Sistema Urogenital en los Años Posmenopáusicos

Síntomas de Atrofia Vulvovaginal

La menopausia conduce inevitablemente a una constelación de síntomas urogenitales, como sequedad vaginal, dispareunia, picazón y ardor vulvar, disuria, incontinencia urinaria e infecciones recurrentes del tracto urinario inferior, denominado síndrome genitourinario de la menopausia.

A pesar de que el impacto de los síntomas genitourinarios es comparable al de los síntomas graves de condiciones médicas (Di Bonaventura et al., 2015). Las mujeres son reacias a informar de estas perturbaciones, por lo que a menudo se descuidan.

Atrofia vulvovaginal

Combinaciones de estrógeno o estrógeno-progestágeno. Los síntomas de atrofia vulvovaginal se pueden tratar con estrógenos tópicos o sistémicos (Rahn et al., 2014). La terapia con estrógenos restaura la normalidad de la flora vaginal, reduce el pH y espesa y revasculariza el revestimiento vaginal.

Gracias a su eficacia y excelente perfil de seguridad (Marjoribanks et al., 2017; Crandall et al., 2018), el estrógeno vaginal es generalmente el enfoque de primera línea para tratar los síntomas de la atrofia vulvovaginal en la mayoría de las mujeres.

De hecho, mientras que la TH sistémica elimina los síntomas de atrofia vulvovaginal en el 75% de los casos, la terapia vaginal tiene éxito en el 80 al 90% de los casos (Goldstein, 2010).

Compuestos estrogénicos locales para el síndrome genitourinario incluyen E2, estriol, EEC y promestriene. Es preferible el estrógeno vaginal en dosis bajas, y está disponible en la forma de insertos vaginales de 4 μg, un anillo vaginal E2 de 7,5 μg o una tableta de E2 de 10 μg (Zdravkovic et al., 2001; Constantine et al., 2018).

Por definición, la dosis baja del estrógeno vaginal se caracteriza por la absorción sistémica dentro niveles normales de E2 posmenopáusico y, lo que es más importante, no induce hiperplasia endometrial (Zdravkovic et al., 2001).

Moduladores selectivos del receptor de estrógenos y complejo estrogénico tejido selectivo Ospemifeno.

El ospemifeno es el primer tratamiento no estrogénico aprobado para la dispareunia moderada a grave en mujeres con atrofia vulvovaginal (Paton, 2014).

El efecto del ospemifeno sobre los síntomas de atrofia vaginal y dispareunia, el epitelio vaginal y el pH de la vagina es comparable al de los estrógenos vaginales (Goldstein, 2010). Características histológicas mejoradas del revestimiento vaginal con una reducción de las células parabasales y un aumento de las células superficiales son alcanzables con esta terapia (Di Donato et al., 2019).

En mujeres posmenopáusicas saludables el ospemifeno administrado por vía oral 60 mg/ día hasta 52 semanas es seguro.

Aunque se han realizado estudios sobre ospemifeno de corta duración, no se ha informado aumento de eventos de cardiovasculares, tromboembólicos, con respecto al placebo durante un período de 52 semanas (Di Donato et al., 2019).

El tratamiento con ospemifeno es estadísticamente asociado con un mayor grosor del endometrio en mujeres con un útero intacto tanto a las 12 semanas como a las 52 semanas. Sin embargo, este aumento no es clínicamente relevante y no ha resultado en patología endometrial en mujeres tratadas durante este período (Di Donato et al., 2019).

Andrógenos – Síntomas de Atrofia Vulvovaginal

DHEA y testosterona, DHEA vaginal. DHEA vaginal pasa por conversión local por enzimas (metabolismo intracrino) a estrógenos y andrógenos como androstenediol, androstenediona, testosterona y DHT (Labrie et al., 2015).

En ensayos clínicos controlados con placebo (Parish, 2013; Archer, 2015; Labrie et al., 2015; Sauer et al., 2018), la aplicación diaria de 0,50% (6,5 mg) de DHEA mejoró el parámetro objetivo de atrofia vaginal: pH vaginal, índice de maduración epitelial vaginal, espesor e integridad epitelial y lubricación (Labrie et al., 2016).

La activación de los receptores de estrógenos y andrógenos a través de los metabolitos de la DHEA en la vagina afecta las tres capas de la pared vaginal, incluidas las fibras del colágeno de la membrana basal y la pared muscular, y da como resultado una mejora significativa de la dispareunia (Labrie et al., 2016).

