TERAPIA HORMONAL NA MENOPAUSA: QUANDO PARAQUEM E COM QUE?QUANDO, PARAQUEM E COM QUE?

Dr Santiago PalaciosDr. Santiago PalaciosInstituto Palacios, Salud y Medicina de la Mujer

Antonio Acuña, 9 - 28009 MadridTeléfono 91 578 05 17Teléfono 91 578 05 17

E-mail: ipalacios@institutopalacios.comwww.institutopalacios.com

www.institutopalacios.com

Diapositivas / Slides

TRH 2011TRH 2011

1. QUANDO

2. PARAQUEM

3. COM QUE

TRH: El nuevo paradigmaTRH: El nuevo paradigma

FDAFDA

•Reduciendo la dosisWHI Reduciendo la dosis•Acortando la duración

Million Women Study

•Mujer sintomática

Dec. 2003

1.0 2.00 0.5 1.5HT and CHD: Meta-Analysisf Ob ti l St di Population-

based cohorts

Cross-

.0 .00 0.5 .5of Observational Studies

Based on more than 40 b i l di f

Crosssectional

Prospective/internal controlve

r U

sers

observational studies of HT and CHD, the summary

l ti i k f CHD

Hospital-based

control

Summary

Ev

relative risks for CHD were 40-50% lower among current or ever users of HT

Summary

Population-based case-controlsor ever users of HT

compared to never users (p<0 001)

Cross-sectional

Prospective/internal re

nt U

sers

(p<0.001).Summary

internal controlCu

rr

From: Grodstein F, Stampfer MJ. Prog Cardiovasc Dis 1995; 38:199-210.

DIFERENCIAS ENTRE ESTUDIOS OBSERVACIONALES Y EL WHI

ObservationalObservationalWHI Studies

Edad de iniciación de la TH 63 años 52 años

Tiempo desde la menopausia 12 años 1-2 añosTiempo desde la menopausia 12 años 1 2 años

Síntomas vasomotores General – General+

IMC 28-30 24-25

Uso de TH Corto LargoUso de TH Corto Largo

Formulaciones de TH CEE+MPA Diversas

Relación de los años desde la menopausia con la ió d t i l i l WHI progresión de arterioesclerosis en el WHI

Adventitia FibrousMMP-9

Media

InternalElastic

FibrousCap

FibrousCap Fibrous

Cap

ElasticLamina Plaque Plaque

Fatty Streak/Plaque

Necrotic CorePlaque Necrotic Core

5 to <10 10 to <15 ≥15<5

Streak/Plaque

Years Postmenopause19% 21% 43%17%% of WHI Enrollees

Mortalidad total asociada con la TRH en mujeres jóvenes y mayores: Meta-análisis de 30 estudios jóvenes y mayores: Meta análisis de 30 estudios controlados randomizados

HRT versus Control OR (95% CI)

All Ages 0.98 (0.87-1.18)

>60 years (Mean age 66 years) 1 03 (0 91-1 16)>60 years (Mean age 66 years) 1.03 (0.91-1.16)

<60 years (Mean age 54 years) 0.61 (0.39-0.95)

Salpeter S et al. J Gen Intern Med 2004;19:791-804

Absolute Excess Risks (cases per 10,000 pys) by Age in the Combined Trials (E+P and E Alone) of the WHIin the Combined Trials (E+P and E-Alone) of the WHI

Outcome Age (years)

50-59 60-69 70-79

CHD -2 -1 +19*

Total mortality -10 -4 +16*

Global index† -4 +15 +43

* P=0.03 compared with age 50-59 years or <10 years since menopause† Global index is a composite outcome of CHD, stroke, pul embolism, breast ca, colorectal ca,

d i l hi f d liendometrial ca, hip fracture and mortality

Source: Rossouw JE, Prentice RL, Manson JE, et al. JAMA2007.

Timing of Hormone Therapy Initiation in Relation to Stage of Atherosclerosis: Observational Studies vs Clinical Trials

Premenopausal Years Postmenopausal Years

of Atherosclerosis: Observational Studies vs Clinical Trials

Years Since Menopause Onset5 10 15 20

Clinical TrialsObservational Studies(1° and 2°Prevention)

Fatty plaquesFatty streaks Atherosclerotic plaques Plaques grow and may rupture

Progression of

Cardiovascular Disease

Favorable Lipid and Prothrombotic and

y p qy p q q g y p

Favorable Lipid and Endothelial Effects of Estrogen Predominate

Prothrombotic and Proinflammatory Effects of Estrogen Predominate(plaque rupture, thrombo-occlusion)

Ad I fl Favorable Influence of Initiating

Exogenous Estrogens

Adverse Influence of Initiating

Exogenous Estrogens From: J Manson, et al. Menopause2006.

