RESUMO
OBJECTIVE: The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17ß-estradiol [E2]/progesterone [P4]) capsules on hot flushes severity (vasomotor symptoms [VMS] severity scale) using the patient-reported Clinical Global Impression (CGI). METHODS: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR in postmenopausal women (40-65 y) with a uterus. Those with frequent moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized in a VMS substudy to daily E2/P4 (1/100, 0.5/100, 0.5/50, or 0.25/50âmg/mg), or placebo. Patients rated VMS severity from 1 (mild) to 3 (severe) and symptom improvements with the CGI. CGI results were an anchor in a nonparametric discriminant analysis to define clinically important differences (CIDs) and minimal CID in VMS severity at weeks 4 and 12. RESULTS: In the VMS substudy (nâ=â726), determined CID and minimal CID severity thresholds were reductions of 0.525 and 0.350 points at week 4, respectively, and 0.775 and 0.225 points at week 12. Significantly more women taking the two highest E2/P4 doses (1/100 and 0.5/100) versus placebo met CID severity thresholds at weeks 4 (40% and 44% vs 17%; Pâ<â0.05) and 12 (56% and 48% vs 29%; Pâ<â0.05). CONCLUSION: REPLENISH trial data demonstrated that E2/P4 1/100 and 0.5/100 provided clinically meaningful improvements in hot flushes severity in postmenopausal women. In conjunction with previously demonstrated clinically meaningful VMS frequency improvements, these data support oral E2/P4 1/100 and 0.5/100 for postmenopausal women with a uterus seeking treatment for moderate to severe VMS.
Assuntos
Pós-Menopausa , Progesterona , Método Duplo-Cego , Estradiol , Feminino , Fogachos/tratamento farmacológico , Humanos , Resultado do TratamentoRESUMO
OBJECTIVE: The softgel 17ß-estradiol (E2) vaginal inserts (4 and 10âµg; Imvexxy; TherapeuticsMD, Boca Raton, FL) are FDA approved for treating moderate to severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy (VVA). The objective here was to determine responder rates at week 2 and whether week-2 findings predicted week-12 responders in the REJOICE trial. METHODS: Postmenopausal women received E2 vaginal inserts 4, 10, or 25âµg, or placebo for 12 weeks. Proportion of responders (having ≥2 of the following: vaginal superficial cells >5%, vaginal pH <5.0, or dyspareunia improvement of ≥1 category) were calculated. Odds ratios (ORs) for positive response at week 12 given a positive response at week 2 were determined in the efficacy evaluable (EE) population. RESULTS: The responder rate (in EE population [nâ=â695]) was 74% to 82% with E2 inserts versus 24% with placebo at week 2, and 72% to 80% versus 33% at week 12. Positive treatment responses were 9- to 14-fold higher with vaginal E2 than with placebo at week 2, and 5- to 8-fold higher at week 12. Response at week 2 predicted response at week 12 in the total population (OR 13.1; 95% CI, 8.8-19.7) and with active treatment only (OR 7.9; 95% CI, 4.7-13.2). CONCLUSIONS: A high percentage of postmenopausal women with moderate to severe dyspareunia responded with the E2 softgel vaginal insert at week 2, and a positive response at week 2 predicted a positive response at week 12.
