Safety and Serum Estradiol Levels in Hormonal Treatments for Vulvovaginal Atrophy in Breast Cancer Survivors: A Systematic Review and Meta-Analysis.

Vulvo-vaginal atrophy (VVA) or genitourinary syndrome of menopause (GSM) is a common condition among breast cancer (BC) patients, especially those undergoing antiestrogen therapy. Despite being an option in refractory cases, the safety of hormonal treatment remains uncertain in this population. The aim of this study was to review the safety and serum estrogen levels of hormonal therapy in patients with BC history presenting with VVA symptoms. Pubmed, Embase, and Cochrane were searched for studies comparing different hormonal treatment options for VVA in breast cancer survivors. Statistical analysis was performed using a random effects model and heterogeneity using Cochran's Q-statistic and the I2 index. We included 17 studies, of which 5 were randomized controlled trials (RCTs). Treatment modalities included in this study were topical vaginal estradiol and estriol preparations, vaginally applied testosterone, DHEA, and ospemifene. We found that, among patients treated with the estriol and estradiol preparations, there was an average increase of 7.67 pg/mL (SMD 7.67 pg/mL; 95% CI -1.00, 16.35; p < .001). Analysis of the testosterone group found temporary peaks of serum estradiol levels, but 1 study showed persistent elevation above normal postmenopausal levels. One study with prasterone revealed no elevation of serum estradiol concentration. One study with ospemifene demonstrated no increase in the risk of BC recurrence. In conclusion, among treatments available for BC survivors, low-dose vaginal estrogen showed the smallest changes in serum estradiol levels and had the most evidence, but safety remains unclear, especially for patients on aromatase inhibitors. Alternative treatments such as ospemifene need more data supporting safety and efficacy. These results suggest that concerns related to cancer recurrence should keep aiming for the lowest possible concentration.

Local ultra-low-dose estriol gel treatment of vulvo-vaginal atrophy: efficacy and safety of long-term treatment.

Vulvo-vaginal atrophy (VVA) is a chronic condition affecting many postmenopausal women. Local estrogen treatment is recommended. Evaluating efficacy and safety of long-term VVA treatment with ultra-low-dose estriol gel, 120 postmenopausal VVA women were enrolled in a prospective study. They received the first cycle of 1 g/day vaginal gel containing 50 µg estriol for 3 weeks and then twice a week for 12 weeks. Moderate or severe VVA women received a second treatment cycle reaching treatment of 30 weeks. Vaginal pH measurement, subjective symptoms, and objective signs assessment of VVA, endometrial thickness and adverse events (AE) were recorded. Of the 99 women, completing the first phase, 43% experienced a complete VVA symptom relief, and 65% presented a milder VVA degree. After 30 weeks, VVA signs significantly improved (p<.01) compared with baseline and first phase results; total objective symptom evaluation including Schiller's test, flattening of folds and vaginal pH significantly improved (p<.01). At study endpoint, none of the patients had severe VVA, 93% had a positive response, 75% had a complete symptom, and sign resolution. No treatment-related endometrial AE were observed. Postmenopausal VVA long term-treatment with ultra-low-dose estriol vaginal gel is safe and effective.

Does vaginal estriol make urodynamic changes in women with overactive bladder syndrome and genitourinary syndrome of menopause?

OBJECTIVES: OAB is a common finding in postmenopausal women. Hypoestrogenism is the root cause of many signs and symptoms of Genitourinary Syndrome of Menopause (vaginal dryness, atrophy, dyspareunia, urinary disorders, etc.). As such the aim of this study was to evaluate the urodynamic effects of ultralowdose estriol vaginal gel formulation to treat women with Genitourinary Syndrome of Menopause and Overactive Bladder Syndrome. STUDY DESIGN: This open-labeled, single center, prospective study involved 37 women with OAB recruited in our Urogynecological Unit between January and July 2016. They received estriol 50 mcg/g vaginal gel, one applicator-dose per day for 3 weeks followed by one dose twice a week for 12 weeks. Objective and subjective parameters were evaluated before and after treatment through the urodynamic examination, Overactive Bladder symptom score and Short Form Health Survey-36 questionnaires. RESULTS: Vaginal atrophy symptoms and signs as well as the overactive bladder subjective symptom parameter improved significantly. Urodynamic evaluation showed significant improvement in first desire to void and maximum cystometric capacity after estriol usage. Patients who had detrusor overactivity did not show any improvement for this parameter after treatment. The voiding function parameters did not significantly change. Short form-36 showed a better quality of life after treatment especially for the emotional role, as well as mental and general health. CONCLUSIONS: A local ultra-low dose concentration of estriol could be effective in women with vaginal atrophy and Overactive Bladder Syndrome for improving both subjective symptoms and urodynamic parameters of storage function not affecting voiding function.