Testosterona vaginal – Síntomas de Atrofia Vulvovaginal

Los investigadores están evaluando la testosterona intravaginal para mejorar la atrofia vulvovaginal; esto puede ser una nueva opción, prometedora, para sobrevivientes de cáncer de mama tratadas con inhibidores de la aromatasa (Santen et al., 2017; Davis et al., 2018), para quienes las opciones disponibles son muy escasas.

En un ensayo aleatorizado controlado con placebo (Davis et al., 2018), se probó la testosterona intravaginal en forma de una crema autoadministrada (300 lg por dosis) al día durante 2 semanas y luego tres veces por semana durante 24 semanas.

Tibolona.

Reduce los síntomas de atrofia vulvovaginal a un grado de nivel similar como la terapia con hormonas combinadas continuas de dosis bajas convencionales, ambas a la dosis de 2,5 mg (Swanson et al., 2006; Hammar et al., 2007) y 1,25 mg/día (Swanson et al., 2006).

Incontinencia urinaria – Síntomas de Atrofia Vulvovaginal

Se prefiere la vía vaginal para el tratamiento estrogénico de síntomas urinarios como frecuencia, nicturia, vejiga hiperactiva, urgencia e incontinencia (Nappi y Davis, 2012). La terapia vaginal con estrógenos también puede ayudar a prevenir infecciones recurrentes del tracto urinario con estrógenos vaginales (Constantine et al., 2018).

Ningún beneficio, por otro lado, es alcanzable en incontinencia de esfuerzo (Townsend et al., 2010; Cody et al., 2012; Nappi y Davis, 2012).

Como para el tratamiento sistémico de TH, los resultados del ensayo HERS revelaron un resultado negativo del impacto de 0,625 mg de EC más 2,5 mg de AMP en pacientes posmenopáusicas mayores con incontinencia, que ya se hizo evidente a los 4 meses de tratamiento (Grady et al., 2001).

Los datos de seguimiento del WHI confirmaron los datos en mujeres asignadas a EEC más AMP (Hendrix et al., 2005) y mostraron que la misma tendencia ocurrió con EEC solo (Manson et al., 2013). Los efectos negativos se atenuaron, pero persistieron después de suspender ambos ensayos (Manson et al., 2013).

Un estudio observacional reciente mostró que la exposición a agentes sistémicos de regímenes de TH, así como E2 vaginal, pueden favorecer el desarrollo de novo o el empeoramiento de la incontinencia urinaria de esfuerzo preexistente (Rahkola-Soisalo et al., 2019).

La TH puede debilitar los músculos del suelo pélvico y también provocar prolapso de órganos pélvicos (Rahkola-Soisalo et al., 2019). Las mujeres con este problema que buscan alivio para los síntomas de la menopausia deben ser conscientes de este riesgo.

Roles de los autores

Andrea R. Genazzani es la autora principal y responsable de la redacción del manuscrito y la discusión crítica.

Patrizia Monteleone es responsable de la búsqueda de literatura, la redacción del manuscrito y la discusión crítica. Andrea Giannini es responsable de la búsqueda de la literatura, la discusión crítica, las figuras y las tablas. Tommaso Simoncini es responsable de la discusión crítica.

Fondos

Los autores declaran no tener ninguna fuente de financiación.

Conflicto de intereses – Síntomas de Atrofia Vulvovaginal

El profesor Tommaso Simoncini declara haber recibido subvenciones de Shionogi y Gedeon Richter, honorarios de consultoría de Astellas, Gedeon Richter, Mitsubishi Tanabe, Sojournix, Estetra, Actavis y honorarios por conferencias, manuscrito, escritura o eventos educativos de Shionogi e Intuitive Quirúrgico.

La profesora Andrea R. Genazzani, la Dra. Patrizia Monteleone y la Dra. Andrea Giannini declaran no tener conflicto de intereses.