National Osteoporosis Society's Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis.

Menopause Int. 2011 Jun;17(2):63-5. Bowring CE, Francis RM.

AbstractHormone replacement therapy (HRT) has been shown to increase bone

d i d h i k f f d f ll li density, reduce the risk of fracture and can successfully relieve menopausal symptoms. From a time when HRT was the major therapeutic option for the management of osteoporosis, women and their clinicians

h g f t t t il bl F ll i g th bli ti f now have a range of treatments available. Following the publication of the Women's Health Initiative (WHI) and the Million Women Study highlighting potential side-effects, such as breast cancer, heart disease and stroke many doctors and women are now reluctant to use HRT The and stroke, many doctors and women are now reluctant to use HRT. The National Osteoporosis Society felt that the role of HRT in the management of osteoporosis needed to be clarified. Using the Charity's expert clinical and scientific advisers and through public consultation with members and and scientific advisers, and through public consultation with members and key stakeholders, a Position Statement has been published. We conclude that HRT has a role to play in the management of osteoporosis in postmenopausal women below the age of 60 years. postmenopausal women below the age of 60 years. The key recommendations of the Position Statement are presented in this paper.

Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011 Mar;124(3):199-205 Am J Med. 2011 Mar;124(3):199 205. Harman SM, Vittinghoff E, Brinton EA, Budoff MJ, Cedars MI, Lobo RA, Merriam GR, Miller VM, Naftolin F, Pal L, Santoro N, Taylor HS, Black DM.

Ab t tAbstractLargely on the basis of the first publication of findings of net harm with menopausal hormone treatment

in the Women's Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the "…shortest duration consistent withrecommendations limit menopausal hormone treatment to the …shortest duration consistent with treatment goals…," with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormoneor time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the "timing hypothesis"). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary h di i k l f 5 6 f C i i h hi fi di i kheart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1.08 (95% confidence interval, 0.86-1.36) in years 1 to 6 and as 0.46 (confidence interval, 0.28-0.78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk:benefit considerations. New research is urgently needed evaluating influences ofon risk:benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients.

TERAPIA HORMONAL NA MENOPAUSA: QUANDO PARAQUEM E COM QUE?QUANDO, PARAQUEM E COM QUE?

QUANDO ÑQUANDO………ANTES DE QUE TRASCURRAN 10 AÑOS DE LA MENOPAUSIA (60 AÑOS)

TRH 2011

1. QUANDO

2. PARAQUEM

3. COM QUE

PARAQUEMPARAQUEM

TRH Y SINTOMAS VASOMOTORESTRH Y SINTOMAS VASOMOTORES

•Ningún otro tratamiento médico ni alternativo ofrece un alivio significativo mejor de los SVM

•La reducción de la frecuencia e intensidad es hasta de un 90% y sostenidade un 90% y sostenida

•El efecto principal se observó en el transcurso de un mes con dosis y via de administración fija

RESPUESTA A DIFERENTES DOSIS DE ECE SOLOS O CON AMP

A BPlacebo

0.3 mg/dX Placebo

0.3/1.5 mg/dX

12

10

8num

ber

12

10

8num

ber

XX X X X X X

0.45 mg/d

0.625 mg/d

0.45/2.5 mg/d

0.625/2.5 mg/d

XX X X X X

6

4

uste

d m

ean

6

4

uste

d m

ean

X X XX X X X

X X X X XX X X X

1 2 3 4

2

0

Adj

u

Week5 6 7 8 9 10 11 12 1 2 3 4

2

0

Adj

u

Week5 6 7 8 9 10 11 12

ECE solos ECE +AMP

Utian, et al. Fertil Steril. 2001.75;1065.

Desaparición de síntomas vasomotores entre baja dosis y ultrabajabaja dosis y ultrabaja

Change Bachmann G, et al Obstet Gynecol 2007; 110:771-9.

