Transcript Diapositive 1 - HRVATSKO DRUŠTVO ZA GINEKOLOŠKU

Controversial
comments
~
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HERS
1996
WHI
2002-2003
MWS
2003-2004
« witch-hunt »
back to reasonable,
adequate analyses,
experience…
HRT – after HERS, WHI, MWS …
WEST (cont.)
WHIMS
E3N
KEEPS – ongoing
WEST – cont. = nothing
new
E3N – advantage of
natural progesterone
DP – HORMOGIN Sao Paulo 2007
Studies:
STAR trial
RUTH study
WISDOM
PEPI
HERS
WHI
MWS
HOPE
NURSE
MISSION…
… etc.
HRT use
kg
M? M? M? M?
2000
2001
DP – HORMOGIN Sao Paulo 2010
2002
2003
2004
2005
2006
2007
2008 2009
HRT – after HERS, WHI, MWS …
HERS and WHI : study population too old
In spite of negative publication, positive
messages for estrogens use
Latest results speak very positively about
benefits of estrogens
DP – HORMOGIN Sao Paulo 2007
Conclusions after WHI
• HT with Prempro (CEE+MPA)
should not be used for prevention
of CHD in women of this age group
• Other therapies, lower doses, other
routes of delivery to be studied
• Shorter duration of treatment is
advised (but for how long?)
MISSION Study
3rd Follow up : The new results
of a French National Cohort on
coronary heart disease incidence
in postmenopausal women
treated by HRT or not
IMS, Rome,June 2011
Progesterone
Progesterone – progestins
BIOAVAILABILITY
Nestorone
Trimeges
NOMAC
Drospir
Progestins
Progesterone
17-OH-progesterone
derivated
PREGNANES
- Hydroxyprogesterone
caproate
- Hydroxyprogesterone
heptanoate
- Gestonorone caproate
- Chlormadinone acetate
- Medrogestone
- Medroxyprogesterone
acetate
- Cyproterone acetate
Dydrogesterone
19-norprogesterone
derivated
NOR-PREGNANES
- Nomegestrol acetate
- Demegestone
- Promegestone
- Nestorone
- Trimegestone
Drospirenone
ESTRANES
GONANES
-Lynestrenol
-Norgestrel
-Levonorgestrel -Desogestrel
-Norethisterone -Gestodene
-Norethisterone -Norgestimate
acetate
-Ethinodiol diacetate
-Norgestrienone
-Dienogest
PROGESTINS






androgenicity
lipid metabolism
glucocorticoids
mineralocorticoids
gonadotrophic action
antiestrogenic properties
THE ROLE OF PROGESTINS IN CARDIOVASCULAR PROTECTION BY HRT
Efficacy
Nomegestrol acetate
Trimegestone
Nestorone
Drospirenone
Cyproterone acetate
MPA
Progesterone
Androgenicity
NETA
Levonorgestrel
Lynestrenol
Ethinodiol
Metabolic
side effects
DP
ACTIONS ON METABOLISM
PROGESTINS
HALF-LIFE & BIOAVAILABILITY
PARAMETER
NET
Noretisterone
acetate (NETA)
Levonorgestrel
(LNG)
Gestodene
(GSD)
Desogestrel
(DSG)
Drospirenone
(DSRP)
NomAc
Bioavailability
% oral dose
65
~50*
100
100
75**
~76
63
Half-life (hours)
8
8*
16
12
12**
30
46
Volume
of
distribution (l)
240
240*
120
32
110**
4L/kg
1200
Progestational Potency
TMG
DSG
MPA
Norgestimate
NET
NOM Ac
Drospirenone
McPhail
Index
NES 100
Ovulation
NES 30
>
>
LNg 10
>
Progesterone 1
LNg 10
>
Progesterone 1
Inhibition
DSG
R.Sitruk-Ware classification 2010
TMG
NET
Drospirenone
Norgestimate
CPA
Dienogest
Androgenic Potency
Progesterone
Testosterone
LNG
Nestorone
NOMAc
Increase
Prostate
DSG
100
0
Growth
(%)
NETA
R.Sitruk-Ware classification 2010
Dienogest
Trimegestone
MPA
Drospirenone
AntiAndrogenic Potency
Dienogest
Chlormadinone
CPA
TMG NOM Ac
Decrease
Rat
100
40
20
Prostate
(%)
Progesterone
Drospirenone
R.Sitruk-Ware classification 2010
Minimal ovulation inhibition
dose
•
•
•
•
•
•
•
•
Gestodene:
40 mcg
Levonorgestrel:
50 mcg
Desogestrel:
60 mcg
Drospirenone:
3 mg
Ciproterone Acetate:
2 mg
Clormadinone Acetate: 2 mg
Nomegestrol Acetate:
1,5 mg
Dienogest:
2 mg
Progestins & hemostatic
factors
• No variations in coagulation factors when
progestins are administered without
estrogens.
• Progestins with glucocorticoid action
increase the procoagulant effects of
thrombin (Herkert O 2001)
• Estrogenicity of COC, indicate an
increase of SHBG, and potentialize the
risk of DVT.
Variations in (%) of SHBG: in monophasic OCs
mean change vs basal of SHBG (%)
300
250
200
E2: 17βestradiol
EE: ethinylestradiol
NOMAc: nomegestrol acetate
LNG: levonorgestrel
NMG: norgestimate
tv: transvaginal
ETN: etonorgestrel
GSD: gestodene
td: transdermal
NMGG: norelgestromine
DSG: desogestrel
DRSP: drospirenone
DNG: dienogest
CPA: cyproterone ac.
150
100
50
0
NOMAc+E2
LNG+EE
NMG+EE
tv ETN+ EE
GSD+EE
td NMGG+EE
DSG+EE
DRSP+EE
Modified from ODLIND V et al., Acta Obstet Gynecol Scand, 2002;81:482-90.
DNG+EE
CPA+EE
Clinical benefits of progestins
with no androgenic activity

