Faculty Bibliography

Objective: Vaginal atrophy is due to low estrogen and affects 10-40% of post-menopausal women. It may manifest as vaginal soreness, dryness, pruritus, dyspareunia, or bleeding on contact. Unlike symptoms such as hot flushes, vaginal atrophy does not diminish over time and often progresses in severity. However, estrogen therapy is generally recommended for short term use, and local estrogen alternatives may cause irritation and be inconvenient to use. Femarelle (DT56a) is an oral selective estrogen receptor modulator derived from botanical source, effective at decreasing hot flushes and increasing bone mass. Pre-clinical and clinical studies have shown it has no increased clotting effect in women and no proliferative effect on breast or uterine tissue. These findings suggest Femarelle may be safe for long-term use. The current study is a pilot examining the use of Femarelle for vaginal atrophy, preceding a large double blind placebo controlled study. Design: 12 post-menopausal women with vaginal atrophy (<5% superficial cells on cervical cytology) with at least one moderate-to-severe symptom (dryness, irritation, soreness, dysuria, dyspareunia, or bleeding with coitus) were recruited for a 12-week open-label pilot study in line with the FDA regulatory guideline for vaginal atrophy. Exclusion criteria included any hormone therapy/soy product use or significant soy in diet. Femarelle capsules were given 2X/day for 12 weeks. At each visit (0 & q4 weeks) subjects had a vaginal atrophy assessment (speculum exam, maturation index, vaginal pH) and completed questionnaires on atrophy symptoms and quality of life. At weeks 0 and 12, physical exams, pap smears, vaginal cultures, and blood work were also performed. Results will be presented in June 2011 at the IMS congress

OBJECTIVE: The purpose of this study was to assess the effect of DT56a (Femarelle), a selective estrogen receptor modulator, on platelet function in normal and thrombophilic women being treated for severe menopausal symptoms. METHODS: The Platelet Function Analyzer-100 (PFA-100) was used to asses platelet reactivity at baseline and after 8 weeks of treatment with Femarelle (644 mg/d in divided doses) in 25 symptomatic postmenopausal women with normal clotting times and seven symptomatic women with shortened clotting times (<61 s). The PFA-100 measure of closure time is considered equal to clotting time in assessing clotting function and platelet adhesion, aggregation, and blood coagulation factors. Closure times were measured after 3 and 8 weeks in all participants and at 1 year in the women with shortened clotting times. The nonparametric Wilcoxon signed rank test was used to assess the changes between baseline and each of the three subsequent measurements. RESULTS: Pretreatment study of all seven women with shortened closure times confirmed abnormalities associated with thrombophilia: four women were heterozygous for the factor V Leiden gene mutation, one was heterozygous for the prothrombin gene mutation, one was found to have protein S deficiency, and one had increased anticardiolipin antibodies. All participants reported improved symptoms during the treatment period. No significant change in closure times was found in the normally clotting participants after 3 or 8 weeks of Femarelle therapy (P > 0.26). No significant change in closure time was seen in the seven thrombophilic women after 3 or 8 weeks or 1 year of Femarelle treatment (P > 0.26). The regression curve for measures over time was not significant (P = 0.26). CONCLUSIONS: Femarelle, whose active ingredient is DT56a, did not adversely affect platelet reactivity as measured by PFA closure times in symptomatic thrombophilic postmenopausal women or normal controls. Femarelle, a novel selective estrogen receptor modulator that inhibits menopausal symptoms without thrombogenicity, may offer a new clinical choice for therapy of symptomatic postmenopausal women

Two clinical trials previously demonstrated the safety of 300 mug/day transdermal testosterone patch (TTP) treatment for up to 6 months in 1094 surgically menopausal women with hypoactive sexual desire disorder (HSDD). Adverse events (AE), clinical laboratory tests, vital signs, physical examinations and mammograms were evaluated in open-label extensions of these two trials for up to 4 years and are presented in this article. Nine hundred and sixty-seven patients received at least one application of the TTP resulting in 1092 patient-years of exposure. There was no increase over time in the rate of new occurrences or severity of AEs, serious AEs, or withdrawals due to AEs. The most common AEs associated with treatment were application site reactions and unwanted hair growth; however, most were mild and rarely resulted in study withdrawal. No clinically meaningful changes in serum chemistry, haematology, lipid profile, carbohydrate metabolism, renal and liver function or coagulation parameters were noted with up to 4 years of therapy. Consistent with age-appropriate expected rates, three cases of invasive breast cancer were observed. No important changes in the safety or tolerability profile of TTP were revealed with long-term use for up to 4 years in otherwise healthy oophorectomised women with HSDD on concomitant oestrogen

