Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study.

Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (>50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC.

A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

OBJECTIVE: A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. METHODS: In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance. RESULTS: Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% ( P = 0.0017), -20.96% ( P = 0.0037), and +34.17% ( P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS ( r = 0.34 and r = 0.31, P < 0.001). CONCLUSIONS: E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS.

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety.

OBJECTIVE: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (-66% vs -49%, P = 0.032) and W12 (-82% vs -65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (-0.59 vs -0.33, P = 0.049) and W12 (-1.04 vs -0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS: Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.

Video Summary:http://links.lww.com/MENO/A591.

Adaptation and translation of the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba language using middle-aged women attending a clinic in Nigeria.

OBJECTIVE: The main objective of the study is to translate and adapt the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba, an indigenous Nigerian language, using middle-aged women attending a Family Medicine clinic in Nigeria. METHODS: A total of 322 middle-aged Nigerian women at various menopausal stages were recruited for the study. Their menopausal status was categorized using the Monash Women's Health Program Menopausal Staging Algorithm into pre-, peri-, and postmenopausal groups. The UQOL Yoruba version (YUQOL), Menopause Rating Scale (MRS), and a semistructured sociodemographic questionnaire were interviewer-administered to the women. The collected data were analyzed using IBM SPSS version 21 software. RESULTS: The overall scale and the four subscales of YUQOL all had acceptable internal consistency scores; they also demonstrated good construct and criterion validities, except the YUQOL sexual subscale had poor convergent validity (average variance extracted = 0.23). CONCLUSIONS: This study has validated the YUQOL as a psychometrically sound research instrument for measuring menopause-specific QOL among women undergoing menopausal transition. Its sexual subscale would, however, need to be further tested, preferably in sexually active menopausal women to fully confirm its true psychometric property.

NAMS-gallup survey on women's knowledge, information sources, and attitudes to menopause and hormone replacement therapy.

The North American Menopause Society (NAMS) sponsored a Gallup Organization survey of 833 women aged 45-60 to determine attitudes and experience with menopause and various forms of hormone replacement therapy (HRT). The results of this survey are presented herein.

The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause.

OBJECTIVE: Quality of life (QOL) is an outcome variable requiring measurement in clinical care or pivotal regulatory trial research. Current menopause QOL measures are mostly life phase or disease symptom inventories or scores. Believing that QOL should refer more to "sense of well-being," we have developed the Utian QOL scale (UQOL) that is strongly based on perception of sense of well-being as distinct from menopausal symptoms. DESIGN: A pool of items sampling various aspects of well-being was developed. Peri- and postmenopausal women (n = 327) responded to the items, and their responses were subjected to a factor analysis. Four factors emerged, each representing a QOL domain. The resulting 23-item instrument was validated in a geographically and socioeconomically diverse sample of peri- and postmenopausal women using the Short Form-36, an established, frequently used QOL inventory. QOL domains were subjected to confirmatory factor analyses, formal item analysis was completed, and the measure was assessed for reliability and validity, including a second sample of women (n = 270). RESULTS: Women (n = 597; mean age, 52.9 years) from 12 communities across the United States completed the measure. The UQOL seems to reflect four components of QOL: occupational QOL, health QOL, emotional QOL, and sexual QOL. The questionnaire and scoring system are presented. CONCLUSION: We are reporting on the process of validating an instrument for quantifying sense of well-being in a perimenopausal population. Substantial reliability and validity estimates for the scale and its subscales support the UQOL as a valuable new tool for use in clinical research and practice.

Menopausal transition in Southern Europe: comparative study of women in Serbia and Portugal.