0

from baseline

No./week

, y ;

-10

0

Placebo Micro-dose E2L d E2/LNG

-20Low-dose E2/LNG

39%

-40

-30

55%

-5074%

-600 1 2 3 4 5 6 7 8 9 10 11 12

Week of treatment

Ultra baja dosisNº de sofocos moderados y severos por semana

PlaceboUltra baja dosis

Atrofia vaginal*significantly (p=0.001) g y (p )different from placebo

Maduración pH vaginal

Panay N et al. Climacteric 2007;10(2):120–131

PARAQUEMPARAQUEM

Meta analysis of placebo controlled trials revealed

estrogen to be more effective than placebo for all estrogen to be more effective than placebo for all

variables measured

Cardozo et al.Obstet Gynecol. 1998

The vaginal route of administration correlated with betterreports of symptomatic relief, greater improvement reports of symptomatic relief, greater improvement

in cytologic findings

Cardozo et al.Obstet Gynecol. 1998

Vagifem® 10µg suministra una dosis b jí i d t di lbajísima de estradiol

• 1.14 mg exposicion annual al estrogenoDosis y administración

Dosis inicial:1 tableta insertada en la vaginadiariamente por 2 semanas. = 14 tabletasMantenimiento:

bl d l d1 tableta insertada vaginalmente dos vecespor semana durante 50 semanas = 100 tabletas

Total por 1 ano:Total por 1 ano:114 tabletas x 10µg = 1140µg

1140µg de estradiol1140µg de estradioladministrado a la paciente en 1 ano = 1.14 mg

Grado de salud vaginalg

p<0.001

p<0.001 p<0.001 p<0.001 p<0.001

Placebo 10µg E2

Simon JA et al. Obstetrics & Gynecology 2008; 12(5): 1053–60

Vaginal application formsg pp

Creams

Premarin®

i l

Vaginal Ring

Estring®

t i

Vagitories

Ortho Gynest®

i l t i l

Vaginal tablets

Vagifem®

fi t d l vaginal cream (PVC) conju-gated equine estrogens (CEE)

contains estradiol,releases estradiol in a consistent

vaginal estriol suppositories

first and only vaginal oestrogen tablet

Estrace®

estradiol cream in an applicator-free tube

a consistent manner over 90 days

free tube

PARAQUEMPARAQUEM

Estrogen on boneg

estrogen estrogen

Osteoblast Osteoclast

Pre-osteoblast replicationNon genomic accion.

Inhibition of osteoclastg

Estren TGF-betaRANK/RANKL/osteoprt iotegerin

.

E+P Pl./10,000wy

111 vs 141

153 vs 210

E P Pl.-30

-57

224 vs 285 -61

Influence of HT on Fracture incidenceR lt f th W ’ H lth I iti ti “ (WHI)Results of the „Women’s Health Initiative“ (WHI)-

-30%(0,63-0,79)

-38% -39%(0,42-0,93) (0,41-0,91)

Fracture ReductionTotal

* Fracture ReductionLumber Spine

Fracture ReductionHip

JAMA 2004, 291: 1701-1712

Baja dosis y prevención de la pérdida de masa ósea

Umbral mínimo de estradiol en plasma probablemente < 20 pg/mlUmbral mínimo de estradiol en plasma probablemente 20 pg/ml

Mujeres > 65 años:con [ E ] < 5 pg/ml tienen > riesgo fractura de cadera y columna que aquellas con [E ]con [ E2] < 5 pg/ml tienen > riesgo fractura de cadera y columna que aquellas con [E2 ]detectables.con [E2 ] entre 5 y 9 pg/ml tienen un riesgo de un 60% menor

Cummings SR et al N Engl J Med 1998; 339:733-738

Autor dosis + Ca AMP R CL cadera T Genant 82 0,15-0,625 No No No Si No NoLindsay 84 0 15-1 25 No No - No No NoLindsay 84 0,15-1,25 No No - No No NoEttinger 87 0,3 Si No Si Si No NoGallaher 91 0,3-0,625 Si Si Si Si No No Webber 94 0 3 0 625 Si Si Si Si Si Si

Cuadros M , Masa ósea y dosis baja de TH. Cap. 3 Tratamiento Hormonal dosis bajas. 2004

Webber 94 0,3-0,625 Si Si Si Si Si Si

Masa ósea y Tibolona

Autor dosis nº estudio R CL FB i 96 * 1 25 2 5 94 ADCPBerning 96 * 1,25-2,5 94 ADCP +Bjarnason 96* 1,25-2,5 91 ADCP + +Gallagher 01 0,3- 2,5 770 ADCP + +Roux 02 1,25-2,5 225 ADCP + +

vs2mgE2+1mgNETAg g

1,25 mg2,5 mg

Menopáusicas > 10 años

placebo

* Si l i * d d ió

Berning 96 Bjarnason 96

* Sin calcio * marcadores de resorción ADCP= estudio aleatorizado,doble ciego y con grupo placeCuadros M , Masa ósea y dosis baja de TH. Cap. 3 Tratamiento Hormonal dosis bajas. 2004

Drospirenona/estrogeno

2 años, doble ciego, randomizado, placebo controlado240 mujeres entre 45 65 años FUR: 1 año240 mujeres entre 45-65 años. FUR: 1 año