no weight gain

no acne

no side-effects on lipids

minimal impact on glucose and
insulin

less impact on vasomotor system
Use of progestins in OC
• different progestins have different
interactions with steroid receptors
(thus different effects)
• non androgenic progestins can
preferably be used with E2
• androgenic progestins can be
combined (and often are) with EE
• most of the progestins does not
modify coagulation
BP
Gestodene
Increased progestative and antigonadotrophic action ,
clinicaly insignificant interaction with androgenic
receptors
Minimal interaction with glucocorticoid, but noted
adhaerence with mineralcorticoid receptor, which can
che determine an competitive inhibition with
aldosterone, although in doses used in OC it does not
seems relevant
Cinetics similar to levonorgestrel, bioavailability close
to 100%, binding to SHBG above 50%.
After oral administration, plasmatic pic is reached
within 1 hour (increasing with repeated intake to 12-18
hours)
EE + Gestodene
Pharmacological
form / C.name
Ethynilestradiol
mcg
Gestodene mg
Note
Ginoden (Bayer)
Minulet (Wyeth)
Kipling (Effik Italia)
Gestiodol (EG)
30
0,075
MONOPHASIC
21 CPS
(A)
Fedra (Bayer)
Harmonet (Wyeth)
Estinette (Effik Italia)
20
0,075
MONOPHASIC
Low dose
21 CPS
Arianna (Bayer)
Minesse (Wyeth)
15
0,060
MONOPHASIC
Low dose
24 CPS + 4
PLB
Milvane (Bayer)
Triminulet (Wyeth)
30
40
30
0,05
0,07
0,1
TRIPHASIC
21 CPS (A)
Desogestrel
High progestative and antigonadotrophic
power caracterised by a minimal antiestrogenic
action.
No estrogenic, gluco and mineralocorticoid
effects and low affinity for androgen receptors.
Desogestrel is a prodrug, rapidly trasformed on
hepatic level to an active compound
(citochrome P450; 3-Ketodesogestrel,
etonorgestrel - ETG)
Binding to SHBG is above 30%, and 58% to
albumins. Bioavailability is 76%.
EE + Desogestrel
Pharmacological
form/name
Ethynilestradiol mcg
Desogestrel mg
Note
Planum (Menarini)
Practil 21 (Organon Italia)
30
0,15
MONOPHASIC
21 CPS
(A)
Mercilon (Organon)
Securgin (Menarini)
Novynette (Finderm)
20
0,15
MONOPHASIC
Low dose
21 CPS
Dueva (Menarini)
Gracial (Organon Italia)
40
30
0,025
0,125
BIPHASICO
22 CPS
Lucille (Organon Italia)
35
30
30
0,05
0,10
0,15
TRIPHASICA
21 CPS
Cyproterone Acetate
Progestin with antiandrogenic activity, thus blocking
the action of testosterone in tissues.
It is stocked on adipose level, with some residual
glucocorticoid activity.
Coadjuvant in hirsutism treatment (EE 35mcg/CPA
2mg).
«Not used in USA; high estrogen content and collateral
hepatic risks; antiacne effect incostante.».
EE + Cyproterone Acetate
Pharmacological
form/name
Diane (Bayer)
Ethynilestradiol
mcg
Cyproterone Acetate mg
Note
35
2
MONOPHASIC
21 CPS
Chlormadinone Acetate
It has antiandrogenic activity (cca 20% of that one
from Ciproterone Acetate) and binding strength for
Progesterone receptor (PR) 1/3 superior to the one of
P and a weak binding with glucocorticoid receptors.
17-OH-progesterone derivated.
Scarse effect of the first hepatic passage with
bioavailability close to 100%.
EE + Chlormadinone Acetate
Pharmacological
form/name
Ethynilestradiol
mcg
Chlormadinone
Acetate mg
Note
Belara (Formenti)
Lybella (Alfa
Wasserman)
30
2
MONOPHASIC
21 CPS
Drospirenone
Drospirenone is an 17-alfa-spirolactone derivative.
Antimineralocorticoid activity of drospirenone, similar
