Prescriber's Guide - Estriol Vaginal Cream
Prescriber's Guide

Estriol

Vaginal Cream

Estriol Vaginal Crea
WHAT IS ESTRIOL VAGINAL CREAM?

Estriol Vaginal Cream is a vaginally administered steroid and has been studied for the treatment of dyspareunia, dryness, itching, and urinary incontinence.1-8

HOW IS ESTRIOL COMPOUNDED?

Estriol vaginal cream is commonly compounded in a hypoallergenic base in following strengths:

  • 0.5mg/ml
  • 1mg/ml
HOW DOES ESTRIOL WORK IN THE BODY?

Estriol contains the natural female hormone estriol. Unlike other estrogens, estriol is short acting since it has only a short retention time in the nuclei of endometrial cells. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms.5, 12

In case of postmenopausal women with atrophy of the lower urogenital tract, estriol induces the normalization of the urogenital epithelium and helps to restore the normal microflora and the physiological pH in the vagina. As a result, it increases the resistance of the urogenital epithelial cells to infection and inflammation reducing vaginal complaints such as dyspareunia, dryness, itching, vaginal and urinary infections, micturition complaints and mild urinary incontinence.1-8

WHICH CONDITION(S) HAS ESTRIOL BEEN STUDIED FOR?
  • For the treatment of vaginal complaints such as dyspareunia, dryness, and itching.1-8
  • Pre- and post-operative therapy in postmenopausal women undergoing vaginal surgery.13
  • Postmenopausal women with hormone-receptor positive breast cancer receiving nonsteroidal aromatase inhibitors.1
WHAT ARE THE RESULTS OF THE CLINICAL STUDIES?
Vaginal Dryness, Atrophy, Pain During Intercourse

Estriol has consistently shown relief from vaginal dryness, atrophy, as well as pain during sexual intercourse, normalizing vaginal flora and improving the maturity index.1-8

Postmenopausal Women, Receptor-Positive Breast Cancer

Low doses of Estriol have also been clinically shown to be effective in treatment of postmenopausal women suffering from vaginal atrophy undergoing aromatase inhibitor treatment.1

50 postmenopausal women with hormone receptor-positive breast cancer receiving nonsteroidal aromatase inhibitors received a 12-week course of low dose estriol 0.005% In a phase II, randomized, double-blind, placebo-controlled trial for evaluation of vaginal maturation, vaginal pH, and vulvovaginal atrophy. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Treatment also improved all domains of the Female Sexual Function Index (FSFI), with the exception of pain. At doses of 0.005%, estradiol and estrone levels remained mostly undetectable.1

Endometrial Hyperplasia

There is a reasonable amount of long-term data on estriol intravaginal treatment that doses are safe and do not present with endometrial hyperplasia.9, 10

AT WHICH DOSES HAS ESTRIOL BEEN STUDIED AND HOW SHOULD IT BE USED?

Estriol has been studied at a wide variety of strengths ranging from 0.05%1 to 1%3.

Administer Estriol vaginal cream intravaginally daily at bedtime for 2-3 weeks, then decrease to 2-3 times weekly.

WHICH SIDE EFFECTS MAY BE CAUSED BY ESTRIOL VAGINAL CREAM?

The following adverse reactions have been reported:

  • Fluid Retention
  • Nausea
  • Breast discomfort and pain
  • Postmenopausal spotting
  • Cervical Discharge
  • Application site irritation and pruritis
  • Flu like symptoms
WHAT PRECAUTIONS SHOULD BE KEPT IN MIND WHEN PRESCRIBING ESTRIOL VAGINAL CREAM?

Current or Past History of Breast Cancer. Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer.**

** Recent trials indicate benefits for vaginal atrophy in hormone receptor positive breast cancer undergoing aromatase inhibitor therapy.1

IS ESTRIOL SAFE DURING PREGNANCY AND CAN I USE IT WHEN BREASTFEEDING?
Pregnancy

This medicine is contraindicated during pregnancy.
If pregnancy occurs during medication with Estriol, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to estrogens indicate no teratogenic or fetotoxic effects.

Lactation

Estriol is not indicated during lactation. Estriol is excreted in breast milk and may decrease milk production.

WHEN SHOULD ESTRIOL NOT BE PRESCRIBED?
  • Prengnacy
  • Lactation
  • Undiagnosed Vaginal Bleeding
  • Current or Past History of Breast Cancer**
WILL ESTRIOL INTERACT WITH OTHER DRUGS AND IF SO HOW?

Use with caution with medications that have thrombogenic or anticoagulant activities.

