The International Menopause Society - SFOG

HRT idag och i morgon:
mot lägre doser och nya regimer
Bo von Schoultz
Professor em
Karolinska sjukhuset

Hotfulla moln över HRT

jan-00
jul-00
jan-01
jul-01
jan-02
jul-02
jan-03
jul-03
jan-04
jul-04
jan-05
jul-05
jan-06
jul-06
jan-07
jul-07
jan-08
jul-08
jan-09
jul-09
jan-10
jul-10
000 cyccles
Sweden CC market Jan 00-July 10
180
160
140
120
100
80
July-02
WHI
Aug-03
MWS
CC
60
40
20
0
Months

AFTER WHI……

Djup förtroendekris
Risker och säkerhet i fokus
Information räcker inte
Nya alternativ behövs

WHI: HT use and mortality by
age at baseline
Age HR 95% CI
50 – 59 0.70 0.51 – 0.96
60 – 69 1.05 0.87 – 1.26
70 – 79 1.14 0.94 – 1.37
Rossouw J et al,
JAMA 2007;297:1465

Postmenopausal Hormone Therapy:
an Endocrine Society Scientific Statement
Santen RJ,Allred DC,Ardoin SP et al.
J Clin Endocrinol Metab 2010;95 (Suppl 1):S1-S66

HRT for 5 years
( started < 10 years after menopause)
Benefits: relief of vasomotor symptoms
reversal of urogenital atrophy
prevention of fractures , diabetes and coronary
artery disease
Risks: venous thrombosis, stroke, cholecystitis
and breast cancer
Reduction of overall mortality

ERT vs HRT
Progestin related side effects

E-only
Women’s Health Initiative
EPT
placebo
CEE
placebo
placebo
CEE + MPA
CEE + MPA
The WHI Steering Committee,
JAMA 2004; 291:1701-12
Chlebowski et al,
JAMA 2003; 289: 3243–53
10

No uterus
no problem !

MPA , NETA
or
natural progesterone

Progesterone and progestins can
reactivate
occult breast cancer stem cells
Horwitz K et al PNAS 2008; 105: 5774
Horwitz K & Sartorius C JCEM 2008; 93: 3295

FIG. 2. Proposed differentiation pathway of ER+, PR+ breast cancers from ER-, PR- stem
cells, and the reversal induced by progestins
Horwitz, K. B. et al.
J Clin Endocrinol Metab
Copyright ©2008 The Endocrine Society
2008;93:3295-3298

Secreted VEGF in T47-D cells in response to
various Progestins
0
VEGF pg/mg protein (X10 -3 )
1 2 3 4 5 6 7
Control
Prog
Prog + RU
MPA
MPA + RU
N-EL
N-EL + RU
N-ONE
N-ONE + RU
*
*
*
*
All steroids used at 10 -8 M
MPA= Medroxyprogesterone acetate; N-EL= norgestrel; N-ONE = norethindrone
Hyder et al, 2001

Risk of BC
from
Estrogen+progesterone
( started within 3 years of menopause)
< 2 years HR: 0.87 CI: 0.57 - 1.32
2 – 5 years HR: 1.01 CI: 0.72 - 1.41
5 – 10 years HR: 1.47 CI: 1.11 - 1.95
>10 years HR: 1.92 CI: 1.34 - 2.74
p for trend 0.002
E3N cohort
Fournier et al
J Clin Oncol 2009;27 :5138-43

Breast stimulation
a
class effect

Går vi mot solnedgången ?

HRT utan bröstpåverkan
Är det möjligt?

Breast cell proliferation and
mammographic density may be
useful as surrogate markers for
breast cancer risk

change in density from different
preparations
follows
current perception of cancer risk

Mot lägre doser !

Vaginal Maturation Index
Placebo
10µg E2
100%
100%
*
* * * *
80%
60%
80%
60%
**
* *
* *
40%
40%
20%
20%
0%
Baseline 2 4 8 12
(LOCF)
Weeks
52
(LOCF)
0%
* * * * *
Baseline 2 4 8 12
(LOCF)
Weeks
52
(LOCF)
Parabasal Intermediate Superficial
* p

Mot lägre doser
2 mg E2/ 1 mg NETA
blev
1 mg E2/ 0.5 mg NETA
blev
0.5 mg E2/ 0.1 mg NETA

Mean number
NUMBER OF MODERATE TO SEVERE
HOT FLUSHES BY WEEK
80
60
40
*
*
20
*
*
*
0
0 3 4 8 12 24
Weeks
• Placebo • Eviana ® *significantly (p=0.001) different from placebo
Panay N et al. Climacteric 2007;10(2):120–131

Base-line
6 months

Mean breast density (%)
Mammographic density – Digitized quantification
30
25
20
15
10
5
0
Placebo ALD 0.1 ALD 0.25
Screening Week 24 No significant difference between groups

Breast related adverse events in the whole
CHOICE trial by system organ class
ALD 0.25 ALD 0.1 Placebo
System organ class
MedDRA preferred term N (%) E N (%) E N (%) E
Breast disorders
• Breast discomfort 1 (1%) 1
• Breast pain 2 (1%) 2 2 (1%) 2 1 (1%) 1
• Breast tenderness 1 (1%) 1 1 (1%) 1 4 (2%) 4

Testosterone addition
inhibits
estrogen induced breast
proliferation
Dimitriakis et al; Menopause 2003; 10:292

Change in density during different
treatments.
45
40
35
30
25
20
Baseline
6 months
15
10
5
0
E2/NETA
n=43
Tibolone
n=49
Black Cohosh
n=64
Placebo
n=53

Tibolone and BC risk
in healthy women
MWS RR: 1.45 CI: 1.25 – 1.68
GPRD RR: 0.86 CI: 0.65 – 1.13
LIFT RCT RH: 0.32 CI: 0.13 – 0.80
Lancet 2003 ; 362: 1160
BJOG 2008; 115: 169
N Engl J Med 2008; 359: 697

Nya principer !

MLS 10 µg LNG/day
Mirena 20 µg LNG/day

Baseline
E2/LNG
after 18
months
Lundström et al 2003

Raloxifene

BAZEDOXIFENE

BZA 20 mg/ CEE 0.45 mg
a 2 year RCT
3397 postmenopausal women
Hot flushes reduced by 85 %
amenorrhea 93 %
improved lipid profile
minor effects on antithrombin III
breast pain similar to placebo
Lobo et al Fertil Steril 2009;92:1025

Progesterone Receptor Antagonists
* *
RU 486 (Mifepristone) ZK98 299 (Onapristone) CDB 4124 (Proellex))
*
(lonapristan)

Mammary Gland Branching in Ducts from Mouse
Mammary Tissue
Normal mice
BRCA1/P53 deficient mice
Mifepristone inhibits mammary tumorigenesis by decreasing ductal branching
and alveolar proliferation in BRCA1/p53 deficient mice
Jovanovic Poole et al, 2006

Ki-67 Positive Nuclei
Baseline
After 84 days of
mifepristone
(50 mg alternate days)
Engman et al, 2008

Options for breast safety
Regim VMS LIPID KOAG Breast
Density
0.5 E2/0.1
NETA
++ neutral neutral neutral
Tibolone ++ - neutral (neutral)
BZA/CEE +++ + - ?
E2/antiprog
E2/Lng-IUD
E2/natural p
Black cohosh
?
+++
+++
(+)
?
+
+
neutral
?
-
-
neutral
?
-
-
neutral

Gryningen kommer!