NAMS sobre la terapia hormonal TH, Hormonas bioidénticas

El término hormonas bioidénticas es a menudo usado para describir las fórmulas magistrales de TH (llamada terapia hormonal bioidéntica (THB) que son realizadas por un individuo de acuerdo a la prescripción de un prestador de salud. El término es usado por proponentes de la THB con el convencimiento que las hormonas que ellos usan son las hormonas producidas por el ovario. En ese aspecto, el término también puede ser usado para referirse a las muchas bien probadas, aprobadas por el gobierno, productos de marca de TH, conteniendo hormonas químicamente idénticas a las producidas por las mujeres (primariamente en los ovarios, tales como el 17ª estradiol y progesterona).

Compuestos tradicionales de TH puede combinar varias hormonas (estradiol, estrona, y estriol) y usar ruta no convencionales de administración (implantes subdérmicos). Algunas de las hormonas no son aprobadas por el gobierno (estriol) o monitorizadas y algunas de las terapias compuestas contienen ingredientes no hormonales (colorantes, preservativos) que algunas mujeres no pueden tolerar. El uso de BHT ha aumentado en los años recientes, junto con el uso de la medición hormonal en saliva, lo cual ha probado no ser exacto ni confiable. Puede haber aumento del riesgo en las mujeres que usan estos productos.

Fórmulas preparadas tradicionales, incluyendo BHT, no han sido probadas para eficacia o seguridad; la información de los productos no es consistente a las mujeres a través de la prescripción, y es requerida con TH disponible comercialmente; la estandarización de los lotes y su pureza puede ser incierta. Las dosis de los compuestos progestacionales son particularmente difícil de valorar porque los niveles en suero, saliva y tejidos son marcadamente diferentes.164 Las drogas preparadas no son aprobadas por el gobierno.

La administración de drogas y alimentos FDA, ha retirado algunos compuestos de farmacias que han tenido reclamos por seguridad y efectividad de –BTH sin reporte de datos de estudios clínicos y considerados que son falsos y engañosos.165 Las farmacias han sido instruidas de no usar estriol sin una autorización de nueva droga. La FDA también establece que no hay bases científicas para usar test en saliva para ajustar los niveles hormonales.

La NAMS recomienda que los productos BTH incluyan un instructivo en los paquetes idénticos a los requeridos para productos que han tenido aprobación del gobierno. En la ausencia de datos de eficacia y seguridad de los BTH, la relación riesgo-beneficio generalizada de los productos comerciales disponibles de TH se pueden aplicar igualmente a los BTH.

Para la mayoría de las mujeres, la TH aprobada por el gobierno va a proveer terapia apropiada sin los riesgos de las preparaciones de medicamentos.

Por lo tanto, la NAMS generalmente no recomienda estas preparaciones de TE y TEP a no ser que sea necesario debido a alergias a los ingredientes contenidos en productos aprobados por el gobierno.

Puntos acerca de tratamiento

Duración de uso

Uno de los temas más desafiantes acerca de la TH es la duración de uso. Datos de seguimientos a largo plazo del WHI han clarificado el aumento de riesgo de cáncer de mama y mortalidad por cáncer de mama con 4 a 5 años de uso después de la menopausia de TEP y un ligero aumento en el inicio de cáncer de mama si se usa después en una exposición a estrógenos.74,78 Acerca de TE, no hubo aumento del riesgo de cáncer de mama con uso en la posmenopausia temprana en el WHI o NHS, y hubo disminución en la incidencia de cáncer de mama usada cuando se usó después de una laguna en la exposición de estrógenos en el WHI.76,85 En el uso a largo plazo de TE (15 a 20 años en el NHS) pudo haberse esperado un aumento en cáncer de mama, pero no en un grado menor que con TEP.85 Se vio enfermedad arterial coronaria potencial y benéfica de ECC.