Distribución de esteroides estrogénicos en plantas de tratamiento de aguas residuales municipales / Distribution of estrogenic steroids in municipal wastewater treatment plants

En la actualidad, existe una preocupación creciente por la presencia de estrógenos en el medio acuático, donde pueden ser introducidos a partir de aguas residuales después de su eliminación incompleta en las plantas de tratamiento. Las aguas residuales sistemáticamente reciben estrógenos naturales y sintéticos, y por lo tanto una comprensión más profunda de la suerte de ellos en el medio ambiente es necesaria. Se evaluaron los niveles de estrógenos en los efluentes de las Plantas de Tratamiento de Aguas Residuales (PTARs) Penha e Ilha do Governador, ambos de tipo convencional de flujo continuo de lodo activado con aireación prolongada. Fue utilizado como el parámetro de determinación de algunos compuestos de interés como estrógenos naturales [estrona (E1), 17β-estradiol (E2), estriol (E3)) y sintéticos (17α-etinilestradiol (EE2)]. Las muestras individuales se recogieron posteriormente al tratamiento de cada PTAR y después de los procedimientos de laboratorio se realizó la determinación de estrógenos basado en la extracción en fase sólida (SPE) y la cromatografía líquida de alta resolución con detector de arreglo de diodos (HPLC-DAD). Las concentraciones fueron de: 0,7 a 5,2 μg/l y de 0,5 a 5,6 de E1; 0,9 a 7,7 y 1,2 a 9,2 μg/l para E2; 2,01 a 6,09 y 1,07 a 4,08 μg/l para EE2 en PTAR Penha y PTAR Ilha do Governador, respectivamente. La capacidad de eliminación de estrógenos fue eficaz, pero denota que la eliminación sistemática de la población es en la actualidad alta. Se recomienda instalar mecanismos para mitigar el consumo exagerado de estas sustancias o implementar una eliminación completa más eficaz.

Currently, there is a growing concern over the presence of estrogens in the aquatic environment, where they can be introduced from wastewater after their incomplete elimination in the treatment plants. Wastewater systematically receives natural and synthetic estrogens, and thus a deeper understanding of the fate of them in the environment is extremely necessary. It was evaluated estrogen levels in the effluent from the Sludge Wastewater Treatment Plants (SWTPs) Penha and Ilha do Governador, both of type conventional continuous-flow activated sludge with extended aeration. The determination of some target compounds as natural estrogens was used as the evaluation parameter [estrone (E1), 17β-estradiol (E2), estriol (E3) and synthetic (17α-ethinylestradiol (EE2)]. Individual samples were collected posterior treatment of each SWTP, and after laboratory procedures, the determination of estrogens was performed by a method based on solid phase extraction (SPE) and high performance liquid chromatography-diode array detector (HPLC-DAD). Concentrations ranged from 0.7 to 5.2 μg/l and from 0.5 to 5.6 for E1; 0.9 to 7.7 and 1.2 to 9.2 μg/l for E2; 2.1 to 6.9 and 1.7 to 4.8 μg/l for EE2 at SWTPs Penha and Ilha do Governador, respectively. The removal capacity of estrogens despite its effectiveness denotes that the systematic elimination by the population is high nowadays and urging mechanisms to mitigate the exaggerated consumption or to implement most effective complete removal.

The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review.

OBJECTIVES: To evaluate the efficacy and safety of estriol for the treatment of vulvovaginal atrophy in postmenopausal women. METHODS: A systematic literature review was performed. We searched the following electronic databases: Medline, Cochrane, Embase, Lilacs, CINHAL and Google Scholar. The studies selected included controlled clinical trials and quasi-experimental studies. Selections were made in pairs and independently, first by title and abstract and then complete texts. RESULTS: We identified 188 studies, 22 of which met the inclusion criteria; 13 were controlled clinical trials and nine were quasi-experimental, and 1217 women were included. These studies confirmed the efficacy of local estrogens to treat symptoms of vulvovaginal atrophy with few adverse effects reported. Following treatment, serum estriol levels rose, peaking at 1 h. At the 6-month follow-up, there was no increase in serum estriol in treated women. CONCLUSIONS: The available evidence (of low and moderate quality) shows that, when administered vaginally, estriol preparations appear to be safe for women who have risk factors related to systemic estrogen therapy.