OBJECTIVE:: To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17beta-estradiol vaginal tablets in postmenopausal women with vaginal atrophy. METHODS:: Endometrial biopsy data from individuals using active treatment (n=205) in a randomized, double-blind, placebo-controlled trial were pooled with the data from an open-label endometrial safety trial (n=336). Patients received 10-microgram estradiol vaginal tablets for 52 weeks. All endometrial biopsy samples were histologically analyzed at baseline and at end of trial by the same laboratory in both trials. RESULTS:: A total of 541 women using estradiol were included in the combined analysis of endometrial safety. A total of 456 women completed the trials, and 443 women had a biopsy performed at week 52: 85.6% were categorized as 'atrophic endometrium,' 12.6% had nonevaluable biopsy samples, 1.1% had polyps, and 0.2% were categorized as 'weakly proliferative.' One case of complex hyperplasia without atypia was reported in an individual exposed to trial drug for only 9 days. One woman's biopsy sample demonstrated endometrioid adenocarcinoma, grade 2, but the lack of an evaluable screening biopsy sample makes it uncertain whether the carcinoma was preexisting. In total, two events of hyperplasia and carcinoma were reported in 386 evaluable biopsy samples (incidence rate 0.52% per year). CONCLUSION:: The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women is 0% to 1%. The results of this pooled analysis therefore support the endometrial safety of unopposed ultra-low-dose vaginal estrogen. There was no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram estradiol vaginal tablets for 1 year under study conditions. CLINICAL TRIAL REGISTRATION:: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748). LEVEL OF EVIDENCE:: II

A new study published in the Journal of Clinical Oncology has ascertained the efficacy of selective serotonin-reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and gabapentin to decrease menopausal hot flashes. Are these nonhormonal treatment options a viable alternative to hormone replacement therapy?

OBJECTIVE: We sought to determine the effects of oral versus transdermal estrogen therapy on platelet function in postmenopausal women. METHODS: Blood obtained from 84 postmenopausal women was tested for closure times using the Platelet Function Analyzer-100 before and after administration of oral or transdermal estrogen for 8 weeks. RESULTS: Women with normal closure times at baseline (n = 71) demonstrated no significant change after receiving estrogen therapy with oral (n = 29) or transdermal (n = 42) estrogen. Women with borderline closure times of 61 to 66 seconds (n = 13) showed a significant acceleration of closure times (P = 0.0008) after oral estrogen therapy (-6.8 +/- 0.7 seconds, n = 5) but no significant change from baseline after transdermal estrogen therapy (1.1 +/- 0.5 seconds, n = 8). CONCLUSIONS: An acceleration of closure times as measured by the Platelet Function Analyzer-100 in women with borderline baseline closure times is associated with the use of oral, but not transdermal, estrogen therapy. These results suggest that oral estrogen therapy increases platelet reactivity in a subset of women

This Practice Point commentary discusses the findings and limitations of a study by Welton et al. that assessed the effect of combined hormone replacement therapy (HRT) on health-related quality of life (QOL) in postmenopausal women. Evidence of the effect of HRT on health-related QOL in this group of patients in prior literature has been lacking, in part because of the varied, nonvalidated instruments used for evaluation. Welton et al. overcame that issue by the use of multiple questionnaires, and included specific questions on sexual functioning. However, all studies on health-related QOL are limited by the subjective selection of the parameters included in the instruments. Within this limitation, these authors concluded that HRT (estrogen alone in women without a uterus, and estrogen plus progestin for women with a uterus) offers more benefit than risk for postmenopausal, symptomatic women

OBJECTIVE: To evaluate the efficacy of ultra-low-dose 10-microgram 17beta-estradiol (E2) vaginal tablets for treatment of vaginal atrophy. METHODS: Postmenopausal women (N=309) were randomly assigned to 10-microgram E2 or placebo vaginal tablets for 52 weeks in a multicenter, double-blind study. Primary efficacy endpoints included change from baseline to week 12 in vaginal cytology, vaginal pH, and most bothersome urogenital symptoms score. Grading of vaginal health was a secondary efficacy assessment. Safety assessments included endometrial biopsy, physical and gynecologic examinations, and recording adverse events. RESULTS: At week 12, the change from baseline for 10 micrograms E2 compared with placebo demonstrated significant improvement in vaginal Maturation Index (proportion of parabasal cells: -37% compared with -9%; superficial cells: 13% compared with 4%; intermediate cells: 24% compared with 5%; P<.001 for each), Maturation Value (25.0 compared with 6.5, P<.001), grading of vaginal health (-0.91 compared with -0.51, P<.001), vaginal pH grade (-1.3 compared with -0.4, P<.001), and most bothersome symptoms score (-1.23 compared with -0.87, P=.003). For each component of vaginal Maturation Index, vaginal Maturation Value, grading of vaginal health, and vaginal pH, treatment effects were statistically different from placebo after 2 weeks of treatment. For most bothersome symptoms, treatment effect became apparent after 4 weeks and reached statistical significance at week 8 of therapy. All treatment effects were statistically significant at week 52. There were no major safety findings regarding physical, gynecologic, or laboratory assessments. CONCLUSION: After 12 weeks of treatment, an ultra-low-dose 10-microgram E2 vaginal tablet, compared with placebo, demonstrated significant improvement for the primary endpoints: vaginal cytology and pH and most bothersome urogenital symptoms score. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00108849 LEVEL OF EVIDENCE: I