Grupo 17 β E2 (mg) Drospirenona ( mg) nºA 1 1 60A 1 1 60B (Angeliq®) 1 2 60C 1 3 60

E 1mg + 1mg D

E 1mg + 2 mg D

E 1mg + 3 mg DD (control) placebo placebo 60E 1mg + 3 mg D

Placebo

Warming I et al Climacteric 2004; 7: 103-11Christiansen C Climacteric 2005; 8 ( suppl 3): 35-41

Ultra-baja dosis. V transdérmicaUltra baja dosis. V transdérmica

Mujeres 60- 80 años ( 417 mujeres randomizado, doble ciego, placebo-controladoE Transdérmico: 0 014 mg/ dia (208) placebo (209))E Transdérmico: 0.014 mg/ dia (208) placebo (209))Calcio + vitamina D 0 1 2 añosDMO: -2 o más alto [ E2] 4’8 pg/ml 8’5 8’6

Osteocalcina y Fosfatasa alcalinaOsteocalcina y Fosfatasa alcalina

Ettinger B et al. Obstetrics and Gynecology 2004, vol 104 nº 3 September

TH baja / ultrabaja dosis de E2 oralj j 2

Mujeres postmenopausicas, no obesas / 2 años. Multicentrico randomizado doble ciego íMulticentrico, randomizado, doble-ciego .Estradiol:1 mg + NETA 0’5 mg x 28 díasEstradiol: 0’5 mg + NETA 0’25 mg x 28 díasGrupo control: 1000 mg calcio día

+ 1000 mg /día calcio

Gambacciani M et al Maturitas 2008; 59: 2-6

TERAPIA HORMONAL NA MENOPAUSA:QUANDO PARAQUEM E COM QUE?QUANDO, PARAQUEM E COM QUE?

QUANDO ÑQUANDO………ANTES DE QUE TRASCURRAN 10 AÑOS DELA MENOPAUSIA (60 AÑOS)PARAQUEMPARAQUEM…...DISMINUCION DE LOS SINTOMASVASOMOTORES, ATROFIA GENITO-URINARIA, SEGUNDAOPCIÓN PARA PREVENCION DE OSTEOPOROSISOPCIÓN, PARA PREVENCION DE OSTEOPOROSIS

TRH 2011TRH 2011

1. QUANDO

2. PARAQUEM

3. COM QUE

BENEFICIOS E INDICACIONES DE TRH

DISMINUCIÓN DE LOS SÍNTOMAS VASOMOTORES• DISMINUCIÓN DE LOS SÍNTOMAS VASOMOTORES

• ATROFIA GENITO-URINARIA

• SEGUNDA OPCIÓN, PARA PREVENCIÓN DE OSTEOPOROSIS

PARÁMETROS DE RIESGO QUE PREOCUPANPARÁMETROS DE RIESGO QUE PREOCUPAN

• PERFIL DE TOLERABILIDAD

Ó• PATRÓN DE SANGRADOS VAGINALES

• RIESGO DE CÁNCER DE MAMA

• RIESGO CARDIOVASCULAR

TRH y Síntomas vasomotoresTRH y Síntomas vasomotores

Dosis bajas y ultrabajas diarias efectivas

Estradiol oral………………………..0,5 -1 mgEstrogenos conjugados equinos….0,3 y 0,45 mgEstradiol transdermico……………..14 microgr

Panay N et al Climacteric 2007;10:120–31Bachmann GA,et al Obstet Gynecol 2007;110:770–9Uti WH t l F til St il 2001 75 1065 79Utian WH,et al Fertil Steril 2001;75:1065–79

WHI: Informe sobre el Cáncer de Mama E-S l li d Solo actualizado

Overall: HR=0 80; CI=0 62-1 04Overall: HR=0.80; CI=0.62-1.04

Adherent Pts: HR=0.67 CI=0.47-0.97Adherent Pts: HR 0.67 CI 0.47 0.97

No effect on in-situ disease.Only ductal cancers and in women with no prior

hormone therapy.

More follow-up /bi i / i imammograms/biopsies/aspirations.