OBJECTIVE: The aim of this study was to assess and compare general menopausal quality of life in Serbia and Portugal. METHODS: In all, 1,503 women aged between 40 and 65 years from Belgrade, Serbia, and Lisbon, Portugal, were included in the study. A sociodemographic questionnaire and the Utian Quality of Life (UQOL) scale were used in data collection. RESULTS: The average age of women was 50 (SD = 5.61) years. Serbian and Portuguese women differed in all sociodemographic characteristics except for body mass index (BMI) and relationship status. There were no significant differences in UQOL total score (P = 0.629) or UQOL sexual score (P = 0.396) between Serbian and Portuguese women. However, occupational (P < 0.001) and health (P = 0.003) scores were significantly higher in the Serbian sample, whereas Portuguese women had higher emotional scores (P < 0.001). Based on the total study sample, women with an average UQOL score were more highly educated, employed, non-smokers, and physically active, and more likely to obtain medical assistance for climacteric symptoms compared with women who reported lower UQOL score. In addition to these characteristics, women with a higher UQOL score had higher annual income, no recent illnesses, and optimal BMI compared with women who reported a lower UQOL score. CONCLUSIONS: This study showed that diverse populations of midlife women can have similar perceptions of quality of life as it encompasses broad dimensions of menopausal somatic and psychosocial symptoms, as well as habits and lifestyle. Further comparative studies using the UQOL scale are warranted to offer more information on the delicate factors influencing well-being in climacteric women worldwide.

Science of intracrinology in postmenopausal women.

OBJECTIVE: To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided. METHODS: Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines. RESULTS: Evolution over 500 million years has engineered the expression of about 30 steroid-forming enzymes specific for each peripheral tissue. These tissue-specific enzymes transform DHEA into the appropriate small amounts of estrogens and androgens for a strictly intracellular and local action. Humans, contrary to species below primates, also possess intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which inactivate the estrogens and androgens at their local site of formation, thus preventing the release of a biologically significant amount of estradiol (E2) and testosterone in the circulation. Since DHEA becomes the unique source of sex steroids after menopause, serum E2 and testosterone are thus maintained at low biologically inactive concentrations with no activity outside the cells of origin. DHEA secretion, unfortunately, starts decreasing at about the age of 30 at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases. Considering this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause). The clinical data obtained using a small dose of intravaginal DHEA (prasterone) confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone. CONCLUSIONS: The symptoms and signs of vulvovaginal atrophy (genitourinary syndrome of menopause) can be successfully treated by the intravaginal administration of DHEA without safety concerns. This strategy exclusively replaces in the vagina the missing cell-specific intracellular estrogens and androgens. This approach avoids systemic exposure and the potential risks of estrogen exposure for the tissues other than the vagina.

[Translation, adaptation and validation of the Brazilian version of the Utian Quality of Life for evaluation of quality of life in the climacteric]. / Tradução, adaptação e validação da versão brasileira do questionário Utian Quality of Life para avaliação da qualidade de vida no climatério.

PURPOSE: To translate, to adapt and to validate the Utian Quality of Life (UQOL) for the Brazilian population. METHODS: Women in the climacteric phase, residents in the city of Natal, Rio Grande do Norte, located in the Brazilian Northeast, were randomly selected. UQOL and SF-36 questionnaires were used, and the translation from English to Portuguese was made by three teachers, while the adaptation stage of the translated version was made by applying the questionnaire to 35 women, which could mark the answer choice "I did not understand the question"; reproducibility measurements (test-retest) and construct validity were used to validate, following international methodological standards. RESULTS: The Brazilian version was fully recognized by the target population, which was comprised of 151 women, as no question showed a percentage of "non-understanding" equal to or greater than 20%. The results for intra and interobserver reproducibility demonstrated significant agreement on all the questionnaire items. This version showed consistency above the required criteria (>70), demonstrating its accuracy, while the construct validity was obtained by statistically significant correlations between the domains occupation, health and emotional of UQOL and the SF-36 domains. The Cronbach's alpha coefficient for the whole instrument was 0.82, representing good accuracy. Item-total correlation analysis showed the scale homogeneity. CONCLUSION: From the steps taken, the UQOL questionnaire was translated and adapted for its use in Brazil, with high reproducibility and validity. Thus, it can be included and used in Brazilian studies that aim at evaluating the quality of life of women during the peri- and postmenopausal.