Estriol: emerging clinical benefits.

OBJECTIVE: Estriol is the main estrogen in pregnancy, but has received less attention outside gestation. It is well known that pregnancy has an immunosuppressive effect on many autoimmune diseases such as multiple sclerosis, psoriasis, thyroiditis, uveitis, and rheumatoid arthritis. Emerging evidence indicates that estriol has potential immunomodulatory benefits for many disease states including autoimmune, inflammatory, and neurodegenerative conditions. In this review, we discuss emerging roles for estriol in the treatment of menopausal symptoms, osteoporosis, cancer, hyperlipidemia, vascular disease, and multiple sclerosis. Estriol appears to offer a potentially cost-effective approach to a variety of conditions and may offer a wide range of health benefits. METHODS: We reviewed the English language MEDLINE literature with estriol in the title with emphasis on publications including nonpregnant females between January 1974 and August 2016. Approximately 393 such articles were considered and 72 articles have been referenced in this review. RESULTS: Estriol offers considerable benefits for postmenopausal women with reduced risks that are normally associated with traditional hormone therapies. These benefits include improved control of menopausal symptoms and better urogenital health. Moreover, the immunomodulatory role of estriol in reducing proinflammatory cytokines may be an important new therapeutic option for chronic autoimmune and neurodegenerative illnesses. Since it is a relatively weak estrogen, there is potential for use in men for conditions such as multiple sclerosis. CONCLUSIONS: We conclude transvaginal estriol potentially offers a suitable physiologic delivery and cost-effective alternative to currently available estrogen regimens in selected patients. Additional studies on mode of delivery, safety, and efficacy merit further investigation.

Coital pain in the elderly: could a low dose estriol gel thrill the vulvar vestibule?

OBJECTIVE: The aim of this study was to evaluate the effectiveness of the application of 0.005% estriol gel to the vulvar vestibule in the management of postmenopausal dyspareunia. STUDY DESIGN: Postmenopausal women with dyspareunia were enrolled in this study. Patients were instructed to use a fingertip to apply 0.25g of vaginal gel containing 25µg of estriol to the vulvar vestibule daily for three weeks and then twice weekly for up to 12 weeks. RESULTS: Assessment of symptoms (dyspareunia and cotton swab test) and signs of vestibular atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. A total of 63 women were included. Of the 63, 59 (93.6%) completed the 12-week treatment period, and four dropped out for vestibular burning. Dyspareunia improved or was cured (score ≤1) by week 12 in 81.4% of patients. The patients also showed a statistically significant reduction in vestibular atrophy and cotton swab test at the end of treatment. CONCLUSIONS: Application of 0.005% estriol gel to the vulvar vestibule is effective in correcting menopausal coital pain. This suggests that reduction in sensory vestibular innervation sensitivity is likely to play a pivotal role in the relief of dyspareunia. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention.

Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women.

OBJECTIVE: To assess whether the orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin could be effective in preventing recurrent cystitis in postmenopausal women and whether its efficacy was conditioned by the concurrent use of local estrogen therapy. STUDY DESIGN: This was a prospective evaluation of 145 postmenopausal women consecutively recruited from the database of three different investigators. All women should have mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections (≥2 episodes within 6 months or ≥3 episodes within 12 months documented by positive urine cultures) during the last year. Patients were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with HA, CS, curcumin and quercetin per os, and the third group was treated with HA, CS, curcumin and quercetin associated with local estrogens. We evaluated the number of patients with <2 infective episodes in the 6-month follow-up and <3 episodes in the 12-month follow-up (main aim definition) and the reduction of related symptoms through a Visual Analog Scale (VAS) and the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Student's t-test and chi-squared test were used for data analysis as appropriate. RESULTS: At 6-month follow up, the main aim rate was 8%, 11.1% and 25% in the three groups, respectively (p<0.05 compared to baseline only in group 3). Although the reduction in the number of recurrent episodes became significant in all groups at 1 year follow-up, the main aim rate was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments. The improvement of related symptoms was significant in all groups at 12-month follow-up. CONCLUSIONS: In postmenopausal women, the combination of HA, CS, curcumin and quercetin per os was effective in preventing recurrent urinary tract infections, especially if administered with vaginal estrogen therapy.

Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women.

OBJECTIVES: To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 µg/g (T1) and 50 µg/g (T2)) compared to Ovestinon® (estriol 500 µg/0.5 g (R)) and placebo in postmenopausal women. METHODS: Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated. RESULTS: Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUCss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good. CONCLUSIONS: Estriol 20 and 50 µg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®.

Estrone - a partial estradiol antagonist in the normal breast.

Oral hormone replacement therapy (HRT) based on estradiol-17ß (E2) greatly increases circulating estrone (E1) levels. E1 is an estrogen receptor agonist but may also be a partial E2 antagonist. We investigated the effects of circulating E1 on the association between circulating E2 and the increase in mammographic density (∂MD) in 46 healthy post-menopausal women treated with E2 2 mg and norethisterone acetate 1 mg daily. MD and serum E1 and E2 were measured before and after 6 months of treatment. At high E1 levels, ∂MD showed significant positive correlations leading to increase (∂-values) in both E1 and E2. Lowering the upper serum E1 limit strengthened the correlations to ∂E2 while the significant correlations to ∂E1 disappeared. E1 at high concentrations may act as a partial E2 antagonist also in the normal breast in vivo and disturb relationships between circulating E2 and biological estrogen effects. When investigating the relations between circulating steroids and their effects, structurally related compounds, which may act as partial antagonists, have to be considered, at least when they are present in higher concentrations.

Add-back therapy with GnRH analogues for uterine fibroids.

BACKGROUND: Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects. OBJECTIVES: To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms. SEARCH METHODS: We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings. AUTHORS' CONCLUSIONS: There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.

Risks and effectiveness of compounded bioidentical hormone therapy: a case series.

After the publication of the Women's Health Initiative, attitudes towards management of menopausal symptoms changed dramatically. One alternative that has received much media attention is the use of bioidentical hormone therapy (BHT). The media and celebrity endorsements have promoted a number of misconceptions about the risks and benefits associated with the various forms of BHT. This article will review the available evidence regarding the safety and efficacy of BHT in comparison to conventional hormone therapy. We will also review several cases seen in our midlife women's referral clinics, which demonstrate concerns for the safety and efficacy of BHT, including unexplained endometrial cancer in otherwise healthy BHT users. Due to the lack of sufficient data to support the efficacy or safety of BHT, we recommend the use of United States Food and Drug Administration-approved regimens in the management of menopausal symptoms.

Is vaginal hyaluronic acid as effective as vaginal estriol for vaginal dryness relief?

In a multicenter, randomized, controlled, open-label, parallel- group trial hyaluronic acid vaginal gel (Hyalofemme) was compared to estriol vaginal cream (Ovestin) in women with vaginal dryness due to various causes. A total of 144 supposedly postmenopausal women below age 70 years were randomized in a 1:1 ratio to either receive hyaluronic acid vaginal gel (5 g per application) or estriol vaginal cream (0.5 g cream per application = 0.5 mg estriol) every 3 days for a total of ten applications, respectively. Exclusion criteria included vaginal infections, conventional contraindications to estrogens, use of vaginal products other than the investigational compounds, being unmarried, pregnant, or breastfeeding. The aim of the study was to test for non-inferiority of hyaluronic acid vaginal gel compared to estriol vaginal cream. The primary efficacy end point was the percentage (%) improvement in vaginal dryness, with the secondary end points being the percentage (%) improvements in vaginal itching, burning, and dyspareunia. Efficacy was assessed by using a visual analog scale (VAS) (0-10; 0 = absent, 10 = intolerable) at baseline (V0), during telephone contact after the third administration (V1), and at the final visit after the tenth administration (V2). Safety parameters included vaginal pH, endometrial thickness, and a vaginal smear for vaginal microecosystem assessment. Adverse events were recorded according to international guidelines. 133 women completed the study. At baseline, participants' characteristics did not differ significantly. Mean age was 54 years, time since menopause was 5 years on average, and cause of menopause was mostly natural. However, mean menstrual cycle days were also reported, although according to inclusion criteria only postmenopausal women were eligible for the study. At V1, an improvement in vaginal dryness was reported by about 49 % of women using hyaluronic acid vaginal gel, and by 53 % of women using estriol vaginal cream (p = 0.31). At V2, the percentage improvement rates were 84 and 89 % (p = 0.13), respectively. Improvement rates for vaginal itching, burning, and dyspareunia at V2 were about 86, 85, and 57 % for hyaluronic acid vaginal gel, and 82, 87, and 62 % for estriol vaginal cream (p[0.05), respectively. After treatment, vaginal pH was significantly lower in estriol-treated women compared to those having received hyaluronic acid. Endometrial thickness did not differ between groups. In the majority of women, the vaginal microenvironment remained unaffected by treatment. However, the proportion of women whose abnormal vaginal microecological results became normal was higher in women using estriol vaginal cream. Adverse events (suspected to be) related to the investigational compounds were minor and included vaginal infection and genital itching. The authors concluded that hyaluronic acid vaginal gel was not inferior to estriol vaginal cream in women presenting with vaginal dryness. They suggest using hyaluronic acid vaginal gel not only as an alternative treatment to vaginal estrogens, but also to consider its general use in women presenting with vaginal dryness of any cause.

