Download Diapositiva 1 - Instituto Palacios

LA DROSPIRENONA EM LA MENOPAUSIA
Terapia hormonal basada en evidencias
Dr. Santiago Palacios
Instituto Palacios, Salud y Medicina de la Mujer
Chairman of CAMS (Council of Affiliated Menopause Societies)
Presidente de SIBOMM (Sociedad Iberoamericana de
Osteología y Metabolismo Óseo Mineral)
Antonio Acuña, 9 - 28009 Madrid
Teléfono 91 578 05 17
E-mail: [email protected]
www.institutopalacios.com
www.institutopalacios.com
Diapositivas / Slides
TRH 2012
 TH
-Ventana de oportunidad
-Baja y ultra-baja dosis de estrógenos.
-Gestágenos con valor añadido
 DATOS SOBRE TRH EN EL 2012
TRH: El nuevo paradigma
FDA
WHI
Million Women Study
Dec. 2003
4
Reduciendo la dosis
Acortando la
duración
Mujer sintomática
Women's Health Initiative (WHI) Estrogen Plus
Progestin E+P Trial: Design and Findings during
Active Intervention
Eligible postmenopausal
Age 50-79
No prior breast cancer
No prior hysterectomy
N= 16,608
Placebo
Conjugated equine estrogen
(CEE) 0.625 mg/d +
medroxyprogesterone
acetate (MPA) 2.5 mg/d
Intervention
median, 5.6 yrs
range, 4.6-8.6 years
HR 95% CI
CHD
Breast Ca
Stroke
PE
Endometrial Ca
Colorectal Ca
Hip Fracture
Global Index
Dementia
1.29 (1.02-1.63)
1.26 (1.00-1.59)
1.41 (1.07-1.85)
2.13 (1.39-3.25)
0.83 (0.47-1.47)
0.63 (0.43-0.92)
0.66 (0.45-0.98)
1.15 (1.03-1.28)
2.05 (1.21-3.48)
WHI Writing Group JAMA 2002; 288: 321
Chlebowski, Hendrix, Langer, et al JAMA 2003; 289: 3253
Rapp, Espeland, Shumaker et al JAMA 2003;289:2651-62
Women's Health Initiative (WHI) Estrogen Alone
Clinical Trial: Design and Primary Outcome
HR 95% CI
Eligible postmenopausal
Age 50-79
No prior breast cancer
Prior hysterectomy
N= 16,608
Placebo
Conjugated equine estrogen
(CEE) 0.625 mg/d
CHD
0.91 (0.75-1.12)
Breast Ca
0.7 (0.59-1.01)
Stroke
1.39 (0.10-1.77)
PE
1.34 (0.87-2.06)
Colorectal Ca
1.08 (.075-1.55)
Hip Fracture
0.61 (0.41-0.91)
Global Index
1.01 (0.91-1.12)
Dementia
1.49 (0.83-2.66)
Intervention 7.1 yrs
Anderson et al JAMA 2004;291:1701
Stefanick et al JAMA 2006;295:1647
E+P and Total Fractures By Age
E+P Effect in All Age Groups
Cauley et al. JAMA 2009; 290:1729
0
HT and CHD: Meta-Analysis
of Observational Studies
Ever Users
Crosssectional
Prospective/
internal
control
Hospitalbased
Summary
Current Users
Based on more than 40
observational studies of HT
and CHD, the summary
relative risks for CHD were
40-50% lower among current
or ever users of HT
compared to never users
(p<0.001).
Populationbased
cohorts
Populationbased casecontrol
Crosssectional
Prospective/
internal
control
Summary
From: Grodstein F, Stampfer MJ. Prog Cardiovasc Dis 1995; 38:199-210.
0.5
1.0 1.5 2.0
DIFERENCIAS ENTRE ESTUDIOS
OBSERVACIONALES Y EL WHI
WHI
Observational
Studies
Edad de iniciación de la TH
63 años
52 años
Tiempo desde la menopausia
12 años
1-2 años
General –
General+
IMC
28-30
24-25
Uso de TH
Corto
Largo
CEE+MPA
Diversas
Síntomas vasomotores
Formulaciones de TH
Relación de los años desde la menopausia con la
progresión de arterioesclerosis en el WHI
Adventitia
Media
MMP-9
Fibrous
Cap
Internal
Elastic
Lamina
Fatty
Streak/Plaque
Plaque
Years Postmenopause
% of WHI Enrollees
<5
17%
Fibrous
Cap
Fibrous
Cap
Plaque
Plaque
Necrotic Core
Necrotic Core
5 to <10
19%
10 to <15
21%
≥15
43%
Mortalidad total asociada con la TRH en mujeres
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 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
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,
endometrial ca, hip fracture and mortality
Source: Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007.
