symptoms related to low estrogen levels and may enhance the effects of estriol and isoflavones, offering potential benefits as part of the management of menopausal women. It's important to note that the included studies had a high risk of bias, emphasising the need for further rigorous research in this area. Should findings continue to show promise, clinicians should consider incorporating probiotics into their strategies for managing menopausal symptoms. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42019146270.