Referencias – Síntomas de Atrofia Vulvovaginal

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Otras Referencias – Síntomas de Atrofia Vulvovaginal

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Bibliografías – Síntomas de Atrofia Vulvovaginal

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Otras Bibliografías – Síntomas de Atrofia Vulvovaginal

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Lecturas Recomendadas – Síntomas de Atrofia Vulvovaginal

• Bondarev D, Laakkonen EK, Finni T, Kokko K, Kujala UM, Aukee P, Kovanen V, Sipilä S. Physical performance in relation to menopause status and physical activity. Menopause 2018;25:1432–1441.
• Bots ML, Evans GW, Riley W, McBride KH, Paskett ED, Helmond FA, Grobbee DE, Investigators OPAL. The effect of tibolone and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate on progression of carotid intima/media thickness: the osteoporosis prevention and arterial effects of tibolone (OPAL) study. Eur Heart J 2006;27:746–755.
• Brandts L, van Poppel FWA, van den Brandt PA. Female reproductive factors and the likelihood of reaching the age of 90 years. The Netherlands Cohort Study. Maturitas 2019;125:70–80.
• Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA, Bachman G, Aguirre OA, Lucas JD, Rodenberg C. et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebocontrolled trial. Arch Intern Med 2005;165:1582– 1589.
• Bray PF, Larson JC, Lacroix AZ, Manson J, Limacher MC, Rossouw JE, Lasser NL, Lawson WE, Stefanick ML, Langer RD. et al.; Women’s Health Initiative Investigators. Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events. Am J Cardiol 2008;101:1599–1605.
• Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci 2008;31:529–537.
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Otras Lecturas Recomendadas – Síntomas de Atrofia Vulvovaginal

• Brunner RL, Aragaki A, Barnabei V, Cochrane BB, Gass M, Hendrix S, Lane D, Ockene J, Woods NF, Yasmeen S. et al. Menopausal symptom experience before and after stopping estrogen therapy in the Women’s Health Initiative randomized, placebo-controlled trial. Menopause 2010;17:946–954.
• Brzezinski A, Brzezinski-Sinai NA, Seeman MV. Treating schizophrenia during menopause. Menopause 2017;24:582–588.
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• Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75:1102–1109.
• Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944–952.
• Calleja-Agius J, Brincat M, Borg M. Skin connective tissue and ageing. Best Pract Res Clin Obstet Gynaecol 2013;27:727–740.
• Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J. et al.; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840–845.
• Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause 2014;21:753–762.

Referencias Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Canonico M, Carcaillon L, Plu-Bureau G, Oger E, Singh-Manoux A, Tubert-Bitter P, Elbaz A, Scarabin PY. Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen. Stroke 2016;47:1734–1741.
• Canonico M, Fournier A, Carcaillon L, Olié V, PluBureau G, Oger E, Mesrine S, Boutron-Ruault M-C, Clavel-Chapelon FOISE, Scarabin P-Y. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism. Results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010;30:340–345.
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Otras Referencias Bibliográficas – Síntomas de Atrofia Vulvovaginal

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• Chlebowski RT, Rohan TE, Manson JE, Aragaki AK, Kaunitz A, Stefanick ML, Simon MS, Johnson KC, Wactawski-Wende J, O’Sullivan MJ. et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women’s Health Initiative Randomized Clinical Trials. JAMA Oncol 2015;1:296–305.
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Citas Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Cintron D, Lahr BD, Bailey KR, Santoro N, Lloyd R, Manson JE, Neal-Perry G, Pal L, Taylor HS, Wharton W. et al. Effects of oral versus transdermal menopausal hormone treatments on selfreported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Menopause 2018;25:145–153.
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• Constantine GD, Simon JA, Pickar JH, Archer DF, Bernick B, Graham S, Mirkin S. Estradiol vaginal inserts (4 mg and 10 mg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data. Curr Med Res Opin 2018;34:2131–2136.
• Constantine GD, Kessler G, Graham S, Goldstein SR. Increased incidence of endometrial cancer following the Women’s Health Initiative: an assessment of risk factors. J Womens Health (Larchmt) 2019;28:237–243.

Otras Citas Bibliográficas – Síntomas de Atrofia Vulvovaginal

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• Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C. et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697–708.
• Cushman M, Larson JC, Rosendaal FR, Heckbert SR, Curb JD, Phillips LS, Baird AE, Eaton CB, Stafford RS. Biomarkers, menopausal hormone therapy and risk of venous thrombosis: the Women’s Health Initiative. Res Pract Thromb Haemost 2018;2:310–319.