Assuntos
Dispareunia/tratamento farmacológico , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Vulva/patologia , Doenças da Vulva/tratamento farmacológico , Administração Intravaginal , Adulto , Idoso , Atrofia/tratamento farmacológico , Método Duplo-Cego , Dispareunia/complicações , Dispareunia/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Resultado do Tratamento , Doenças Vaginais/complicações , Doenças Vaginais/patologia , Doenças da Vulva/complicações , Doenças da Vulva/patologiaRESUMO
OBJECTIVE: The aim of the study was to systematically review studies that evaluated endometrial hyperplasia or cancer incidence with unopposed vaginal estrogens. METHODS: PubMed and EMBASE were searched from inception to August 2017 for relevant articles and abstracts. Bibliographies of review articles and abstracts of major women's health medical meetings were examined. Eligible studies (independently reviewed by 4 authors) had to report menopausal vaginal estrogen use and endometrial histology, or incidence of endometrial hyperplasia or cancer. RESULTS: Of 5,593 abstracts from the literature search and 47 articles from other sources, 36 articles and 2 abstracts were eligible, describing 20 randomized controlled studies, 8 interventional studies, and 10 observational studies. Collectively, the studies did not support an increased risk of endometrial hyperplasia or cancer with low-dose vaginal estrogens. Rates of endometrial cancer and hyperplasia were 0.03% and 0.4%, respectively, from 20 randomized controlled trials (2,983 women) of vaginal estrogens. Overall, reports of endometrial hyperplasia were observed with various doses and durations and appeared sporadic (except 1.25âmg conjugated equine estrogens), consistent with endometrial hyperplasia rates in the general population. A Denmark registry study was an exception and may be of limited applicability to the United States. The Women's Health Initiative Observational Study showed no association (1.3 cases/1,000 women-years with vaginal estrogens versus 1.0/1,000 women-years for nonuse). CONCLUSION: This systematic review supports the use of low-dose vaginal estrogens for treating vulvar and vaginal atrophy in menopausal women without a concomitant progestogen. This review does not support increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens; however, longer-term, real-world data are needed.
Assuntos
Hiperplasia Endometrial/epidemiologia , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Medicina Baseada em Evidências , Menopausa , Administração Intravaginal , Relação Dose-Resposta a Droga , Estrogênios Conjugados (USP)/administração & dosagem , Feminino , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Estados Unidos/epidemiologia , Saúde da MulherRESUMO
OBJECTIVE: The aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus. METHODS: In the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (≥7/d or ≥50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17ß-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods. RESULTS: In the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression-based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥25 moderate to severe VMS: 82-88% vs 69%; all, Pâ<â0.05) and CID (weekly reduction of ≥39 VMS: 68%-73% vs 52%; all, Pâ<â0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life-based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥34 VMS: 74%-81% vs 55%; all, Pâ<â0.01) and CID (weekly reduction of ≥44 VMS: 61%-69% vs 42%; all, Pâ<â0.01) at week 12. CONCLUSIONS: TX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.
Assuntos
Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios/métodos , Estrogênios/uso terapêutico , Fogachos/tratamento farmacológico , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Combinação de Medicamentos , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , ÚteroRESUMO
OBJECTIVE: To evaluate the response of the vaginal mucosa with TX-004HR and its correlation with vulvar and vaginal atrophy (VVA) symptoms, and whether visual examination is a useful measure for assessing VVA. METHODS: REJOICE was a 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study of a vaginal, muco-adhesive, 17ß-estradiol softgel capsule (TX-004HR 4, 10, and 25âµg) in postmenopausal women with VVA and moderate-to-severe dyspareunia. Treatments were self-administered vaginally once per day for 2 weeks, then twice per week for 10 weeks. The vagina was visually examined at baseline and at weeks 2, 6, 8, and 12; changes were evaluated using a 4-item scale for vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal secretions. RESULTS: Significant improvements were observed with all three TX-004HR doses versus placebo in vaginal color (least square mean score changes of -0.96 to -1.06 for TX-004HR doses vs -0.60 for placebo at week 12), epithelial integrity (-0.97 to -1.07 vs -0.60), epithelial surface thickness (-0.94 to -1.03 vs -0.61), and secretions (-1.01 to -1.06 vs -0.64) (Pâ<â0.001 for all comparisons at all time points). Both Pearson's correlations and logistic regression receiver-operating characteristic curve analyses significantly correlated the sum of the individual visual assessment scores with dyspareunia (Pâ<â0.0001) and vaginal dryness (Pâ<â0.0001) at 12 weeks. CONCLUSIONS: Greater improvements in the vaginal mucosa of postmenopausal women with VVA and moderate-to-severe dyspareunia were observed with TX-004HR versus placebo, and vaginal mucosa assessment scores correlated with vaginal symptoms of dyspareunia and dryness. Visual vaginal assessment by healthcare professionals is a useful measure for diagnosing VVA and assessing response to treatment.