Evaluation of the efficacy and safety of hyaluronic acid vaginal gel to ease vaginal dryness: a multicenter, randomized, controlled, open-label, parallel-group, clinical trial.

INTRODUCTION: Atrophic vaginitis is a common occurrence, particularly among postmenopausal women; however, few seek or receive treatment. One therapeutic solution is topically applied products. Estrogen-based treatments have been shown to be effective; however, many patients are reluctant to use such formulations due to health concerns, hence the need to assess the efficacy of acceptable alternatives. AIM: This multicenter, randomized, controlled, open-label, parallel-group clinical trial set out to evaluate the efficacy and safety of hyaluronic acid vaginal gel to treat vaginal dryness compared with estriol cream in postmenopausal women. METHODS: One hundred forty-four subjects were randomized, 72 to the test group treated with hyaluronic acid vaginal gel (Hyalofemme) and 72 to the control group treated with estriol cream (Ovestin). Treatment in both groups was applied by means of a device once every 3 days for a total of 10 applications over 30 days. MAIN OUTCOME MEASURES: Efficacy was measured by grading vaginal dryness and three other vaginal symptoms on a visual analog scale. Safety assessments included vital signs, laboratory examinations of the vaginal microecosystem, vaginal pH value, vaginal B ultrasound, and incidence of adverse events. Assessments were performed at baseline, by telephone after the third application, and at the final visit. RESULTS: Both hyaluronic acid vaginal gel and estriol cream can significantly improve the clinical symptoms of vaginal dryness in postmenopausal women, with improvement rate of 84.44% and 89.42%, respectively, after 10 applications, without statistically significant difference between them. CONCLUSION: Both hyaluronic acid vaginal gel and estriol cream are effective in the treatment of vaginal dryness. Hyaluronic acid vaginal gel may be considered as a valid alternative to estrogen-based treatments in relieving the symptoms of vaginal dryness.

The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a new low-concentration estriol formulation (0.005% estriol vaginal gel), providing an ultra low dose of estriol per application (50 µg), for the local treatment of postmenopausal vaginal atrophy. METHODS: Postmenopausal women with symptoms and signs of vaginal atrophy were enrolled in a prospective, double-blind, placebo-controlled study. Women received either 1 g of vaginal gel containing 50 µg of estriol or placebo gel, daily for 3 weeks and then twice weekly up to 12 weeks. A cytological vaginal study, evaluation of vaginal pH, and assessment of symptoms and signs of vaginal atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. RESULTS: A total of 167 women were included (114 received estriol and 53 received placebo). After 12 weeks of therapy, a superiority of estriol compared with placebo gel was shown in the change in maturation value and vaginal pH (P < 0.001 and P < 0.001, respectively). The superiority of estriol was well demonstrated in improvement of vaginal dryness (P = 0.001) and the Global Symptom Score (P = 0.018). Estriol gel proved also superior in the improvement of several of the most outstanding vaginal signs of vaginal atrophy evaluated. After 3 weeks, estriol gel also showed a superiority over the placebo gel in most symptoms and signs evaluated. Treatment-related adverse events were similar among groups. CONCLUSIONS: 0.005% Estriol vaginal gel, a new formulation providing an ultra low dose of estriol per application, was shown to be safe and effective in the treatment of postmenopausal vaginal atrophy.