WHI E+P Trial: Time Since Menopause May Be Better Than Age at
Predicting CHD Risk with HT
Age (years)
1.27
50–59
1.05
60–69
1.44
70–79
Years Since Menopause
0.89
<10
1.22
10–19
1.71
20
0,5
1,0
1,5
2,0
2,5
Hazard Ratio for CHD
The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant.
Manson JE, et al. N Engl J Med. 2003;349:523-34.
Timing of Hormone Therapy Initiation in Relation to Stage of Atherosclerosis:
Observational Studies vs Clinical Trials
Premenopausal Years
Postmenopausal Years
Years Since Menopause Onset
10
15
5
Observational Studies
20
Clinical Trials
(1° and 2° Prevention)
Progression of
Cardiovascular
Disease
Fatty streaks
Fatty plaques
Atherosclerotic plaques
Favorable Lipid and
Endothelial Effects of
Estrogen Predominate
Plaques grow and may rupture
Prothrombotic and
Proinflammatory Effects of
Estrogen Predominate
(plaque rupture, thrombo-occlusion)
From: J Manson, et al. Menopause 2006.
Favorable Influence
Adverse Influence
of Initiating
of Initiating
Exogenous Estrogens
Exogenous Estrogens
Timing and duration of menopausal hormone
treatment may affect cardiovascular outcomes.
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.
Abstract
Largely 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 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 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 heart 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 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.
1,8
RR for CHD events
1,6
1,4
1,2
1
0,8
<10
10 -- 19
>20
0,6
0,4
0,2
0
Time since menopause (years)
E Alone
E+P
Estrogen Alone Age Specific Results
50-59 years
CHD/Total MI
60-69 years
70-79 years
0
Stroke
0
DVT/PE
0
0
Breast cancer
Colorectal cancer
0
Hip fracture
0
0
All-cause mortality
0
Global index
0
Beginning E alone at younger age likely CHD and breast cancer benefit
LaCroix, Chlebowski, Manson, et al. JAMA 2011;305(13):1305-
Re-analisis de la TRH del WHI
■ Porcentaje de retirada del estudio fué 30% en el
grupo E+P y 45% en el de E solos = Por lo que el
nivel de evidencia es B
■ La edad de inicio de la THS es importante. La
hipotesis del tiempo es cierta
 Riesgo de ECV< 60 años no existe o es beneficioso y
con E solos es beneficioso
 Riesgo de cancer de mama < 60 años puede?
Ser mayor
…NURSES´HEALTH STUDY=WHI < 60 AÑOS
TRH 2012
 TH
-Ventana de oportunidad
-Baja y ultra-baja dosis de estrógenos.
-Gestágenos con valor añadido
 DATOS SOBRE TRH EN EL 2012
Balance entre desaparición de unos
síntomas-aparición de otros
Reducción de:
Aumento de :
Síntomas
vasomotores
Tensión mamaria
Sangrado vaginal
Dose Response to Estrogen Therapy
Number of moderate-severe hot flushes
80
Placebo
0.25 mg E2
70
0.5 mg E2
60
1 mg E2
50
2 mg E2
Significantly (P<0.05) from
placebo
*
40
30
20
*
*
*
10
*
0
*
0
1
2
3
4
5
6
7
8
*
*
*
9
10
Notelovitz et al. Obstet Gynecol. 2000;95;726.