Material Bibliográfico – Síntomas de Atrofia Vulvovaginal

• Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ. et al. SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 2013;381:1827–1834.
• Dalgård C, Benetos A, Verhulst S, Labat C, Kark JD, Christensen K, Kimura M, Kyvik KO, Aviv A. Leukocyte telomere length dynamics in women and men: menopause vs age effects. Int J Epidemiol 2015;44:1688–1695.
• Davis SR, Robinson PJ, Jane F, White S, White M, Bell RJ. Intravaginal testosterone improves sexual satisfaction and vaginal symptoms associated with aromatase inhibitors. J Clin Endocrinol Metab 2018;103:4146–4154.
• Davis SR, Baber R, Panay N, Bitzer J, Cerdas Perez S, Islam RM, Kaunitz AM, Kingsberg SA, Lambrinoudaki I, Liu J. et al. Global consensus position statement on the use of testosterone therapy for women. Climacteric 2019;22:429–434.
• de Lauzon-Guillain B, Fournier A, Fabre A, Simon N, Mesrine S, Boutron-Ruault M-C, Balkau B, Clavel-Chapelon F. Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Generale de l’Education Nationale (E3N) cohort. Diabetologia 2009;52:2092–2100.
• Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST. et al.; Multiple Outcomes of Raloxifene Evaluation Investigators. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002;87:3609–3617.
• de Kruif M, Spijker AT, Molendijk ML. Depression during the perimenopause: a meta-analysis. J Affect Disord 2016;206:174–180.

Otros Materiales Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Di Bonaventura M, Luo X, Moffatt M, Bushmakin AG, Kumar M, Bobula J. The association between vulvovaginal atrophy symptoms and quality of life among postmenopausal women in the United States and western Europe. J Womens Health (Larchmt) 2015;24:713–722.
• Di Donato V, Schiavi MC, Iacobelli V, D’oria O, Kontopantelis E, Simoncini T, Muzii L, Benedetti Panici P. Ospemifene for the treatment of vulvar and vaginal atrophy: a meta-analysis of randomized trials. Part I: evaluation of efficacy. Maturitas 2019;121:86–92.
• Di Donato V, Schiavi MC, Iacobelli V, D’oria O, Kontopantelis E, Simoncini T, Muzii L, Benedetti Panici P. Ospemifene for the treatment of vulvar and vaginal atrophy: a meta-analysis of randomized trials. Part II: evaluation of tolerability and safety. Maturitas 2019;121:93–100.
• Domchek SM, Mitchell G, Lindeman GJ, Tung NM, Balmaña J, Isakoff SJ, Schmutzler R, Audeh MW, Loman N, Scott C. et al. Challenges to the development of new agents for molecularly defined patient subsets: lessons from BRCA1/2- associated breast cancer. J Clin Oncol 2011;29: 4224–4226.
• Dören M, Rübig A, Coelingh Bennink HJ, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril 2001;75:554–558.
• Drogos LL, Rubin LH, Geller SE, Banuvar S, Shulman LP, Maki PM. Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms. Menopause 2013;20:1236–1242.
• Dubaut JP, Dong F, Tjaden BL, Grainger DA, Duong J, Tatpati LL. Prescribing bioidentical menopausal hormone therapy: a survey of physician views and practices. J Womens Health (Larchmt) 2018;27:859–866. doi: 10.1089/ jwh.2017.6637.

Anexos Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Eisen A, Lubinski J, Gronwald J, Moller P, Lynch HT, Klijn J, Kim-Sing C, Neuhausen SL, Gilbert L, Ghadirian P et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008;100:1361–1367.
• El Khoudary SR, Wang L, Brooks MM, Thurston RC, Derby CA, Matthews KA. Increase HDL-C level over the menopausal transition is associated with greater atherosclerotic progression. J Clin Lipidol 2016;10:962–969.
• Ensrud K, Genazzani AR, Geiger MJ, McNabb M, Dowsett SA, Cox DA, Barrett-Connor E. Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis. Am J Cardiol 2006;97:520–527.
• Espeland MA, Hogan PE, Fineberg SE, Howard G, Schrott H, Waclawiw MA, Bush TL; The Pepi Investigators. Effect of postmenopausal hormone therapy on glucose and insulin concentrations. Postmenopausal Estrogen/Progestin Interventions. Diabetes Care 1998;21:1589–1595.
• Espeland MA, Shumaker SA, Leng I, Manson JE, Brown CM, LeBlanc ES, Vaughan L, Robinson J, Rapp SR, Goveas JS. et al.; WHIMSY Study Group. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med 2013;173:1429–1436.
• Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, Yankov V, Vittinghoff E, Grady D. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol 2004104:443–451.
• Ettinger B. Tibolone for prevention and treatment of postmenopausal osteoporosis. Maturitas 2007;57:35–38.
• Ewertz M, Mellemkjaer L, Poulsen AH, Friis S, Sørensen HT, Pedersen L, McLaughlin JK, Olsen JH. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer 2005;92:1293–1297.

