Estriol used individually or in combination with Vitamin D3 has been studied for treatment in women with stress and urgency urinary incontinence.1,2
Estriol is typically compounded in strengths ranging from 0.05%-1%.
Vitamin D3 vaginal cream is compounded separately from Estriol.
Each cream is typically dispensed in a tube accompanied with a vaginal applicator.
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 helps to alleviate menopausal symptoms.9,10
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.8-17
Low levels of Vitamin D3 have been associated with pelvic floor disorders among women.5,6,7 Vitamin D receptors are present in the bladder and striated muscle of the pelvic floor musculature.3,4 Skeletal muscle control and strength is vital for voluntary control of the urethral sphincter and pelvic floor muscle and likely a significant factor in achieving continence.
Urge & Stage I, II, & III Stress Urinary Incontinence
In an open, prospective, multicenter, controlled study1, 629 women suffering from stress and urgency urinary incontinence were treated with vaginal estriol at a dose of 10 mg daily for 3 weeks, and 10mg twice weekly for another 3 weeks. Of the 629 women who started the study, 552 were available for follow-up after 6-weeks of treatment.
Subjective improvements in symptoms of stress urinary incontinence (SUI) were 82% for grade 1, 77% for grade 2, and 69% for grade 3.
Voluntary urinary control and symptoms of urgency were improved in more than 80% of patients, and frequency was reduced in almost 50% of women. Compared with conditions at the outset of the study, after 6 weeks, vaginal lubrication was normalized in 77%, and intercourse was no longer painful for 88% of women.
Stage 1 & II Stress Urinary Incontinence
In a combination use study2 of 60 postmenopausal women with stage I and II stress urinary incontinence, estriol 0.5mg was co-administered with vitamin D3 12,500 IU intravaginally 3 times a week for 6 weeks after subjects failed a 6-week treatment of estriol 0.5 mg + Pelvic Floor Muscle Training (PFMT).
The results of the study showed complete remission of urinary incontinence in 1/3 of the women and another 1/3 of the women studied showed a 75% improvement in urinary retention.
Estriol has been studied for the treatment of Urge & Stage I, II, & III Stress Urinary Incontinence.1
Estriol in combination with Vitamin D3 has been studied for the treatment of postmenopausal stage I and stage II urinary incontinence.2
For Urge & Stage I, II, & III Stress Urinary Incontinence, estriol was studied using vaginal estriol at a dose of 10 mg daily for 3 weeks, and 10mg twice weekly for another 3 weeks.1
For stage I & II Stress Urinary Incontinence, a combination therapy using nightly vaginal estriol 0.5mg and vitamin D3 12,500IU was studied for 3 weeks.2
No examples of interactions between Estriol and other medicines have been reported in clinical practice. Although data are limited, interactions between Estriol and other medicinal products may occur. The following interactions have been described with use of combined oral contraceptives which may also be relevant for Estriol.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. hydantoins (phenytoin), barbiturates (phenobarbital), carbamazepine), anti-infectives (e.g. griseofulvin, rifamycins (rifampicin, rifabutin), and antiretroviral agents (nevirapine, efavirenz)).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John’s wort (Hypericum Perforatum) may induce the metabolism of oestrogens.
Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.
Estriol may possibly increase the pharmacological effects of corticosteroids, succinylcholine, theophyllines and troleandomycin.
Use Vitamin D3 cautiously in patients taking:
From literature and safety surveillance monitoring, the following adverse reactions have been reported for estriol.
- Fluid Retention
- Breast discomfort and pain
- Postmenopausal spotting
- Cervical Discharge
- Application site irritation and pruritis
- Flu like symptoms
Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer; although recent trials8 indicate benefits for vaginal atrophy in hormone receptor positive breast cancer undergoing aromatase inhibitor therapy.
Vitamin D3 should be use cautiously in patients with arrhythmic, electrolyte imbalance, hypercalcemia, renal dysfunction and hepatobiliary dysfunction.
Estriol 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.
Estriol is not indicated during lactation. Estriol is excreted in breast milk and may decrease milk production.
Use Vitamin D3 cautiously in patients with renal dysfunction.
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.
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.
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.
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.
Previous studies have indicated that Vitamin D3 is absorbed efficiently through the dermal route.
Vitamin D3, or Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol), which is then converted to calcitriol in the kidney, the biologically active form of Vitamin D3 and released for use in the blood stream.
Calcitriol (1,25-dihydroxyvitamin D3), the active form of vitamin D, has a half-life of about 15 hours, while calcidiol (25-hydroxyvitamin D3) has a half-life of about 15 days.
The products of vitamin D metabolism are excreted through the bile into the feces, and very little is eliminated through the urine.
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.
Vitamin D toxicity is rare. Vitamin D overdose causes hypercalcemia, which is a strong indication of vitamin D toxicity – this can be noted with an increase in urination and thirst. If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage.
The main symptoms of vitamin D overdose which are those of hypercalcemia including anorexia, nausea, and vomiting. These may be followed by polyuria, polydipsia, weakness, insomnia, nervousness, pruritus and ultimately kidney failure. Furthermore, proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop. Other symptoms of vitamin D toxicity include abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.
Store at room temperature.
- Schmidbauer CP. Vaginale Ostriolapplikation zur Behandlung der postmenopausalen Harninkontinenz [Vaginal estriol administration in treatment of postmenopausal urinary incontinence]. Urologe A. 1992;31(6):384-389
- Schulte-Uebbing C, Schlett S, Craiut D, Bumbu G. Stage I and II Stress Incontinence (SIC): High dosed vitamin D may improve effects of local estriol. Dermatoendocrinol. 2016;8(1)
- Crescioli C, Morelli A, Adorini L, et al. Human bladder as a novel target for vitamin D receptor ligands. J Clin Endocrinol Metab. 2005;90(2):962-972. doi:10.1210/jc.2004-1496
- Bischoff HA, Borchers M, Gudat F, et al. In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J. 2001;33(1):19-24.
- Badalian SS, Rosenbaum PF. Vitamin D and Pelvic Floor Disorders in Women: Results From the National Health and Nutrition Examination Survey. Obstetr Gynecol. 2010;115(4):795–803.
- Vaughan CP, Johnson TM, II, Goode PS, Redden DT, Burgio KL, Markland AD. Vitamin D and lower urinary tract symptoms among US men: results from the 2005–2006 National Health and Nutrition Examination Survey. Urology. 2011;78(6):1292–7.
- Navaneethan PR, Kekre A, Jacob KS, Varghese L. Vitamin D deficiency in postmenopausal women with pelvic floor disorders. J Mid-life Health. 2015;6(2):66–9.
- Hirschberg, Angelica Lind√©n MD, PhD1; S√°nchez-Rovira, Pedro MD, PhD2; Presa-Lorite, Jes√∫s MD3; Campos-Delgado, Miriam MD4; Gil-Gil, Miguel MD5; Lidbrink, Elisabet MD, PhD6; Su√°rez-Almarza, Javier Pharm, BSND7; Nieto-Magro, Concepci√≥n 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
- 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.
- Shiroyama 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
- 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.
- 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.
- 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
- 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
- Yoshimura T, Okamura H. Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women. Maturitas. 2001 Sep28;39(3):253-7
- 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.
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