A randomized, pilot trial comparing vaginal hyaluronic acid to vaginal estrogen for the treatment of genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study was to compare the efficacy of a non-hormone alternative, vaginal hyaluronic acid (HLA), to a standard-of-care therapy, vaginal estrogen, for the treatment of genitourinary syndrome of menopause (GSM). METHODS: This was a randomized, parallel arm pilot trial. Women with GSM were randomized to an HLA vaginal suppository or vaginal estrogen cream for 12 wk to compare the primary outcome, the vulvovaginal symptom questionnaire (VSQ) score. Secondary outcomes included the following: the female sexual function index (FSFI), the vaginal symptom index (VSI), visual analog scale (VAS) for dyspareunia, vaginal itching, and vaginal dryness, patient global impression of improvement (PGI-I) at follow-up, vaginal maturation index, and vaginal pH. Differences between treatment groups were estimated using the two-sided, two-sample t -test and 95% confidence intervals. RESULTS: Forty-nine women were randomized and 45 participants (vaginal estrogen = 23, vaginal HLA = 22) provided data at week 12. Baseline characteristics were similar in both groups. On the VSQ, there was no observed difference in overall scores between the HLA and vaginal estrogen groups at 12 wk ( P = 0.81). Improvement was seen within both treatment groups on the VSQ after 12 wk. The VAS score, total VSI score, total FSFI score, and vaginal pH improved over time; however, improvement did not differ between study arms. Over 90% participants noted improvement on the PGI-I in both groups ( P = 0.61). No treatment-related serious adverse events occurred. CONCLUSIONS: There were no clinically meaningful differences between vaginal HLA and vaginal estrogen for the treatment of GSM after 12 wk. Vaginal HLA may be a promising non-hormone therapy for GSM.

Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment.

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.

The Women's Health Initiative trial and related studies: 10 years later: a clinician's view.

The Women's Health Initiative (WHI) assessed the long-term effects of hormone therapy (HT) in postmenopausal women. The WHI started HT treatment on women aged 50-79 years in order to ascertain these effects. The study was ended early, due to findings of increased risk of coronary heart disease, breast cancer, stroke, and thromboembolic complications in women receiving estrogen plus progestin, compared to placebo. An increased risk of thromboembolic complications was also demonstrated in the estrogen only component of the WHI. The WHI results were initially reported for all subjects, and showed little difference when data were not analyzed by age. New WHI sub-analyses stratifying results by age, and an extended follow-up of the WHI offer a more complete picture of the effects of HT, revealing that starting HT in postmenopausal women less than ten years from last menstrual period appears to have less risk. In addition, hysterectomized women treated with estrogen only in the WHI have showed less risk of adverse outcomes than women in the estrogen plus progestin group. In this paper, we review data supporting the use of HT administered to postmenopausal women, showing it to have more benefit than risk for symptom control, prevention of bone mineral loss and fracture, and improvement of the metabolic profile in women who began HT when they were less than 60 years of age and had their last menstrual period less than ten years previous. In hysterectomized women treated with estrogen only, a reduction in breast cancer risk was noted in all age groups. The WHI raised many important questions. Ten years later, some have been answered, including confirmation that HT for most newly menopausal women is safe and effective. The treatment of the aging woman, including hormone treatment after menopause, should remain one of our highest research priorities. This article is part of a Special Issue entitled 'Menopause'.

Current attitudes on self-use and prescription of hormone therapy among New York City gynaecologists.

OBJECTIVE: The results of the Women's Health Initiative studies dramatically altered hormone therapy use around the world. In countries outside the United States, self-use in physicians remained unaltered while prescription use declined, implying that physicians may not concur with the findings. We wished to explore prevailing attitudes among American physicians by examining New York City obstetrician-gynaecologists' self-use and prescription use of hormone therapy. STUDY DESIGN: All board-certified obstetrician-gynaecologists in New York City were invited to complete and return a detailed, previously validated questionnaire concerning hormone therapy use. RESULTS: Two hundred and nine questionnaires were returned, for a response rate of 12% (209/1797). Gynaecologists agreed with the findings from the Women's Health Initiative studies regarding indications and contraindications to hormone therapy use. Even so, three-quarters of female gynaecologists and female partners of male gynaecologists (74%; 67/91) use or have previously used hormone therapy. However, only 27.3% (21/77) of male gynaecologists and 12.3% (14/114) of female gynaecologists recommend hormone therapy to all menopausal women regardless of contraindications. Gynaecologists remain divided in their attitude toward hormone therapy; 30% of gynaecologists felt that hormone therapy use generally prolonged women's lives, 36% felt it was not useful in prolonging women's lives, and 33% were unsure. CONCLUSION: Since the publication of the Women's Health Initiative findings, New York City gynaecologists prescribe hormone therapy to fewer patients. However, they continue to self-use hormone therapy at much higher rates, even as they seem to concur with Women's Health Initiative recommendations, contributing to the ongoing controversy surrounding the validity of the Women's Health Initiative findings.

Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen.

Two clinical trials previously demonstrated the safety of 300 µg/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.

The selective estrogen receptor modulator DT56a (Femarelle) does not affect platelet reactivity in normal or thrombophilic postmenopausal women.

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.

Endometrial safety of ultra-low-dose estradiol vaginal tablets.

OBJECTIVE: To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17ß-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.

Therapy: nonhormonal treatment of hot flashes-a viable alternative?

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?

Does combined hormone replacement therapy improve the health-related quality of life of postmenopausal 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.

Association of oral but not transdermal estrogen therapy with enhanced platelet reactivity in a subset of 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.