JAMA 2006;295:1647

French E3N Cohort Studyy

SPEROFF

54,548 women; 0.1-10.6 years follow-up55% l 45% h

SPEROFF

55% gels; 45% patches

E l 30 1 1 (0 8 1 6)E alone 30 cases 1.1 (0.8-1.6)E/Progesterone 55 cases 0.9 (0.7-1.2)E/P g ti 268 1 4 (1 2 1 7)E/Progestins 268 cases 1.4 (1.2-1.7)

Int J Cancer 2005;114:448Int J Cancer 2005;114:448

Progestágenos: efectos en los receptoresProgestágenos: efectos en los receptores

(progesterone derivatives)

Progestogen EST A-E AND A-A GLU A-M

progesterone - + - (+) (+) +

d t ( )medroxyprogesterone - + (+) - + -

dydrogesterone - + - - - (+)

chlormadinone acetate + + +chlormadinone acetate - + - + + -

medrogestone - + - (+) - -

cyproterone acetate + + +cyproterone acetate - + - + + -

drospirenone - + - + - +

Breast cancer risk in relation to the interval between menopause and starting hormone therapy.J Natl Cancer Inst 2011 Feb 16;103(4):296-305 J Natl Cancer Inst. 2011 Feb 16;103(4):296-305. Beral V, Reeves G, Bull D, Green J; Million Women Study Collaborators.Collaborators

AbstractBACKGROUND: Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only

formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence.

METHODS: A total of 1,129,025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided.

RESULTS: During 4.05 million woman-years of follow-up, 15,759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (P(heterogeneity) < .001, for both estrogen-only and estrogen-progestin formulations) Among current users of estrogen only formulations there was little or no progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 users of estrogen progestin formulations (RR 1.53, 95% CI 1.38 to 1.70, and RR 2.04, 95% CI 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause.

CONCLUSIONS: There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.

Impact of HT on DVT by route of administration and type of progestin

Cannonico et al. Circulation 2007

Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogensadministration and progestogens.Menopause. 2011 Aug;18(8):873-9.Scarabin PY, Hemker HC, Clément C, Soisson V, Alhenc-Gelas M.

AbstractOBJECTIVE: Increased thrombin generation has emerged as a new surrogate marker of

venous thromboembolism. Using calibrated automated thrombography, we tested the influence of the route of estrogen administration and progestogens on thrombin

ti t l i h thgeneration among postmenopausal women using hormone therapy.METHODS: Baseline thrombin generation, together with clotting factors and inhibitors,

was determined in plasma from 115 healthy postmenopausal women. Women were classified by the use of hormone therapy into three groups: nonusers (n = 38) users classified by the use of hormone therapy into three groups: nonusers (n = 38), users of oral estrogens (n = 38), and users of transdermal estrogens (n = 39).

RESULTS: Oral estrogens dose dependently increased thrombin generation. Thrombin generation was increased among users of transdermal estrogens combined with g g gprogestins but was similar to nonusers among women using transdermal estrogens plus progesterone. Prothrombin was the main determinant of thrombin generation and explained a part of these differences. However, single clotting factors and inhibitors contributed little to the hormone related changes in thrombin inhibitors contributed little to the hormone-related changes in thrombin generation.

CONCLUSIONS: Increased thrombin generation can be detected in women using hormone therapy, but this hypercoagulable phenotype depends both on the hormone therapy, but this hypercoagulable phenotype depends both on the route of estrogen administration and the type of progestogens. These findings are consistent with current data on the risk of venous thromboembolism related to hormone therapy.

EFFECTS OF E/TE ON FUNCTIONAL MRI

APHRODITE (Transdermal Testosterone Patch Only)d l S i f i S l A i i 24 k

Increased Total Satisfying Sexual Activity at 24 Weeks

onth

p<0.0001*

ivit

y/M

oBa

selin

e *p-value, vs. placebo

xual

Act

ange

fro

m B

sfyi

ng S

eM

ean

Cha

Sati

s

Placebo n=265

150mg/day n=252

300mg/day n=254

Transdermal Testosterone Patch

TERAPIA HORMONAL NA MENOPAUSA: QUANDO TERAPIA HORMONAL NA MENOPAUSA: QUANDO, PARAQUEM E PARA QUÊ?

QUANDO………ANTES DE QUE TRASCURRAN 10 AÑOS DE LA MENOPAUSIA (60 AÑOS)MENOPAUSIA (60 AÑOS)

PARAQUEN… DISMINUCION DE LOS SINTOMAS VASOMOTORES, ATROFIA GENITO-URINARIASEGUNDA OPCCIÓN ,PARA PREVENCION DE OSTEOPOROSIS

COM QUE…………..ESTRADIOL DOSIS BAJAS O ULTRABAJAS COM QUE…………..ESTRADIOL DOSIS BAJAS O ULTRABAJAS, PROGESTERONA NATURAL O SEMEJANTE , RUTA TRANSDERMICA O PERCUTANEA?, CON TESTOSTERONA CUANDO SEA NECESARIO O TIBOLONATIBOLONA