Tradução, adaptação e validação da versão brasileira do questionário Utian Quality of Life para avaliação da qualidade de vida no climatério / Translation, adaptation and validation of the Brazilian version of the Utian Quality of Life for evaluation of quality of life in the climacteric

OBJETIVOTraduzir, realizar a equivalência e validar o questionário Utian Quality of Life(UQOL) para a população brasileira.MÉTODOSParticiparam do estudo mulheres selecionadas aleatoriamente, na fase do climatério, residentes na cidade de Natal, Rio Grande do Norte, localizada na região do nordeste brasileiro. Foram utilizados os questionários UQOL e SF-36, sendo a fase da tradução realizada da língua inglesa para o português por três professores, enquanto que a fase de adaptação da versão traduzida foi feita através da aplicação do questionário a 35 mulheres, que poderiam marcar a opção de resposta "não compreendi a questão"; e para a validação foram usadas as medidas de reprodutibilidade (teste-reteste) e validade de construto, seguindo as normas metodológicas padronizadas internacionalmenteRESULTADOSA versão brasileira foi reconhecida plenamente pela população-alvo, que foi composta por 151 mulheres, devido a nenhuma questão apresentar percentual de "não compreensão" igual ou superior a 20%. Os resultados obtidos para a reprodutibilidade intra e interobservador demonstraram concordância significativa em todos os itens do questionário. Essa versão apresentou consistência acima do critério requerido (>70), demonstrando sua precisão, enquanto que a validade de construto foi obtida através de correlações estatisticamente significativas entre os domínios ocupação, saúde e emocional do UQOL com os domínios do SF-36. O coeficiente alfa de Cronbach para o instrumento como um todo foi de 0,82, representando boa precisão. Análise da correlação item-total demonstrou a homogeneidade da escala.CONCLUSÃOA partir das etapas realizadas, o questionário UQOL foi traduzido e adaptado para aplicação no Brasil, apresentando alta reprodutibilidade e validade. Dessa forma, pode ser incluído e utilizado em estudos brasileiros que visem avaliar a qualidade de vida durante a peri e pós-menopausa.

PURPOSETo translate, to adapt and to validate the Utian Quality of Life (UQOL) for the Brazilian population.METHODSWomen in the climacteric phase, residents in the city of Natal, Rio Grande do Norte, located in the Brazilian Northeast, were randomly selected. UQOL and SF-36 questionnaires were used, and the translation from English to Portuguese was made by three teachers, while the adaptation stage of the translated version was made by applying the questionnaire to 35 women, which could mark the answer choice "I did not understand the question"; reproducibility measurements (test-retest) and construct validity were used to validate, following international methodological standards.RESULTSThe Brazilian version was fully recognized by the target population, which was comprised of 151 women, as no question showed a percentage of "non-understanding" equal to or greater than 20%. The results for intra and interobserver reproducibility demonstrated significant agreement on all the questionnaire items. This version showed consistency above the required criteria (>70), demonstrating its accuracy, while the construct validity was obtained by statistically significant correlations between the domains occupation, health and emotional of UQOL and the SF-36 domains. The Cronbach's alpha coefficient for the whole instrument was 0.82, representing good accuracy. Item-total correlation analysis showed the scale homogeneityCONCLUSIONFrom the steps taken, the UQOL questionnaire was translated and adapted for its use in Brazil, with high reproducibility and validity. Thus, it can be included and used in Brazilian studies that aim at evaluating the quality of life of women during the peri- and postmenopausal.

Use of compounded hormone therapy in the United States: report of The North American Menopause Society Survey.

