Faculty Bibliography

Reports have correlated the use of estrogen for the treatment of menopausal symptoms with beneficial effects on the cardiovascular system. Molecular, biochemical, preclinical, and clinical studies have furnished a wealth of evidence in support of this outcome of estrogen action. The prospective randomized Women's Health Initiative (WHI) and the Early Versus Late Intervention Trial (ELITE) showed that starting menopausal hormone treatment (MHT) within 5 to 10 years of menopause is fundamental to the success of estrogen's cardioprotection in post-menopausal women without adverse effects. Age stratification of the WHI data has shown that starting hormone treatment within the first decade after menopause is both safe and effective, and the long-term WHI follow-up studies are supportive of cardioprotection. This is especially true in estrogen-treated women who underwent surgical menopause. A critique of the WHI and other relevant studies is presented, supporting that the timely use of estrogens protects against age- and hormone-related cardiovascular complications. Salutary long-term hormone treatment for menopausal symptoms and prevention of complications has been widely reported, but there are no prospective trials defining the correct length to continue MHT. At present, women undergoing premature menopause receive estrogen treatment (ET) until evidence of hormone-related complications intervenes. Normal women started on MHT who receive treatment for decades without hormone-related complications have been reported, and the WHI follow-up studies are promising of long-term post-treatment cardioprotection. A prevention-based holistic approach is proposed for timely and continuing MHT/ET administration as part of the general management of the menopausal woman. But this should be undertaken only with scheduled, annual patient visits including evaluations of cardiovascular status. Because of the continued occurrence of reproductive cancers well into older ages, these visits should include genital and breast cancer screening.

Prevention of osteoporosis should begin in childhood and continue throughout adulthood. Although genetic determinants of muscle and bone mass may offer other therapeutic options in the future, currently, counseling should primarily focus on lifestyle modification including healthy dietary practices and regular exercise. Vitamin supplementation, particularly vitamin D, should be considered to enhance diet based on patient's need. Attention to estrogen status is also important. In addition, patients should be counseled regularly about cigarette cessation and avoiding moderate alcohol intake.

Objective: Symptomatic vaginal atrophy affects one out of three menopausal women. Hormone therapy, both systemic and local, is effective and indicated for the relief of this problem but may not be acceptable to all patients. DT56a (Femarelle), a selective estrogen receptor modulator derived from botanical source, was found to be effective at decreasing menopausal hot flushes and increasing bone mass. We performed a pilot study testing the use of DT56a for vaginal atrophy. Design: 12 post-menopausal women with vaginal atrophy (<5% superficial cells on cervical cytology) with at least one moderate-to-severe symptom, were recruited for an TRB-approved 12-week open-label pilot study. DT56a (322mg) was given by mouth 2X/day for 12 weeks. At each visit (0&q4 weeks) subjects had a vaginal atrophy assessment (speculum exam, vaginal pH) and completed questionnaires on atrophy symptoms and quality of life (Utian QoL scale).At weeks 0 and 12, a pap smear with maturation index and vaginal cultures were performed. Results: The main bothersome symptoms were: Dyspareunia- 5 Patients,Vaginal soreness- 3 Patients.Vaginal dryness- 2 Patients.Vaginal irritation-1 Patient and Bleeding with coitus-1 Patient. All patients reported significant improvement in their most bothersome symptom. All women had a significant reduction in vaginal pH. The average pH went from baseline 7.7+/-2.2 to 4.9+/-1.4 on week 12,p<0.0001. The maturation index also improved as shown in the figure below: Parabasal cells that were 100% at entry were 43% following 12 weeks of treatment, Intermediate cells were changed from 0 to 47% and Superficial cells that were 0 at entry, were 10% following 12 weeks of treatment with DT56a (all statistically significant, p<0.001). A significant improvement was found in UQoL index from mean pre-treatment of 75.4+/-22.7 points to mean post-treatment of 88.9+/-26.8, p<0.001.In the sexual domains of the UQoL there was a significant improvement from 6.5+2 points (mean pre-treatment) to 10.6+ 3.2 (mean post-treatment), p<0.001. Conclusion: In this open-label prospective study DT56a was effective against symptomatic vulvo-vaginal atrophy in both subjective and objective measures. The changes in symptoms and pH were prompt and paralleled symptomatic relief. DT56a furnished a significant improvement in UQoL. As the placebo effect on the maturation index and vaginal pH is negligible, this 12 patient study provides an indicative measurement of the positive effect of DT56a for the treatment of vulvo-vaginal atrophy and a large double blind placebo controlled trial is planned. (Table presented)

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

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