Assuntos
Estradiol/administração & dosagem , Mucosa/patologia , Pós-Menopausa , Vagina/patologia , Vulva/patologia , Administração Intravaginal , Idoso , Atrofia/tratamento farmacológico , Cor , Método Duplo-Cego , Dispareunia/tratamento farmacológico , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Placebos , Curva ROC , Resultado do Tratamento , Vagina/metabolismo , Doenças Vaginais/tratamento farmacológico , Doenças da Vulva/tratamento farmacológico , Doenças da Vulva/patologiaRESUMO
OBJECTIVE: TX-004HR is an investigational, muco-adhesive, vaginal, softgel capsule containing low-dose, solubilized, 17ß-estradiol designed to treat postmenopausal vulvar and vaginal atrophy (VVA) and improve user experience without an applicator and less mess. METHODS: As part of the 12-week, placebo-controlled, double-blind, phase 3 REJOICE trial evaluating the efficacy/safety of 4-, 10-, and 25-µg TX-004HR in 764 postmenopausal women with VVA, a five-question product survey was administered. Pearson correlation coefficients were used to evaluate correlations between clinical endpoints (vaginal physiology, dyspareunia, and vaginal dryness) and patient acceptability and satisfaction. RESULTS: Majority of the women receiving TX-004HR or placebo reported that the product was easy to use (85.4%-92.1%) and rated ease of capsule insertion as "good" to "excellent" (75.0%-82.6%). A significantly greater percentage of women reported being "very satisfied" or "satisfied" with TX-004HR (68.6%-76.3%) than with placebo (56.8%, Pâ<â0.05 for all). A greater percentage of women "somewhat" or "very much" preferred TX-004HR over their previous treatment versus those taking placebo (Pâ<â0.05). Significantly more women receiving TX-004HR (72.8%-80.5%) versus placebo (62.5%, Pâ<â0.05) would "probably" or "definitely" consider using the product again. Dyspareunia and vaginal dryness reductions were correlated with higher product satisfaction and the percentage of women who would consider re-using TX-004HR. CONCLUSIONS: TX-004HR had a high level of product acceptability, and more women were satisfied with TX-004HR, preferred it over their previous treatment, and would consider using it again versus placebo. Women may find TX-004HR to be a more acceptable product than current options to treat their dyspareunia associated with postmenopausal VVA.
Assuntos
Estradiol/administração & dosagem , Satisfação do Paciente , Doenças da Vulva/tratamento farmacológico , Administração Intravaginal , Adulto , Idoso , Atrofia/tratamento farmacológico , Método Duplo-Cego , Dispareunia/tratamento farmacológico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos , Vagina/patologiaRESUMO
OBJECTIVE: The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause. METHODS: This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100âmg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment. RESULTS: One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100âmg groups). The response in the 10âmg group was significantly different from placebo at 4 weeks (Pâ=â0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS: Daily treatment with 10âmg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.
Assuntos
Fogachos/tratamento farmacológico , Pós-Menopausa/fisiologia , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tetra-Hidronaftalenos/uso terapêutico , Sistema Vasomotor/efeitos dos fármacos , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Ligantes , Pessoa de Meia-Idade , Moduladores Seletivos de Receptor Estrogênico/sangue , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: Ospemifene is an estrogen-receptor agonist/antagonist (also known as a selective estrogen-receptor modulator) that is FDA approved for the treatment of moderate-to-severe dyspareunia, a symptom of vulvovaginal atrophy, due to menopause. Preclinical and clinical data suggest that ospemifene may also have an effect on bone health in postmenopausal women. METHODS: Relevant articles, including cellular and preclinical studies and clinical trials written in English pertaining to ospemifene and bone health, were identified from a database search of PubMed (from its inception to June 2015) and summarized in this comprehensive review. RESULTS: In vitro data suggest that ospemifene may mediate a positive effect on bone through osteoblasts. Ospemifene effectively reduced bone loss and resorption in ovariectomized rats, with activity comparable to estradiol and raloxifene. Clinical data from three phase 1 or 2 clinical trials (2 placebo- and 1 raloxifene-controlled) found ospemifene 60âmg/d to have a positive effect on the biochemical markers for bone turnover in healthy, postmenopausal women with significant improvements relative to placebo and comparable to raloxifene. CONCLUSIONS: Ospemifene 60âmg/d may have a protective effect on the bone health of women being treated for dyspareunia. The initial clinical data for ospemifene follows a trend similar to raloxifene and bazedoxifene, suggesting that ospemifene may have bone-protective effects in postmenopausal women. However, additional rigorous clinical trials are necessary to confirm any positive effects ospemifene may have on vertebral fractures and bone mineral density in healthy and osteoporotic women.