Otros Anexos Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Finkelstein JS, Brockwell SE, Mehta V, Greendale GA, Sowers MR, Ettinger B, Lo JC, Johnston JM, Cauley JA, Danielson ME. et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab 2008;93:861–868.
• Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Womens Health Gend Based Med 2000;9:381–387.
• Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V, Marata AM, Magrini N, D’Amico R, Bassi C. et al. Short-term and longterm effects of tibolone in postmenopausal women. Cochrane Database Syst Rev 2016;10: CD008536.
• Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–111.
• Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014;145:535–543.
• Francucci CM, Pantaleo D, Iori N, Camilletti A, Massi F, Boscaro M. Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women. J Endocrinol Invest 2005;28:623–631.
• Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol 2011;117:1095–1104.
• Gambacciani M, Ciaponi M, Cappagli B, Monteleone P, Benussi C, Bevilacqua G, Vacca F, Genazzani AR. Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women. Maturitas 2005;50:91–97.
• Gambacciani M, Cappagli B, Ciaponi M, Pepe A, Vacca F, Genazzani AR. Ultra-low-dose hormone replacement therapy and bone protection in postmenopausal women. Maturitas 2008;59:2–6.

Comentario Bibliográfico – Síntomas de Atrofia Vulvovaginal

• Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years. Menopause 2018;25:1331–1338.
• Gass ML, Cochrane BB, Larson JC, Manson JE, Barnabei VM, Brzyski RG, Lane DS, LaValleur J, Ockene JK, Mouton CP. et al. Patterns and predictors of sexual activity among women in the Hormone Therapy trials of the Women’s Health Initiative. Menopause 2011;18:1160–1171.
• Gass M, Larson J, Cochrane B, Manson JE, Lane D, Barnabei V, Ockene J, Stefanick ML, Mouton C. Sexual activity and vaginal symptoms in the postintervention phase of the Women’s Health Initiative Hormone Therapy Trials. Menopause 2018;25:252–264.
• Gemmell LC, Webster KE, Kirtley S, Vincent K, Zondervan KT, Becker CM. The management of menopause in women with a history of endometriosis: a systematic review. Hum Reprod Update 2017;23:481–500.
• Genazzani AR, Gambacciani M. Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution. Gynecol Endocrinol 2006;22:145–150.
• Genazzani AR, Pluchino N, Begliuomini S, Stomati M, Bernardi F, Pieri M, Casarosa E, Palumbo M, Genazzani AD, Luisi M. Longterm low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women. Gynecol Endocrinol 2006;22: 627–635.
• Genazzani AR, Pluchino N, Luisi S, Luisi M. Estrogen, cognition and female ageing. Hum Reprod Update 2007;13:175–187.
• Genazzani AR, Stomati M, Valentino V, Pluchino N, Pot E, Casarosa E, Merlini S, Giannini A, Luisi M. Effect of 1-year, low-dose DHEA therapy on climacteric symptoms and female sexuality. Climacteric 2011;14:661–668.

Otros Comentarios Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR. et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015;12: e1001833.
• Goldstein I. Recognizing and treating urogenital atrophy in postmenopausal women. J Womens Health 2010;19:425–432.
• Gordhandas S, Norquist BM, Pennington KP, Yung RL, Laya MB, Swisher EM. Hormone replacement therapy after risk reducing salpingooophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol 2019;153:192–200.
• Gordon JL, Eisenlohr-Moul TA, Rubinow DR, Schrubbe L, Girdler SS. Naturally occurring changes in estradiol concentrations in the menopause transition predict morning cortisol and negative mood in perimenopausal depression. Clin Psychol Sci 2016;4:919–935.
• Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry 2018;75:149–157.
• Gower BA, Muñoz J, Desmond R, Hilario-Hailey T, Jiao X. Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use. Obesity (Silver Spring) 2006;14:1046–1055.
• Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T, HERS, Research G. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116–120.
• Grady D, Ettinger B, Tosteson ANA, Pressman A, Macer JL. Predictors of difficulty when discontinuing postmenopausal hormone therapy. Obstet Gynecol 2003;102:1233–1239.