Comparative uterine effects on ovariectomized rats after repeated treatment with different vaginal estrogen formulations.

OBJECTIVE: Topical estrogen therapy is recommended for the treatment of vaginal atrophy. This study was designed to compare the uterotrophic effects of a new estrogen vaginal formulation (0.005% estriol vaginal gel) and other existing topical treatments (Ovestinon(®) and Colpotrofin(®)). METHODS: Each one of the studied formulations was administered intravaginally to groups of ovariectomized rats with cytologically confirmed vaginal atrophy. The doses were adjusted by animal weight according to human dosage. After daily treatment for 14days, the animals were sacrificed and their vaginas and uteri removed. All uteri were weighted. Uteri and vaginas were fixed for histological evaluation. RESULTS: All three active formulations proved to be very effective in the cytological reversal of vaginal atrophy. However, they differ in their effects in the uteri. Ovestinon(®) and Colpotrofin(®) produced a significant increase in uterine weight, myometrial and endometrial thickness as well as histological modifications in the endometrium suggestive of estrogenic activity. Conversely, animals treated with 0.005% estriol vaginal gel, did not show significant weight increase or any other macroscopical or microcospical modifications of the uteri, an effect comparable to placebo. CONCLUSIONS: There are significant differences in the uterotrophic effect of three different topical estrogen formulations as tested in a rat model of vaginal postmenopausal atrophy. While the three formulations were equally effective in reversing vaginal atrophy, only the newly developed ultra-low dose 0.005% estriol vaginal gel has proved to lack any significant estrogenic effect on the uterus.

Systemic bioavailability of estriol following single and repeated vaginal administration of 0.03 mg estriol containing pessaries.

UNLABELLED: A prospective monocentric open-label and single-arm trial was performed in 19 postmenopausal women with diagnosed vaginal atrophy. The aim was to determine the extent of a systemic exposure to estriol (CAS 50-27-1). Administration of estriol containing pessaries was daily for 21 days. In order to establish a pharmacokinetic profile after single as well as multiple vaginal doses of 0.03 mg estriol blood samples were taken after the first vaginal administration as well as at day 21 after the last administration. Moreover, in order to control for accumulation additional blood samples were taken predose at days 6, 11 and 16. RESULTS: The initial administration increased the population mean estriol plasma concentration to a maximum of 42.1 pg/ml 1 h after dosing. However, already 12 h after administration the estriol concentration had again dropped below 5 pg/ml (lower limit of quantification) in all patients. Repeated administration did not result in an accumulation of estriol, since 2 h after application of the 21st pessary, the population mean estriol concentration reached a maximum of only 11.9 pg/ml. Moreover, no severe or serious adverse events occurred, and no clinically relevant findings were reported. CONCLUSION: Single vaginal application of pessaries containing 0.03 mg estriol resulted in a very low systemic bioavailability, which decreased even more after multiple dosing confirming a favourable safety profile of low dose pessaries administered daily over 21 days.

The risk of breast cancer linked to menopausal hormone therapy.

BACKGROUND: The Norwegian "Women and cancer" study has shown that when combination hormone replacement products were used for more than five years the relative risk of breast cancer was almost tripled. The population attributable risk was 27 %. In a nested case-control study we have updated the risk estimates for hormone replacement therapy in post-menopausal women since 2002. MATERIAL AND METHOD: We selected an age-matched control for each of the 589 women (aged 46-63) who were found in the period 2004-8 to have invasive breast cancer or cancer in situ. These women responded in 2003-6 to a questionnaire on menstruation and the use of hormone replacement therapy. The data from this and earlier questionnaires were compared and analysed using logistical regression. RESULTS: 226 (26 %) of the women were using hormone replacement at the time of the survey. The average time of use was ten years. Current users had a higher risk of breast cancer than never-users: adjusted OR 2.1 (95 % CI 1.5-3.0). The use of combination therapy for more than five years resulted in the highest risk: OR 3.0 (95 % CI 1.9-4.7). Earlier use of oestrogen products did not result in a higher risk. Neither oestradiol nor tibolon caused a statistically significant increase in risk. 232 cases of breast cancer (17 %) in women aged 45-64 could be attributed to the use of hormones. INTERPRETATION: Long-term use of combination products increases the risk of breast cancer. Relative risk estimates have undergone little change since the previous study, but population attributable risk has fallen along with the decline in new users.