Francisco Vázquez

Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids

BACKGROUND The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear. METHODS In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a prespecified noninferiority margin of -20%. RESULTS Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], -9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate). CONCLUSIONS Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. (Funded by PregLem; ClinicalTrials.gov number, NCT00740831.).

Long-term treatment of uterine fibroids with ulipristal acetate ☆

OBJECTIVE To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids. DESIGN Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo. SETTING European clinical gynecology centers. PATIENT(S) Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding. INTERVENTION(S) Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo. MAIN OUTCOME MEASURE(S) Amenorrhea, fibroid volume, endometrial histology. RESULT(S) After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2-6 days). Median fibroid volume change was -45% (interquartile range, -66%; -25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were -63%, -67%, and -72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. CONCLUSION(S) Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension).

Changes of the basement membrane and type IV collagen in human skin during aging

OBJECTIVES To determine the relationship between skin collagen IV and basement membrane changes during aging, a total of 35 women who had been admitted for surgery, were studied. METHODS Subjects were arranged into six age-groups (from 35 to 60 years). Skin biopsies were performed in all patients and the samples were taken from a site 6 cm above the pubic symphysis. The collagen IV content and the epithelial basement membrane were analyzed by using immunohistochemical, transmission electron microscopy and computer-assisted image analysis methods. The skin collagen IV content was measured by an image analysis program and expressed in arbitrary units of integrate optical density, and, the basement membrane thickness was expressed in nanometers. RESULTS Type IV collagen content decreased with age after 35 years (r = -0.9561). The epithelial basement membrane thickness increased significantly with age (r = 0.98192; P < 0.01) and there is an inverse correlation between these two parameters (r = -0.990502). CONCLUSIONS Although type IV collagen is a basement membrane component and declines with aging, the total thickness of this membrane increases, which suggests a reduction in tissue turnover.

Endometrial safety assessment of a specific and standardized soy extract according to international guidelines.

Objective: To assess the effects of an oral soy isoflavone extract (Phytosoya) on endometrium (evaluated by biopsy and ultrasonography) in postmenopausal women treated for 12 months. Design: A total of 395 postmenopausal women were included in this international prospective, open-label study. The women were treated for 12 months with a specific standardized soy isoflavone extract (total of 70 mg/d). Endometrial biopsy and transvaginal ultrasonography were performed before and after 12 months of treatment according to European guidelines. Results: A total of 301 assessable biopsy specimens were obtained from women treated for 12 months; the results were 99.67% atrophic/inactive endometrium and 0.33% proliferative endometrium. No case of hyperplasia or carcinoma was diagnosed, demonstrating the endometrial safety of this extract (point estimate: 0.0; upper limit of 95% CI: 0.012). Endometrial thickness did not show any increase after 12 months of treatment (2.2 mm at inclusion and 2.12 mm at the end of the study). Only eight women reported some kind of bleeding as an adverse event during the study. Conclusions: These results of endometrial biopsy and endometrial thickness suggest that daily administration of 70 mg of a specific and standardized isoflavone extract for 12 months does not stimulate the endometrium.

Safety after extended repeated use of ulipristal acetate for uterine fibroids.

Objective To assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters. Methods This long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety. Results All data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10–18 days after the start of menses following treatment courses 5–8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush. Conclusion The results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.

Knowledge and compliance from patients with postmenopausal osteoporosis treatment

Objective The aim of this study was to evaluate the knowledge, attitudes and expectations of patients receiving treatment for postmenopausal osteoporosis, analysing the factors related to good compliance with treatment. Methods A national, epidemiological, cross-sectional study collected information on personal medical history, family history, bone densitometry, and treatment and compliance of patients over 45 years who were receiving treatment for osteoporosis and provided their informed consent. The patients anonymously completed a questionnaire about their knowledge of osteoporosis and the Morisky and Green treatment compliance evaluation test. Results Three hundred and fifteen specialists in gynaecology participated, recruiting 1179 patients with postmenopausal osteoporosis. The mean age was 59.9 years (standard deviation [SD] = 7.5). Only 22.6% of the patients showed an acceptable knowledge of osteoporosis (the criterion established was correct response to 80% of the questions). Treatment compliance was evaluated using a combination of Morisky–Green and Haynes–Sackett criteria. Of the patients 39.2% were classified as compliant, 74.6% of the patients were very or quite concerned about their condition and 53.3%; described their health status as excellent or good. However, 63.6% of the patients indicated that they needed more information about osteoporosis. The factors related to good compliance were the existence of one or no concomitant disease (odds ratio [OR] = 1.38, P = 0.025) and the type of knowledge about their disease (acceptable knowledge: OR = 1.33, P = 0.043). Conclusions Correct knowledge about osteoporosis would increase the possibility of appropriate compliance with the prescribed treatment, thus reducing the risk of osteoporotic fractures.

Lowering the age at menarche and risk of early menarche in a population of Spanish postmenopausal women during the past two decades.