Relatos Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Grady D, Cauley JA, Geiger MJ, Kornitzer M, Mosca L, Collins P, Wenger NK, Song J, Mershon J, Barrett-Connor E; Raloxifene Use for The Heart Trial Investigators. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst 2008;100:854–861.
• Greendale GA, Huang M-H, Wight RG, Seeman T, Luetters C, Avis NE, Johnston J, Karlamangla AS. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72:1850–1857.
• Griffiths A, Ceausu I, Depypere H, Lambrinoudaki I, Mueck A, Pérez-López FR, van der Schouw YT, Senturk LM, Simoncini T, Stevenson JC. et al. EMAS recommendations for conditions in the workplace for menopausal women. Maturitas 2016;85:79–81.
• Grodstein F, Martinez ME, Platz EA, Giovannucci E, Colditz GA, Kautzky M, Fuchs C, Stampfer MJ. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998; 128:705–712.
• Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–941.
• Grodstein F, Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med 2008;168:861–866.
• Hammar ML, van de Weijer P, Franke HR, Pornel B, von Mauw EM, Nijland EA; TOTAL Study Investigators Group. Tibolone and lowdose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability. BJOG 2007;114:1522–1529.
• Hara Y, Waters EM, McEwen BS, Morrison JH. Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol Rev 2015;95:785–807.

Otros Relatos Bibliográficos – Síntomas de Atrofia Vulvovaginal

• Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAWþ10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop þ10: addressing the unfinished agenda of staging reproductive aging. Climacteric 2012;15:105–114.
• Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR. et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249–260.
• Haskell SG, Bean-Mayberry B, Gordon K. Discontinuing postmenopausal hormone therapy: an observational study of tapering versus quitting cold turkey: is there a difference in recurrence of menopausal symptoms? Menopause 2009;16: 494–499.
• Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ. et al.; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839–1854.
• Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015;12:464–474.
• Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75–78.
• Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA; MIRAGE Study Group. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry 2005;76:103–105.
• Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis. Neurology 2016;87:699–708.
• Hendrix SL, Cochrane BB, Nygaard IE, Handa VL, Barnabei VM, Iglesia C, Aragaki A, Naughton MJ, Wallace RB, McNeeley SG. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293:935–948.

Reseñas Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Herrera AY, Hodis HN, Mack WJ, Mather M. Estradiol therapy after menopause mitigates effects of stress on cortisol and working memory. J Clin Endocrinol Metab 2017;102:4457–4466.

• Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N. et al.; ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221–1231.
• Holm M, Olsen A, Au Yeung SL, Overvad K, Lidegaard Ø, Kroman N, Tjønneland A. Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort. BJOG 2019;126:55–63.
• Honigberg MC, Zekavat SM, Aragam K, Finneran P, Klarin D, Bhatt DL, Januzzi JL Jr, Scott NS, Natarajan P. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA 2019;322:2411.
• Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018;19:371–384.
• Huang AJ, Ettinger B, Vittinghoff E, Ensrud KE, Johnson KC, Cummings SR. Endogenous estrogen levels and the effects of ultralow-dose transdermal estradiol therapy on bone turnover and BMD in postmenopausal women. J Bone Miner Res 2007;22:1791–1797.
• Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–613.
• Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, Collins P, Rosano GM. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebocontrolled study. J Am Coll Cardiol 2010;56:1310–1316.
• Imtiaz B, Tuppurainen M, Rikkonen T, Kivipelto M, Soininen H, Kröger H, Tolppanen AM. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology 2017;88: 1062–1068.

Otras Reseñas Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL. Accelerated cell aging in female APOE-e4 carriers: implications for hormone therapy use. PLoS One 2013; 8:e54713.