to the one progesterone, is linked to the action in
renin-angiotensine-aldosterone system.
Better control of body weight and of hydric retention.
Antiandrogenic caracteristics is blocking the
androgenic receptor (1/3 activity of ciproterone
acetate).
Does not have androgenic, estrogenic, glucocorticoid
or antiglucocorticoide actions.
EE + Drospirenone
Pharmacological
form/name
Ethynilestradiol
mcg
Drospirenone mg
Note
Yasmin (Bayer)
30
3
MONOPHASIC
21 CPS
Yasminelle (Bayer)
20
3
MONOPHASIC
Low dose
21 CPS
Yaz (Bayer)
20
3
MONOPHASIC
Low dose
28 CPS
(24+4PLB)
Levonorgestrel
Has a very efficient progestative activity, high
antigonadotrophic action, strong antiestrogenic
activity and a weak androgenic and anabolic activity
Thanks to the strong antiestrogenic activity of LNG,
increase of SHBG, in connection to OC use, is lower
than other progestins; but after 1-3 cycles this effects
dissapears.
LNG is considered as progestin with minor risks of
venous tromboembolism (Lidegaard O, 2009 – van
Hylckama A, 2009), and is a gold standard in
comparison with other progestins in the issue of
coagulation profile.
EE + Levonorgestrel
Pharmacological
form/name
Ethynilestradiol
mcg
Levonorgestrel mg
Note
Novogyn 21 (Bayer)*
Microgynon (Bayer)
50
50
0,250
0,125
MONOPHASIC
Rarely used
21 CPS
(A)
(*Morning after pill
Yuzpe)
Egogyn 30 (Bayer)
30
0,150
MONOPHASIC
21 CPS
Loette (Wyeth)
Miranova (Bayer)
Lestronette (Theramex)
20
0,100
MONOPHASIC
Low dose
21 CPS
E2V+Dienogest
Quadriphasic (+2 placebo; 26+2)
(Qlaira)
E2+Nomegestrol Acetate (NomAc)
Monophasic (+4 placebo; 24+4)
(Zoely)
Nestorone
Trimeges
NOMAC
Drospir
Progestins (use):
• HT
Progestins (use):
• HT
• DUB
Progestins (use):
• HT
• DUB
• OC (COC, POP)
Progestins (use):
•
•
•
•
HT
DUB
OC (COC, POP)
Endometriosis
Progestins (use):
•
•
•
•
•
•
HT
DUB
OC (COC, POP)
Endometriosis
Oncology (rare)
…..
Progestins (use):
•
•
•
•
•
•
HT
DUB
OC (COC, POP)
Endometriosis
Oncology (rare)
…..
SPRMs !
Progesterone
Dydrogesterone
NomAc
17-OH-progesterone
derivated
PREGNANES
- Hydroxyprogesterone
caproate
- Hydroxyprogesterone
heptanoate
- Gestonorone caproate
- Chlormadinone acetate
- Medrogestone
- Medroxyprogesterone
acetate
- Cyproterone acetate
19-norprogesterone
derivated
Nestorone
Trimegestone
Drospirenone
NOR-PREGNANES
- Nomegestrol acetate
- Demegestone
- Promegestone
- Nestorone
- Trimegestone
Drospirenone
ESTRANES
GONANES
-Lynestrenol
-Norgestrel
-Levonorgestrel -Desogestrel
-Norethisterone -Gestodene
-Norethisterone -Norgestimate
acetate
-Ethinodiol diacetate
-Norgestrienone
-Dienogest
KEEPS is designed to test this theory by recruiting
720 healthy, recently menopausal women for a
randomized, placebo-controlled, double-blinded trial
of HT for four years.
Five-year, randomized, placebo-controlled, double-blinded
study, each participant will be evaluated for four years.
ORAL
E/P
Conducted at nine national sites
Approximately 720 recently menopausal women ages 42 to
58 is being recruited
Study participants will be divided into three groups and will
receive either transdermal estrogen (via skin patch), oral
estrogen or placebo
Women who are receiving active estrogen will also receive
progesterone (the bio-identical human progestin) for 12
days per month.
Study Start Date:
September 2005
Estimated Study Completion Fall 2011
TD
E/P
Placebo
USE OF HORMONES
1890’s
2010’s
The concepts change with
time…