Con el uso temprano de TE, en el estudio WHI, las mujeres entre los 50 a 59 años de edad tenían significativamente menor riesgo de resultados finales combinados incluyendo ECC y mortalidad total por IM y no elevación en el riesgo de cáncer de mama.28 Estudios observacionales sugieren que mayor tiempo de uso se asocia con un reducido riesgo de ECC y mortalidad relacionada.166 Los RCTs WHI y el estudio observacional sugiere un patrón de más bajo riesgo entre mujeres quienes usan TH por 5 años o más,49 pero esto no es concluyente, podría ser considerado a la luz por otros factores alterados por la duración de la terapia, tales como cáncer de mama. En contraste, tanto la TE como TEP están asociados con un aumento inicial en riesgo de ECC entre mujeres quienes están más distantes de la menopausia al tiempo de la iniciación de la TH.38,167,168 Estos hallazgos permiten una más larga duración de uso de TE basados en los síntomas de la mujer preferencias y perfil benéfico actual de riesgo-beneficios.

Está previsto que la mujer esté bien conciente de los potenciales beneficios y riesgos que tiene supervisión clínica. El uso extendido de TEP con la dosis efectiva más baja es aceptable bajo algunas circunstancias, incluyendo: 1. para las mujeres quienes han determinado que los beneficios del alivio de los síntomas menopáusicos sobrepasa los riesgos, notablemente después de la falla en suspender la TEP, y 2. para la mujer con alto riesgo de fractura para quien las terapias alternativas no son apropiadas o les causa efectos adversos inaceptables.

Suspensión de la terapia

Datos de seguimiento a largo plazo de mujeres quienes suspendieron la terapia TE y TEP, han aumentado nuestro conocimiento de las secuelas de la suspensión de la TH. En el WHI, las mujeres en el grupo TEP quienes habían suspendido la TH por tres años tenían una tasa de eventos cardiovasculares, fracturas y cánceres de colon similar a las mujeres que habían sido asignadas a placebo.27 La única diferencia estadística fue un aumento de las tasas de todos los cánceres en mujeres quienes habían sido asignadas a EP con un exceso de 30 cánceres por 10.000 mujeres por año de TEP, incluyendo un número de canceres fatales de pulmón.27,77 En mujeres sin útero, seguidas por tres años después de suspender TE, no hubo aumento o disminución del riesgo global de ECC, trombosis venosa profunda, ACV fractura de cadera, cáncer colorrectal o mortalidad total.

Una disminución estadísticamente significante del riesgo de cáncer invasivo de cáncer de mama persistió (8 casos menos/10.000 mujeres).28 La suspensión de la TH llevará a un aumento transitorio de la incidencia de fractura, incluyendo fractura de cadera.169 Después de cuatro años de seguimiento en el brazo de TE del WHI, las tasas acumulativas de fractura fueron similares para los grupos de TE y placebo.28

RRs para todas las causas de mortalidad, reflejando el balance de todos los resultados de arriba y otros más, tendieron a la neutralidad en ambos grupos de TEP y TE del WHI (RR, 0.98 y 1.04, respectivamente).

Durante los tres años posteriores a la fase de intervención en el estudio de TEP, las tasas de mortalidad estuvieron elevadas en el límite (RR, 1.15; IC 95%, 0.95-1.39) primariamente debido al citado aumento en cáncer. Durante todo el periodo de seguimiento de TEP (tratamiento activo más fases pos-suspensión), el RR de todas las causas de mortalidad en el brazo de TEP fue de 1.04 (IC 95% 0.91-1.18)27 y 1.02 (IC 95%, 0.91-1.15) en el brazo de TE.28

Con relación a otros resultados después de la suspensión de la TEP, un análisis inicial de los datos del registro del National Cancer Institute’s Surveillance, Epidemiology and End Results, mostró que la tasa de incidencia de cáncer de mama ajustado por la edad en mujeres en EE.UU. cayo dramáticamente (6.7%) en el 2003, comparada con la tasa del 2002.170 La disminución fue evidente solo en mujeres de 50 años de edad o mayores y más evidente en cánceres que eran receptores de estrógenos positivos, lo cual representa la mayoría de los cánceres de mama. Se teorizó que la caída podría estar relacionada con el gran número de mujeres que suspendieron la TH después de la terminación prematura del brazo de TEP del WHI.

Los síntomas vasomotores tienen un chance aproximado del 50% de recurrencia cuando la TH se suspende, independiente de la edad y la duración de uso.171,172 En un RCT, disminuyendo la dosis de TH por un mes y una abrupta suspensión, tuvo un impacto similar sobre los síntomas vasomotores.173 La decisión de continuar la TH debería individualizarse basado en la severidad de los síntomas y las consideraciones actuales de la relación riesgo-beneficio.