11
12
12
10
Changes mean (2 SEM)
annual percentage and each
subject’s spinal trabecular
bone density (TBD) in 46
postmenopausal women
given micronized estradiol
(phase 1). All subjects
received calcium
supplements
Annual percent change spinal TBD
8
6
4
2
0
-2
-4
-6
-8
-10
-12
-14
-2 SEM
-16
-18
Ettinger et al. Am J Obstet Gynecol 1992
+2 SEM
Placebo
0.5 mg
1.0 mg 2.0 mg
Micronized estradiol
ANGELIQ®
1/2 H2O
DROSPIRENONA
ESTRADIOL
Numero de bochornos co E 1 mg y
drosperinona
Mean number of hot flushes/week
80
70
Placebo (n=46)
60
50
40
30
20
*
10
0
BL
1
2
3
4
5
6
7
8
9
Treatment week
Schürmann R et al. Climacteric 2004;7:189-196
10
11
12
13
14
15
16
*P<0.001
BL, baseline
EFECTO DE ESTRADIOL/DROSPERINONA SOBRE
LA DMO
Spine BMD
Change from 8.0
baseline (%)
E/DRSP (n=60)
6.0
4.0
P < 0.001
2.0
Placebo (n=60)
0.0
–2.0
0
6
12
18
24
Total hip BMD
Change from 8.0
baseline (%)
6.0
E/DRSP (n=60)
4.0
2.0
P < 0.001
0.0
–2.0
Placebo (n=60)
0
Warming L et al. Climacteric 2004;7:103-111
6
12
18
24
EFECTO DE E/DRSP SOBRE LA DMO EN OSTEOPENICAS
E/DRSP (n=18)
Placebo (n=18)
Change from
baseline in
lumbar spine
BMD (%)
6
5
4
3
2
1
0
-1
-2
Months
of treatment
BL
3
6
12
18
24
Osteopenic women
Schering AG, data on file
BL: baseline; BMD: bone mineral density
DMO EN CADERA
Change from
baseline in
left hip
BMD (%)
E/DRSP (n=18)
Placebo (n=18)
4
3
2
P<0.05
1
0
-1
Months
of treatment
BL
3
6
12
18
24
Osteopenic women
Schering AG, data on file
BL: baseline; BMD: bone mineral density
TRH 2012
■ TH
-Ventana de oportunidad
-Baja y ultra-baja dosis de estrógenos.
-Gestágenos con valor añadido
■ DATOS SOBRE TRH EN EL 2012
DRSP:PROPIEDADES PARA USAR COMO
TRH
1. Porqué un nuevo gestageno
2. Perfil farmacologíco
3. Las diferencias el efecto PARA
4. La eficacia
5. El desafio
WHI HT Trials: Increased Risk of
Venous Thromboembolism
HR (95% CI)
E+P1
E alone2
2.06 (1.57, 2.70)
1.33 (0.99, 1.79)
0.5
1.0
2.0
Hazard Ratio
1Cushman
2Women's
M, et al. JAMA. 2004;292:1573-80.
Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
5.0
Impact of HT on DVT by route of administration
and type of progestin
Cannonico et al. Circulation 2007
WHI: Informe sobre el Cáncer de Mama E-Solo
actualizado
Overall:
HR=0.80;
CI=0.62-1.04
Adherent 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
mammograms/biopsies/aspirations.
JAMA 2006;295:1647
Estudio Frances E3N y numero
de canceres de mama
SPEROFF
54,548 women; 0.1-10.6 years follow-up
55% gels; 45% patches
E alone
30 cases
E/Progesterone 55 cases
E/Progestins
268 cases
1.1 (0.8-1.6)
0.9 (0.7-1.2)
1.4 (1.2-1.7)
Int J Cancer 2005;114:448
WHI Results: Overall Attributable Risk
Attributable Risk or Benefit per 10,000 Women/Year
Event
E+P Arm1-7
E-Alone Arm8,9
CHD
Risk (6)
Benefit (5)
Breast cancer
Risk (8)
Benefit (7)
Dementia*
Risk (23)
Risk (12)
Stroke
Risk (7)
Risk (12)
VTE
Risk (18)
Risk (7)
PE
Risk (8)
Risk (3)
Colorectal cancer
Benefit (6)
Risk (1)
Hip fractures
Benefit (5)
Benefit (6)
Total fractures
Benefit (47)
Benefit (56)
*Only in women 65 years of age at baseline.
1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Chlebowski RT, et al. JAMA. 2003;289:3243-53; 3Shumaker SA,
et al. JAMA. 2003;289:2651-62; 4Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; 5Writing Group for the WHI
Investigators. JAMA. 2002;288:321-33; 6Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; 7Cauley JA, et al.
JAMA. 2003;290:1729-38; 8Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12; 9Shumaker SA, et
al. JAMA. 2004;291:2947-58.
ANTIANDROGÉNICOS
E
A
NORETIS
ANMIN.
MIN.
IE
CPA
ANAND.
ANT E
Why we need a new Progestin
Recommendations on Postmenopausal Hormone Therapy
■ HT include a wide range of hormonal
products with potentially different risks and
benefits. Thus, the term “class effect” is
confusing and inappropriate.
■ In general, progestogen should be added to
systemic estrogens for all women with a
uterus to prevent endometrial hyperplasia and
cancer. However, progesterone and some
progestins have specific beneficial effects that
could justify their use besides the expected
actions on the endometrium.