OBJECTIVE: A national survey was conducted to determine the extent of use of compounded hormone therapy (C-HT) and to characterize the differences between C-HT users and users of hormone therapy approved by the US Food and Drug Administration (FDA-HT users). METHODS: This Internet survey enrolled 3,725 women aged 40 to 84 years who were postmenopausal or experiencing the menopause transition. The sample was weighted slightly by age, region, education, and race to reflect population attributes based on US Census data. RESULTS: Overall, 9% of women were current users of HT, and 28% of all respondents were ever-users of HT. C-HT users represented 31% of ever-users of HT, 35% of current users of HT, and 41% of ever-users aged 40 to 49 years. Approximately 13% of ever-users indicated current or past use of testosterone. The most cited reason for using HT was vasomotor symptoms (∼70%). Nonapproved indications for using HT were selected more often by C-HT users. There were four reports of endometrial cancer among the 326 C-HT users compared with none reported among the 738 FDA-HT users. Significance was not determined because of small numbers. CONCLUSIONS: This survey indicates substantial use of C-HT across the country and the possibility of higher rates of endometrial side effects with such products. There is a need for standardized data collection on the extent of use of compounded hormones and their potential risks.

S-equol: a potential nonhormonal agent for menopause-related symptom relief.

Many women suffering from vasomotor symptoms (VMS) are now seeking nonpharmaceutical treatments for symptom relief. Recently, S-equol, an intestinal bacterial metabolite of the soybean isoflavone daidzein has received attention for its ability to alleviate VMS and provide other important health benefits to menopausal women. S-equol is found in very few foods and only in traces. About 50% of Asians and 25% of non-Asians host the intestinal bacteria that convert daidzein into S-equol. Clinical trials that evaluated the efficacy of an S-equol-containing product found that VMS were alleviated but these trials were limited in scope and primarily involved Japanese women for whom hot flashes are a minor complaint. The only trial in the United States evaluating hot flashes found symptoms were significantly reduced by S-equol, but the study lacked a placebo group, although it did include a positive control. The daily dose of S-equol used in most trials was 10 mg, and because the half-life of S-equol is 7-10 hours, to maximize efficacy, it was taken twice daily. Subanalysis of epidemiologic studies suggests that equol producers are more likely to benefit from soyfood consumption than nonproducers with respect to both cardiovascular disease and osteoporosis, although the data are inconsistent. The limited safety data for S-equol do not suggest cause for concern, especially with regard to its effects on breast and endometrial tissue. Further studies are needed before definitive conclusions of its effectiveness for VMS can be made, but the preliminary evidence warrants clinicians discussing the potential of S-equol for the alleviation of VMS with patients.

Translation and validation of the Utian Quality of Life Scale in Serbian peri- and postmenopausal women.

OBJECTIVE: This study aimed to translate the Utian Quality of Life Scale (UQOL) into the Serbian and to assess its validity and psychometric properties in Serbian peri- and postmenopausal women. METHODS: This survey included 200 perimenopausal and postmenopausal women. Women were approached after their regular gynecological checkup in two community health centers (city center and outskirts) in the capital city Belgrade. The following instruments were used: general questionnaire (sociodemographics, habits, and medical history), UQOL, Short Form-36, and Beck Depression Inventory. The UQOL was translated according to the recommended methodology for translating questionnaires, and its psychometric properties (internal consistency, factor analysis, discriminant validity, construct validity, and criterion validity) were tested. RESULTS: The mean (SD) UQOL total score was 80.5 (13.5). The Cronbach's α coefficient for the entire scale was 0.83 (Occupational, α = 0.76; Health-Related, α = 0.72; Emotional, α = 0.36; Sexual, α = 0.66). All corrected item-total correlation coefficients were greater than 0.40, confirming that all items were appropriate parts of the UQOL. On exploratory factor analysis, we obtained six factors (five items formed two new clusters: Physical Fitness and Professional Recognition) that explained 85.7% of the total variance. The UQOL total score was significantly negatively correlated with Beck Depression Inventory score (P = 0.001) and significantly positively correlated with all Short Form-36 domains (P = 0.001). In addition, significant intercorrelations of UQOL domains also indicated good criterion validity. CONCLUSIONS: The Serbian version of the UQOL demonstrates satisfactory reliability and validity in the assessment of quality of life among peri- and postmenopausal women. The Serbian version of the UQOL is an adequate quality-of-life instrument in the Serbian language that can be applied in the everyday clinical setting.