Conclusiones y recomendaciones

La individualización es la clave importante en la decisión del uso de TH y debería incorporarse como prioridad de calidad de vida, en la salud de la mujer al igual que sus factores de riesgo personales de trombosis venosa, ECC, ACV y cáncer de mama.

La recomendación de la duración de la terapia difiere para TEP y TE. Para TEP, la duración está limitada por el aumento del riesgo de cáncer de mama y de mortalidad por cáncer de mama asociado con el uso de tres a cinco años; para TE, un perfil de riesgo-beneficio más favorable se observa durante un promedio de siete años de uso y cuatro años de seguimiento; un hallazgo que permite más flexibilidad en su uso.

La TE es el tratamiento más efectivo de los síntomas de atrofia vulvar y vaginal; bajas dosis de TE local vaginal se recomiendan cuando solo los síntomas vaginales están presentes.

En mujeres con menopausia prematura o temprana quienes por otra parte son candidatas para TH, pueden usar TE al menos hasta la edad promedio de la menopausia natural (51 años).

Si la duración del tratamiento es más largo, se puede considerar si se necesita el manejo de los síntomas.

Aunque la TE no aumenta el riesgo de cáncer de mama en el WHI, faltan datos de seguridad del uso de TE en las pacientes sobrevivientes de cáncer de mama, y un RCT reportó el aumento mayor en tasas de recurrencia de cáncer de mama.

Tanto la iba transdérmica como las bajas dosis de estrógenos orales se ha asociado con riesgos menores de TEV y ACV que las dosis estándares de estrógenos orales, pero no hay evidencia RCT de ello.

Resumen

Desde la primera publicación de los resultados del estudio WHI-TEP, hemos aprendido mucho. Hay creciente evidencia de formulaciones de TH, rutas de administración, tiempo de la terapia, los cuales producen diferentes efectos.

Un perfil constructivo e individual de riesgo beneficios es esencial para cada mujer considerando cualquier tipo de régimen de TH. El interés de la mujer en usar TH va a variar dependiendo de la situación individual, particularmente la severidad de sus síntomas menopáusicos y sus efectos en la calidad de vida. El riesgo absoluto conocido hasta el momento del uso de TH en mujeres sanas entre 50 a 59 años, es bajos.
En contraste, TH a largo plazo o inicio de TH en mujeres mayores está asociado con riesgo mayor.

La recomendación de duración de uso difiere entre TE y TEP. Dado el perfil más favorable de TE, podría considerarse para terapia de más larga duración en la ausencia de efectos adversos y factores de riesgo. Las mujeres que experimenten menopausia prematura tienen un riesgo aumentado de osteoporosis y, posiblemente, enfermedad cardiovascular. A menudo ellas experimentan síntomas más intensos que las mujeres que llegan a la menopausia en edad mediana. Por lo tanto, la TH generalmente es recomendada para esas mujeres jóvenes hasta la edad media de la menopausia, cuando el tratamiento debe reevaluarse.

Se necesita investigación adicional para entender los diferentes efectos de la TE y TEP, y cómo debe aplicarse a la mujeres individualmente como también para delinear más claramente el papel del envejecimiento versus la menopausia y los efectos genéticos, de estilo de vida y características clínicas individuales, en la salud de la mujer de edad mediana.

Reconocimientos

NAMS appreciates the contributions of the following members of the Advisory Panel: Co- Chairs: Margery L.S. Gass, MD, NCMPV Executive Director, The North American Menopause Society, Mayfield Heights, OH; Consultant, Cleveland Clinic Center for Specialized Women’s Health, Cleveland, OH, and JoAnn E. Manson, MD, DrPH, NCMPV Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief of Preventive Medicine, Co-Director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Boston, MA. Panelists: Felicia Cosman, MDV Professor of Clinical Medicine, Columbia University; Clinical Director, National Osteoporosis Foundation, Medical Director, Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY. Francine Grodstein, ScDV Associate Professor of Medicine, Channing Lab, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. aig Jordan, OBE, PhD, DSc, FmedSciV Scientific Director and Vice Chairman of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, Richard H. Karas, MD, PhDV Professor of Medicine, Director, Women’s Heart Center; Co-Director, Molecular Cardiology Research Center, Tufts University School of Medicine, Boston, MA. Andrew M.