DRSP:PROPIEDADES PARA USAR
COMO TRH
1. Porqué un nuevo gestageno
2. Perfil farmacologíco
3. Las diferencias el efecto PARA
4. La eficacia
5. El desafio
Comparación de Drospirenona con
Otras Progestinas (continuación)
Actividad
Progestagénica
Actividad
Actividad
Actividad
Androgénica Antiandrogénica Antialdosterona
Actividad
Glucocorticoide
Progesterona
+
–
(+)
+
–
Drospirenona
+
–
+
+
–
Ciproterona
+
–
+
–
(+)
Desogestrel
+
(+)
–
–
–
Dienogest
+
–
+
–
–
Gestodeno
+
(+)
–
(+)
–
Levonorgestrel
+
(+)
–
–
–
MPA
+
(+)
–
–
(+)
Noretisterona
+
(+)
–
–
–
Norgestimato
+
(+)
–
–
–
Tibolona
+
+
–
–
–
+ actividad relevante;
39
(+) actividad no relevante;
MPA: Acetato de medroxiprogesterona
– no actividad
Schindler AE et al. Maturitas. 2003;46(suppl 1):S7-S16; Rübig A. Climacteric. 2003;6(suppl 3):49-54.
DRSP:PROPIEDADES PARA USAR
COMO TRH
1. Porqué un nuevo gestageno
2. Perfil farmacologíco
3. Las diferencias el efecto PARA
4. La eficacia
5. El desafio
Renin-angiotensin-aldosterone system
(RAAS)
Angiotensin I
+
Estrogen
Renin substrate
(angiotensinogen)
Renin
- Increased plasma volume
- Increased blood pressure in susceptibles
- Water retention-related symptoms
(edema, bloating, weight gain, breast tension)
Na+/water retention
K+ elimination
Progesterone
Aldosterone
Angiotensin II
Renin-angiotensin-aldosterone system
(RAAS)
Angiotensin I
+
Estrogen
Renin substrate
(angiotensinogen)
Renin
- Increased plasma volume
- Increased blood pressure in susceptibles
- Water retention-related symptoms
(edema, bloating, weight gain, breast tension)
Na+/water retention
K+ elimination
Progesterone
Drospirenone
Aldosterone
Angiotensin II
DRSP:PROPIEDADES PARA USAR
COMO TRH
1. Porqué un nuevo gestageno
2. Perfil farmacologíco
3. Las diferencias el efecto PARA
4. La eficacia
5. El desafio
Effects on endometrium
Participants, no*
Endometrial hyperplasia,
no (%)
Simple without atypia
Complex without atypia
Complex with atypia
1-year probability
Archer D et al. Menopause 2005;12:716-27
Estradiol 1
mg
173
E/DRSP®
8 (4.6)
1 (0.7)
4 (2.3)
3 (1.7)
1 (0.6)
0.060
1 (0.7)
0 (0)
0 (0)
0.007
149
Amenorrhea
Women with
no bleeding
(%)
100
90
80
70
60
50
40
30
20
10
0
Cycle number
1
2
Warming L et al. Climacteric 2004;7:103-111
3
4
5
6
7
8
9
10
11
12
13
CAMBIOS LIPIDICOS CON E/DRSP
20
17,5
Estradiol 1 mg
15
10
4,2
5
1,4
0,6
0
0,1
0,1
-0,2
-5
-6,7
-10
-15
-12,8
Total C
Archer D et al. Menopause 2005;12:716-27
-12,7
LDL-C
HDL-C
TG
HDL/LDL
progestins and breast cancer
Number of genes regulated by progestin treatment in T47D breast cancer cells
The number of up-regulated (white bars) and down-regulated (black bars) genes are indicated.
DRSP acts differently from other progestins on gene expression in breast cancer cells.
Bray et al, Journal of Steroid Biochemistry & Molecular Biology, 2005
DRSP:PROPIEDADES PARA USAR
COMO TRH
1. Porqué un nuevo gestageno
2. Perfil farmacologíco
3. Las diferencias el efecto PARA
4. La eficacia
5. El desafio
Presión arterial en el subgrupo de mujeres
hipertensas del estudio de seguridad endometrial
(análisis post hoc)
mmHg
0
TA Sistólica
-1
-2
TA Diastólica
-3
-4
-2,7
-3,7
-5
-6
-5.7*
*
-7
-8
-9
-9#
-10
Estradiol 1mg (n=15)
49
Archer
et al. Menopause. 2005;12:716.