Assuntos
Osso e Ossos/efeitos dos fármacos , Dispareunia/tratamento farmacológico , Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/análogos & derivados , Animais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Ensaios Clínicos Controlados como Assunto , Feminino , Humanos , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Tamoxifeno/uso terapêuticoRESUMO
OBJECTIVE: From a survey of compounding pharmacists, specific questions regarding compounded menopausal hormone therapy were used to estimate compounded hormone therapy (CHT) prescribing in the United States. METHODS: A national online survey was conducted by Rose Research--a market research company consisting of 12,250 US pharmacists from independent community pharmacies (ICPs) and compounding pharmacies (CPs). Pharmacists who completed the survey and met the prespecified criteria were eligible. Data from the survey were extrapolated to estimate overall CHT prescription volume and annual costs of CHT prescriptions for the United States based upon industry data from the National Community Pharmacists Association and IBISWorld. RESULTS: Surveys were completed by 483 pharmacies, including 365 ICPs and 118 CPs. On the basis of the survey responses and extrapolated industry data, an estimated 26 to 33 million CHT prescriptions were filled annually, with total sales estimated at $1.3 to $1.6 billion. CPs (vs ICPs) accounted for a higher proportion of CHT prescriptions. More than half of the ICPs (52%) and CPs (75%) expected continued compounding business growth, with most predicting 5% to 25% growth within 2 years, despite the potential effect of restrictive legislation regarding compounding. CONCLUSIONS: On the basis of extrapolated data from numbers of prescriptions reported by pharmacists participating in the survey, the volume of CHT seems to approach that of Food and Drug Administration (FDA)-approved menopausal hormone therapy, and growth in the CHT market is expected. Thus, physicians should educate themselves and the women consulting them about the differences between the FDA-approved and the less-tested CHT formulations. More research on the efficacy, safety, and consistency of non-FDA-approved CHT is needed.
Assuntos
Aprovação de Drogas/legislação & jurisprudência , Terapia de Reposição de Estrogênios , Menopausa , Medicamentos sob Prescrição , Inquéritos e Questionários , United States Food and Drug Administration/legislação & jurisprudência , Composição de Medicamentos , Indústria Farmacêutica/legislação & jurisprudência , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Terapia de Reposição de Estrogênios/estatística & dados numéricos , Estrogênios , Feminino , Humanos , Internet , Farmacêuticos , Progestinas , Estados UnidosRESUMO
OBJECTIVE: Treatment of menopausal symptoms by compounds with tissue-selective estrogen agonist/antagonist effects, often called selective estrogen receptor modulators, has been researched as an alternative to the use of estrogen therapy. These structurally diverse molecules elicit tissue-dependent responses in hormone-responsive tissues and organs, exhibiting variations in estrogenic activity in preclinical models of postmenopausal reproductive tissues that may improve postmenopausal women's health (eg, prevention and treatment of breast cancer, osteoporosis, and vulvar and vaginal atrophy). METHODS: This literature review investigates whether preclinical data predicted the clinical effects of ospemifene on female reproductive and urinary tract tissues and compares these findings with the specific vaginal effects of other estrogen receptor agonists/antagonists (tamoxifen, raloxifene, and bazedoxifene) in preclinical and clinical studies. Lasofoxifene, although not currently available, is included because of its unique effects on vaginal tissue. RESULTS: The response of endometrial and vaginal tissues to estrogen receptor agonists/antagonists can be differentiated using transvaginal ultrasound, endometrial histopathology, cytologic examination of vaginal smears, assessment of physical changes in the vagina, and relief of symptoms associated with vulvar and vaginal atrophy (such as dyspareunia). CONCLUSIONS: Available evidence indicates that ospemifene has unique effects on tissue, leading to a favorable long-term profile for the relief of vulvar and vaginal atrophy compared with other estrogen receptor agonists/antagonists (eg, tamoxifen, raloxifene, and bazedoxifene) with no short-term concerns about endometrial safety (based on endometrial hyperplasia, carcinoma, endometrial spotting, and endometrial bleeding).