Kaunitz, MDV Professor and Associate Chair, Department of Obstetrics & Gynecology, Associate Program Director, Residency Program in Obstetrics & Gynecology, University of Florida College of Medicine, Jacksonville, FL. Pauline M. Maki, PhDV Associate Professor of Psychiatry and Psychology, Director, Women’s Mental Health Research, University of Illinois at Chicago College of Medicine, Chicago, IL. Peter J. Schmidt, MDV Acting Chief, Behavioral Endocrinology Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Jan L. Shifren, MD, NCMPV Associate Professor of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School; Director, Menopause Program, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, MA. Cynthia A. Stuenkel, MD, NCMPV Clinical Professor of Medicine, Endocrinology andSchool of Medicine, oston, MA. Andrew M. Metabolism, University of California, San Diego, La Jolla. CA. Wulf H. Utian, MD, PhD, DSc(Med), School of Medicine, Boston, MA. Andrew M.NCMPV Professor Emeritus, Case Western Reserve University School of Medicine, Executive Director Emeritus, The North American Menopause Society, Cleveland, OH. The Society also acknowledges the editorial contributions of Kathryn J. Wisch, NAMS Managing Editor, and Angela M. Bilancini, NAMS Associate Medical ditor.

The position statement was reviewed and approved by the 2011-2012 NAMS Board of Trustees: Thomas B. Clarkson, DVMV Professor of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, Margery L.S. Gass, MD, NCMPV Executive Hormonas bioidénticasirector, The North American Menopause Society, Mayfield Heights, OH; Consultant, Cleveland Clinic Center for Specialized Women’s Health, Cleveland, OH. Steven R. Goldstein, MD, FACOG, CCD, NCMPV Professor of Obstetrics and Gynecology, New York University School of Medicine, New York, Risa Kagan, MD, FACOG, CCD, NCMPV Clinical Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, East Bay Physicians Medical Group, Berkeley, CA. Andrew M. Kaunitz, MDV Professor and Associate Chair, Department of Obstetrics and Gynecology, Associate Program Director, Residency Program in Obstetrics & Gynecology, University of Florida College of Medicine, Jacksonville, FL. Pauline M. Maki, PhD (Secretary)V Associate Professor of Psychiatry and Psychology, Director, Women’s Mental Health Research, University of Illinois at Chicago College of Medicine, Chicago, IL. JoAnn Manson, MD, DrPH, NCMP (President)V Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief of Preventive Medicine, Co-Director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Boston, MA. Diane T. Pace, PhD, FNP, FAANP, NCMP (President-Elect) Assistant Dean for Faculty Practice, Director, University Health Services, University of Tennessee Health Science Center, College of Nursing, Memphis, TN. Isaac Schiff, MD (Ex Officio)VJoe Vincent Meigs Professor of Gynecology, Harvard Medical School; Chief, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, MA. Peter F. Schnatz, DO, FACOG, FACP, NCMPV Associate Chairman and Residency Program Director, Department of Obstetrics and Gynecology, The Reading Hospital and Medical Center, Reading, PA. Marla Shapiro, MDCM, CCFP, MHSc, FRCP(C), FCFP, NCMPV Associate Professor, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada. Jan L. Shifren, MD, NCMP (Treasurer)V Associate Professor of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School; Director, Menopause Program, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, MA. Lynnette Leidy Sievert, PhDV Professor, Department of Anthropology, University of Massachusetts, Amherst, MA. Wulf H. Utian, MD, PhD, DSc (Med)V Professor Emeritus, Case Western Reserve University School of Medicine; Executive Director Emeritus, The North American Menopause Society, Cleveland, Michelle P. Warren, MD, NCMPV Medical Director, Center for Menopause, Hormonal Disorders, and Women’s Health; Professor of Medicine, Obstetrics and Gynecology, Wyeth Professor of Women’s Health, Columbia Presbyterian Medical Center, Department of Obstetrics and Gynecology, New York, NY. Financial disclosure/conflicts of interest: For the Advisory Panel, Dr. Cosman reports: Consultant/Advisory Board: Amgen, Eli Lilly, Merck, Novartis, Zosano; Grants/ Research Support: Eli Lilly, Novartis; Speaker’s Bureau: Amgen, Eli Lilly, Novartis; Dr. Gass reports: No significant financial relationships. Dr. Grodstein reports: No significant financial relationships. Dr. Jordan reports: No signifAngela M. Bilancini, NAMS Associate Medicalicant financial relationships. Dr. Karas reports: No significant financial relationships. Dr. Kaunitz reports: Consultant/Advisory Board: Bayer, Merck, Noven, Teva; Grants/Research Support: Bayer, Endoceutics, Medical Diagnostic Laboratories, Merck, Noven, Teva.