Aim. The purpose of this study is to confirm in our population the decreasing secular trend in the age of menarche (AAM) observed in other European countries. Another aim is to investigate the association between early menarche and breast cancer, metabolic disorders risk or early menopause. Materials and Methods We conducted a nationwide population-based study of 1980 Caucasoid Spanish postmenopausal women from 2003 to 2006 to investigate the AAM, the duration of the fertile period and the relation of early menarche with breast cancer and some metabolic disorders. Results Regression analysis of AAM demonstrates a trend towards the younger AAM in our population during the past decades (P > 0.001). Parallel to this decrease we observe a significant increase in the fertility period and the height of our population (P < 0.001). In the women with AAM less than 11 years, there is an increased risk of hypercholesterolaemia, being overweight and obesity. However, early menarche does not raise the risk of adult onset diabetes, hypertension or breast cancer. Conclusions These data indicate a decreasing secular trend of AAM in a Spanish population in the last decades. Furthermore, hypercholesterolaemia and obesity, but not breast cancer, appears to be influenced by younger AAM. Only women who have their menarche at the age of nine years or less are more likely to have an earlier menopause.

Multigenic combination of estrogen-related genes is associated with age at natural menopause in a Spanish population

Objective Age at natural menopause (ANM) can be considered a complex parameter that depends on the interaction of multiple factors. In the present study, the role of interaction between genetic variants within estrogen synthesis and signalling pathways in the ANM in Spanish women is studied. Material and methods Nine single nucleotide polymorphisms (SNPs) located at different candidate genes related to the estrogen signalling pathway were analysed in 1980 Spanish postmenopausal women. Results Independently, none of the nine markers were significantly associated with early ANM. Only heterozygosis at the NRIP rs2229741 locus could be associated with early menopause; however, this marker does not maintain statistical significance. In contrast, linear regression analysis suggests several epistatic interactions including these markers in relation to ANM, especially between ESR2, NRIP1 and BMP15. The genetic variant that appears most in these interactions is that of the BMP15 rs3897937. It was observed that AA-TC combined genotype for NRIP-BMP15 (rs3897937), respectively, appears to be associated with a lower ANM than other possible combinations of these SNP (46.1±5.9 versus 50.4±3.3; P = 0.002). In the multilocus analysis, the multigenic interaction formed by ESR2 (AA), BMP15 rs3897937 (TC) and NRIP1 (AA) has the lower ANM (45.37±6.8 versus 48.69±5; P = 0.038). Conclusions The results suggest that epistatic interactions of estrogen-related alleles may contribute to variance in ANM in Spanish women. Moreover, BMP15 and NRIP1 also appear as attractive candidate genes for premature menopause but require further investigation to confirm them.

Actitudes, conocimiento y expectativas de las pacientes con osteoporosis posmenopáusica en España

Resumen Objetivo Este estudio describe el perfil, las actitudes, conocimiento y expectativas de las pacientes con osteoporosis posmenopausica. Sujetos y metodos Estudio epidemiologico, transversal, realizado en Espana. Participaron pacientes en tratamiento para osteoporosis posmenopausica > 45 anos. Se recogieron antecedentes personales y familiares, enfermedades y farmacos concomitantes, habitos toxicos, dieteticos y de actividad fisica, tipo de diagnostico, tratamiento y cumplimiento. Todas las pacientes cumplimentaron un cuestionario de 17 preguntas sobre las actitudes, el conocimiento y las expectativas en relacion con su afeccion. Resultados Se incluyo a 1.179 pacientes con osteoporosis posmenopausica validas, con una edad media ± desviacion estandar de 59,89 ± 7,53 anos. Solo el 22,6% mostro un conocimiento aceptable sobre la osteoporosis. Al 74,6% de las pacientes les preocupaba su enfermedad mucho/bastante. El 53,3% describio su estado de salud como excelente/bueno. No obstante, el 63,6% indico que necesitaba mas informacion sobre la osteoporosis. Conclusiones Este estudio ha evidenciado la necesidad de promover el correcto conocimiento de las pacientes con osteoporosis posmenopausica sobre su afeccion.

Factores reguladores del recambio óseo: estrógenos y vitamina D

Resumen El tejido oseo es un efector de las hormonas gonadales esteroides y de la vitamina D. El recambio oseo es el proceso de renovacion del tejido deteriorado y los estrogenos desempenan un papel significativo en el tejido, la regulacion cellular y a nivel molecular. A partir de la menopausia predomina la resorcion osea y aumenta el riesgo de osteoporosis. El sistema endocrino de la vitamina D regula el metabolismo celular oseo a traves de receptores especificos y por mecanismos no genomicos. El deficit de vitamina D es un problema muy extendido en la poblacion general que guarda relacion con la baja exposicion solar y baja ingesta de precursores de la vitamina. El suplemento de vitamina D es una parte importante de las acciones terapeuticas de los tratamientos antirresortivos y para mantener la salud osteomuscular.