Estiol is a substate for Cyp 3A4 and PGP. Efficacy may be decreased with CYP 3A4 inducers (Phenytoin, Smoking, Oxcarbazepine, Phenobarbitol, Rifabutin, St. John’s Wort, etc.)

Estriol is a substrate for Cyp 3A4 and . Levels may increase with grapefruit juice, protease inhibitors, Azole anti-fungals, cimetidine, cyclosporin, cobistat, macrolides, amiodarone, verapamil, diltiazem, etc.)

HOW DOES ESTRIOL MOVE THROUGH THE HUMAN BODY?
Absorption

Intravaginal administration of estriol ensures optimal availability at the site of action. Estriol is also absorbed into the general circulation, as is shown by a sharp rise in the plasma levels of unconjugated estriol.

Distribution

Peak plasma levels are reached 1-2 hours after application. After vaginal application of 0.5 mg estriol, Cmax is approximately 100 pg/ml, Cmin is approximately 25 pg/ml and Caverage is approximately 70 pg/ml. After 3 weeks of daily administration of 0.5 mg vaginal estriol, Caverage has decreased to 40 pg/ml.

Metabolism

Nearly all (90%) estriol is bound to albumin in the plasma and in contrast with other estrogens, hardly any estriol is bound to sex hormone-binding globulin (SHBG). The metabolism of estriol consists principally of conjugation and deconjugation during the enterohepatic circulation.

Elimination

Estriol, being a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small part (±2 %) is excreted via the feces, mainly as unconjugated estriol.

WHAT CAN HAPPEN IF TOO MUCH ESTRIOL IS USED?

The acute toxicity of estriol in animals is very low. Overdosage with Estriol cream after vaginal administration is unlikely. However, in cases where large quantities are ingested, nausea, vomiting and withdrawal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.

HOW IS ESTRIOL VAGINAL CREAM STORED?
  • Keep tightly closed after each use
  • Keep out of reach from children.
  • Store in a cool and dry place.
REFERENCES
  1. Hirschberg, Angelica Lindén MD, PhD1; Sánchez-Rovira, Pedro MD, PhD2; Presa-Lorite, Jesús MD3; Campos-Delgado, Miriam MD4; Gil-Gil, Miguel MD5; Lidbrink, Elisabet MD, PhD6; Suárez-Almarza, Javier Pharm, BSND7; Nieto-Magro, Concepción MD, PhD7 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: May 2020 - Volume 27 - Issue 5 - p 526-534
  2. Barentsen R. The climacteric in The Netherlands: a review of Dutch studies on epidemiology, attitudes and use of hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol. 1996;64 Suppl:S7-S11.
  3. Ishiko O, Hirai K, Sumi T, Tatsuta I, Ogita S. Hormone replacement therapy plus pelvic floor muscle exercise for postmenopausal stress incontinence. A randomized, controlled trial. J Reprod Med. 2001;46(3):213-220.
  4. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993 Sep9; 329:753-6
  5. Melis GB, Cagnacci A, Bruni V, et al. Salmon calcitonin plus intravaginal estriol: an effective treatment for the menopause. Maturitas. 1996;24(1-2):83-90.
  6. Trevoux R, van der Velden WH, Popovic D. Ovestin vaginal cream and suppositories for the treatment of menopausal vaginal atrophy. Reproduction. 1982 Apr-Jun;6(2):101-6
  7. Yoshimura T, Okamura H. Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women. Maturitas. 2001 Sep28;39(3):253-7
  8. Bottiglione F, Volpe A, Esposito G, Aloysio DD. Transvaginal estriol administration in postmenopausal women:a double blind comparative study of two different doses. Maturitas. 1995Nov:22(3):227-32.
  9. Head KA. Estriol: safety and efficacy. Altern Med Rev. 1998;3(2):101-113.
  10. Voojijs GP, Geurts TBP. Review of the Endometrial Safety During Intravaginal Treatment with Estriol. European Journal of Obstetrics & Gynecology and Reproductive Biology.1995Sep;62(1):101-6
  11. Granberg S, Eurenius K, Lindgren R, Wilhelmsson L. The effects of oral estriol on the endometrium in postmenopausal women. Maturitas. 2002 Jun25;42(2):149-56
  12. Ushiroyama T, Sakai M, Higashiyama Tet al. Estrogen replacement therapy in postmenopausal women: a study of the efficacy of estriol and changes in plasma gonadotropin levels. Gynecol Ednocrinol 2001;15:74-80
  1. Gaspar A, et al. Efficacy of Erbium: YAG Laser Treatment Compared to Topical Estriol Treatment for Symptoms of Genitourinary Syndrome of Menopause. Laswers in Surger and Medicine 49:160-168 (2017).
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