Dr. Maki reports: Consultant/Advisory Board: Noven. Dr. Manson reports: No significant financial relationships. Dr. Schmidt reports: No significant financial relationships. Dr. Shifren reports: Consultant/ Advisory Board: New England Research Institutes; Grants/Research Support: Boehringer Ingelheim. Dr. Stuenkel reports: Consultant/ Advisory Board: Noven, Pharmavite. Dr. Utian reports: Consultant/Advisory Board: Bayer, Bionovo, Cleveland Clinic Foundation Innovations Center, Hygeia (Orcas Therapeutics), Lupin, Merck, Novogyne, Pharmavite. For additional contributors, Ms. Bilancini and Ms. Wisch report no significant financial relationships. For the NAMS Board of Trustees, Dr. Clarkson reports: Consultant/Advisory Board: Pfizer; Grants/Research Support: Merck, Pfizer. Dr. Gass reports: No significant financial relationships. Dr. Goldstein reports: Board of Directors/Trustees: NYU School of Medicine Alumni Corporation (President- Elect), American Institute of Ultrasound in Medicine, SonoSite (President); Consultant/ Advisory Board: Amgen, Bayer, Cook Ob/ Gyn, Philips, Ultrasound, Shionogi; Speaker’s Bureau: Amgen, Warner Chilcott. Dr. Kagan reports: Consultant/Advisory Board: Amgen, Bionovo, Depomed, Foundation for Osteoporosis Research and Education/American Bone Health, Merck, Novo Nordisk, Own the Bone Advisory Board of the American Orthopedic Association, Pfizer, Shionogi; Grants/Research Support: Boehringer Ingelheim, Bionovo, Biosante, Depomed, Pfizer; Speaker’s Bureau: Amgen, Novogyne, Novo Nordisk. Dr. Kaunitz reports: Consultant/ Advisory Board: Bayer, Merck, Noven, Teva; Grants/Research Support: Bayer, Endoceutics, Medical Diagnostic Laboratories, Merck, Noven, Teva. Dr. Maki reports: Consultant/ Advisory Board: Noven. Dr. Manson reports: No significant financial relationships. Dr. Pace reports: Consultant/Advisory Board: Novo Nordisk; Speaker’s Bureau: Novo Nordisk. Dr. Schiff reports: No significant financial relationships. Dr. Schnatz reports: Board of Directors/Trustees: FaithCare. Dr. Shapiro reports: Board of Directors/Trustees: Baycrest, Research Canada, Canadian Partnership Against Cancer, SIGMA Canadian Menopause Society; Employment: Consultant, CTV Canada AM, CTV National News, CTV News Channel, Parents Canada, Canadian Health Consultant/Advisory Board: Amgen, Astra-Zeneca, Novartis, Pfizer; Grants/Research Support: Amgen, Pfizer, SIGMA; Speaker’s Bureau: Amgen, AstraZeneca, Bayer, Glaxo-SmithKline, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi Pasteur, Warner Chilcott; Website Writer: CTV.ca. Dr. Shifren reports: Consultant/Advisory Board: New England Research Institutes; Grants/Research Support: Boehringer Ingelheim. Dr. Sievert reports: No significant financial relationships. Dr. Utian reports: Consultant/Advisory Board: Bayer, Bionovo, Cleveland Clinic Foundation Innovations Center, Hygeia (Orcas Therapeutics), Lupin, Merck, Novogyne, Pharmavite. Dr. Warren reports: Consultant/Advisory Board: Pfizer, Yoplait; Grants/Research Support: Pfizer; Speaker’s Bureau: Amgen, Ascend Therapeutics, Pfizer, Upsher Smith.

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