• Jacobsen DE, Samson MM, Emmelot-Vonk MH, Verhaar HJ. Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial. Eur J Endocrinol 2010;162:371–376.
• Jaffe AB, Toran-Allerand CD, Greengard P, Gandy SE. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem 1994;269:13065–13068.
• Jensen LB, Vestergaard P, Hermann AP, Gram J, Eiken P, Abrahamsen B, Brot C, Kolthoff N, Sørensen OH, Beck-Nielsen H. et al. Hormone replacement therapy dissociates fat mass and bone mass and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study. J Bone Miner Res 2003;18:333–342.
• Jones ME, Schoemaker MJ, Wright L, McFadden E, Griffin J, Thomas D, Hemming J, Wright K, Ashworth A, Swerdlow AJ. Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? Br J Cancer 2016;115:607–615.
• Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 2015;22:R1–R31.
• Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, Cauley JA, Barrett-Connor E; Heart and Estrogen/progestin Replacement Study. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/ progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1–9.
• Kang JH, Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology 2004;63:101–107.

Mención Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Karim R, Dell RM, Greene DF, Mack WJ, Gallagher JC, Hodis HN. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause 2011;18: 1172–1177.
• Kenny AM, Kleppinger A, Wang Y, Prestwood KM. Effects of ultralow-dose estrogen therapy on muscle and physical function in older women. J Am Geriatr Soc 2005;53:1973–1977.
• Kerlikowske K, Miglioretti DL, Ballard-Barbash R, Weaver DL, Buist DSM, Barlow WE, Cutter G, Geller BM, Yankaskas B, Taplin SH. et al. Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population. J Clin Oncol 2003;21:4314–4321.
• Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol 2013;86:1627–1642.
• Kling JM, Manson JE, Naughton MJ, Temkit M, Sullivan SD, Gower EW, Hale L, Weitlauf JC, Nowakowski S, Crandall CJ. Association of sleep disturbance and sexual function in postmenopausal women. Menopause 2017;24: 604–612.
• Knuuti J, Kalliokoski R, Janatuinen T, Hannukainen J, Kalliokoski KK, Koskenvuo J, Lundt S. Effect of estradiol-drospirenone hormone treatment on myocardial perfusion reserve in postmenopausal women with angina pectoris. Am J Cardiol 2007;99:1648–1652.
• Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 2014;90:71–81.
• Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Climacteric 2015;18:503–511.
• Kotsopoulos J, Gronwald J, Karlan BY, Huzarski T, Tung N, Moller P, Armel S, Lynch HT, Senter L, Eisen A. et al.; Hereditary Breast Cancer Clinical Study Group. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol 2018;4:1059–1065.

Otras Menciones Bibliográficas – Síntomas de Atrofia Vulvovaginal

• Kravitz HM, Joffe H. Sleep during the perimenopause: a SWAN story. Obstet Gynecol Clin North Am 2011;38:567–586.
• Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol 2005;69:113–132. Kresovich JK, Parks CG, Sandler DP, Taylor JA. Reproductive history and blood cell telomere length. Aging (Albany NY) 2018;10:2383–2393.
• Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M. et al. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause 2009;16:923–931.
• Labrie F, Derogatis L, Archer DF, Koltun W, Vachon A, Young D, Frenette L, Portman D, Montesino M, CôtéI, Parent J. et al.; Members of the VVA Prasterone Research Group. Effect of intravaginal prasterone on sexual dysfunction in postmenopausal women with vulvovaginal atrophy. J Sex Med 2015;12:2401–2412.
• Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L, Portman D, Montesino M, CôtéI, Parent J. et al.; VVA Prasterone Research Group. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause 2016;23:243–256.
• Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause 2018;25:1297–1305.
• Lasco A, Gaudio A, Morabito N, Previti M, Mileto A, Frisina N, Cucinotta D. Effects of a long-term treatment with raloxifene on insulin sensitivity in postmenopausal women. Diabetologia 2004;47: 571–574.

Observación Bibliográfica – Síntomas de Atrofia Vulvovaginal

• Lee CG, Carr MC, Murdoch SJ, Mitchell E, Woods NF, Wener MH, Chandler WL, Boyko EJ, Brunzell JD. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. J Clin Endocrinol Metab 2009;94:1104–1110.
• Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB, Ferrucci L, Bandinelli S, Salfati E, Manson JE, Quach A. et al. Menopause accelerates biological aging. Proc Natl Acad Sci U S A 2016;113:9327–9332.
• Lin J, Kroenke CH, Epel E, Kenna HA, Wolkowitz OM, Blackburn E, Rasgon NL. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res 2011;1379:- 224–231.