ANGELIQ (n=15)
* p< .001 vs basal
# p= .011 vs basal
Dose ranging study: Results
Placebo-adjusted mean change in 24-hour
ambulatory systolic and diastolic blood
pressure (ABPM)
Mean
change in
blood
pressure
(mmHg)
2
SBP DBP
0,1
0
-0,8
-2
-2,4*
-3,3‡
-4
-2,2
†
-2,6
-3,2*
-5,0 ‡
-6
DRSP 3 mg/E2
(n=125)
DRSP 2 mg/E2
(n=123)
DRSP 1 mg/E2
(n=123)
E2
(n=125)
*P<0.01; †P<0.001; ‡P<0.0001
White WB et al. Hypertension 2006;48:246-253
Effect of DRSP and estradiol on
blood pressure
SBP
DBP
Mean change in blood
pressure [mmHg]
2
0
-2
-4
–2.9*
-6
-8
-10
–6.0†
DRSP 2 mg/E2 (n=124)
*P<0.05; †P<0.001
White B et al. J Am Soc Hypert 2008; 2(1): 20-27
DRSP/E2 has an additive effect on BP when given
along with antihypertensive drugs
E2/DRSP (3mg) +
antihypertensive
drug
Enalapril 10 mg
BID
ACEI/ARB at high
dose
HCTZ 25 mg
Additional
effect on
systolic BP
Adverse
effect on
potassium
-9.2 mm Hg
No
-8.6 mm Hg
No
-7.2 mm Hg
No
Preston RA, et al. Am J Hypertens 2002;15:816–22
Preston RA, et al. Am J Hypertens 2005;18:797–804
Preston RA, et al. Menopause 2007;14:408–414
Population strategy: Distributions of
systolic blood pressure
Before
intervention
After
intervention
Reduction
of B.P.
Reduction of Systolic B.P. mmHg
% change in mortality
Ictus Coronary disease Total
2
–6
–4
–3
3
–8
–5
–4
5
– 14
–9
–7
Study Outline
Design:
Treatment:
Controlled, prospective, non-interventional, active surveillance study in
7 European countries: Austria, Belgium, Germany, Italy, Netherlands,
Spain, Turkey
Angeliq*
Other cc HRT
Objectives:
To compare incidence rates of serious adverse events – in particular
cardiovascular outcomes – in users of continuous combined HRT
products
Supervision:
Independent Scientific Advisory Board (S. Shapiro, A. Genazzani, A.
Gompel, S. Palacios, M. Neves-e-Castro, J. Boivin)
* 2 mg DRSP, 1 mg E2
Exposure [WY]
Exposure – 101,715 WY
Events/10,000 WY
Serious Adverse Events by Organ
System (ICD 10)
*Any adverse event that results in death, a life-threatening experience, inpatient hospitalization, persistent or significant
disability/incapacity, or requires medical/surgical intervention to prevent one of the said outcomes.
Cardiovascular SAEs (N=1,543)
240
HRadj.* : 0.7 (95% CI: 0.6 – 0.9); p=0.002
Events/10,000 WY
HRcrude: 0.6 (95% CI: 0.5 – 0.7); p<0.001
180
120
60
0
* adjusted for age, BMI, family history of VTE/ATE, region, user status, diabetes, smoking, hypertension
Venous Thromboembolism (VTE)
N=74
N=26
Events/10,000 WY
N=24
HRadj: 0.76 (95% CI: 0.51 – 1.26)
HRadj: 1.01 (95% CI: 0.58 – 1.77)
* adjusted for age, BMI, family history of VTE/ATE, region, user status, diabetes, smoking, hypertension
Arterial Thromboembolism (N=265)
Events/10,000 WY
N=95
N=33
N=15
HRadj.: 0.5 (95% CI: 0.3 – 0.8)
HRcrude: 0.4 (95% CI: 0.2 – 0.7)
N=23
N=99
CONCLUSIONES
● Existen evidencias de que la TRH aumenta la
masa osea y reducen las fracturas
● Dosis Bajas de 1 mgr de estradiol han demostrado
ser efectivos como dosis normales , pero con
menos riesgo.
● El uso de gestagenos similares a la progesterona ,
confieren menores riesgos y poosibles beneficios
añadidos
● El uso de TRH en mujeres sintomaticas de menos
de 60 años es beneficioso
CONCLUSIONES
■
■
■
■
■
■
Años 1950s la TRH elisir de la juventud
Años 1970s la TRH produce ca de endometrio
Años 1980s la TRH previene el ca de endometrio
Años 1980s y 90s TRH aumenta el ca de mama
Años 1990s TRH previene el riesgo cardiovascular
Primera decada del siglo XXI la TRH aumenta el riesgo
cardiovascular
■ Y en la segunda decada del siglo XXI….
EL PENDULO DE LA TRH
VUELVE
PERO
NO COMETAMOS LOS
MISMOS ERRORES