controversial comments ~ hers 1996 ~ whi 2002-2003 ~ mws2003-2004 ~ « witch-hunt » ~ back to...
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Controversialcomments
~ HERS 1996~ WHI 2002-2003~ MWS 2003-2004~ « witch-hunt »~ back to reasonable, adequate analyses, experience…
HRT – after HERS, WHI, MWS …
WEST (cont.)WHIMS
E3NKEEPS – ongoing
WEST – cont. = nothing new
E3N – advantage of natural progesterone
Studies:
STAR trialRUTH studyWISDOMPEPIHERSWHIMWSHOPENURSEMISSION…… etc.
DP – HORMOGIN Sao Paulo 2007
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?)
IMS, Rome,June 2011IMS, Rome,June 2011
MISSION Study MISSION Study 3rd Follow up : The new results 3rd Follow up : The new results of a French National Cohort on of a French National Cohort on
coronary heart disease incidence coronary heart disease incidence in postmenopausal women in postmenopausal women
treated by HRT or nottreated by HRT or not
Progesterone
Related
to progest
erone
Related
to tes
tosterone
Drospirenone
Progesterone
17-OH-progesteronederivated
19-norprogesteronederivated
PREGNANES NOR-PREGNANESESTRANES- Hydroxyprogesterone
caproate- Hydroxyprogesterone heptanoate- Gestonorone caproate- Chlormadinone acetate- Medrogestone- Medroxyprogesterone acetate- Cyproterone acetate
- Nomegestrol acetate- Demegestone- Promegestone- Nestorone- Trimegestone
-Lynestrenol-Levonorgestrel-Norethisterone-Norethisterone acetate-Ethinodiol diacetate-Norgestrienone-Dienogest
GONANES
-Norgestrel-Desogestrel-Gestodene-Norgestimate
Dydrogesterone
androgenicity lipid metabolism glucocorticoids mineralocorticoids gonadotrophic action antiestrogenic properties
PROGESTINS
DP
THE ROLE OF PROGESTINS IN CARDIOVASCULAR PROTECTION BY HRT
Efficacy
Metabolicside effects
Androgenicity
Nomegestrol acetate
Trimegestone
DrospirenoneNestorone
MPA
Cyproterone acetate
Progesterone
Levonorgestrel
NETA
Lynestrenol
Ethinodiol
ACTIONS ON METABOLISM
HALF-LIFE & BIOAVAILABILITY
PROGESTINS
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
NES 100 > LNg 10 > Progesterone 1 NES 100 > LNg 10 > Progesterone 1
NES 30 > LNg 10 > Progesterone 1 NES 30 > LNg 10 > Progesterone 1
McPhail
Index
McPhail
IndexOvulation
Inhibition
Ovulation
Inhibition
DSG TMG
Norgestimate
DrospirenoneNET
Dienogest
DSG NOM Ac
MPA
Norgestimate
DrospirenoneNETTMG
CPA
R.Sitruk-Ware classification 2010
Androgenic Potency
100 0100 0
Increase
Prostate
Growth
(%)
Increase
Prostate
Growth
(%)
NETA
MPA Drospirenone
Dienogest
LNG DSG Nestorone
Progesterone
Testosterone
NOMAc
Trimegestone
R.Sitruk-Ware classification 2010
AntiAndrogenic Potency
Decrease
Rat
Prostate
(%)
Decrease
Rat
Prostate
(%)
Progesterone
Drospirenone
NOM AcTMGCPA
DienogestChlormadinone
100 40 20 100 40 20
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.
Modified from ODLIND V et al., Acta Obstet Gynecol Scand, 2002;81:482-90.
0
50
100
150
200
250
300
me
an
ch
an
ge
vs
ba
sa
l of
SH
BG
(%
)
NOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EE td NMGG+EE td NMGG+EE DSG+EE DRSP+EE DNG+EE CPA+EE DSG+EE DRSP+EE DNG+EE CPA+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EE td NMGG+EE td NMGG+EE DSG+EE DRSP+EE DNG+EE CPA+EE DSG+EE DRSP+EE DNG+EE CPA+EE
E2: 17E2: 17ββestradiolestradiol td: transdermal td: transdermalEE: ethinylestradiol EE: ethinylestradiol NMGG: norelgestromine NMGG: norelgestromineNOMAc: nomegestrol acetate DSG: desogestrelNOMAc: nomegestrol acetate DSG: desogestrelLNG: levonorgestrelLNG: levonorgestrel DRSP: drospirenone DRSP: drospirenone NMG: norgestimateNMG: norgestimate DNG: dienogest DNG: dienogest tv: transvaginaltv: transvaginal CPA: cyproterone ac. CPA: cyproterone ac.ETN: etonorgestrelETN: etonorgestrelGSD: gestodeneGSD: gestodene
E2: 17E2: 17ββestradiolestradiol td: transdermal td: transdermalEE: ethinylestradiol EE: ethinylestradiol NMGG: norelgestromine NMGG: norelgestromineNOMAc: nomegestrol acetate DSG: desogestrelNOMAc: nomegestrol acetate DSG: desogestrelLNG: levonorgestrelLNG: levonorgestrel DRSP: drospirenone DRSP: drospirenone NMG: norgestimateNMG: norgestimate DNG: dienogest DNG: dienogest tv: transvaginaltv: transvaginal CPA: cyproterone ac. CPA: cyproterone ac.ETN: etonorgestrelETN: etonorgestrelGSD: gestodeneGSD: gestodene
Variations in (%) of SHBG: in monophasic OCs
no weight gain
no acne
no side-effects on lipids
minimal impact on glucose and insulin
less impact on vasomotor system
Clinical benefits of progestins with no androgenic activity
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
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)
Gestodene
EE + Gestodene
Pharmacological form / C.name
Ethynilestradiol mcg
Gestodene mg Note
Ginoden (Bayer)Minulet (Wyeth)Kipling (Effik Italia)Gestiodol (EG)
30 0,075 MONOPHASIC21 CPS (A)
Fedra (Bayer)Harmonet (Wyeth)Estinette (Effik Italia)
20 0,075 MONOPHASICLow dose21 CPS
Arianna (Bayer)Minesse (Wyeth)
15 0,060 MONOPHASICLow dose 24 CPS + 4 PLB
Milvane (Bayer)Triminulet (Wyeth)
304030
0,050,070,1
TRIPHASIC21 CPS (A)
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%.
Desogestrel
EE + Desogestrel
Pharmacological form/name
Ethynilestradiol mcg Desogestrel mg Note
Planum (Menarini)Practil 21 (Organon Italia)
30 0,15 MONOPHASIC21 CPS (A)
Mercilon (Organon)Securgin (Menarini)Novynette (Finderm)
20 0,15 MONOPHASICLow dose21 CPS
Dueva (Menarini)Gracial (Organon Italia)
4030
0,0250,125
BIPHASICO22 CPS
Lucille (Organon Italia) 353030
0,050,100,15
TRIPHASICA21 CPS
Cyproterone Acetate 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 EE + Cyproterone Acetate
Pharmaco-logical form/name
Ethynilestradiol mcg
Cyproterone Acetate mg Note
Diane (Bayer) 35 2 MONOPHASIC21 CPS
Chlormadinone AcetateChlormadinone 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%.
Pharmacological form/name
Ethynilestradiol mcg
Chlormadinone Acetate mg
Note
Belara (Formenti)Lybella (Alfa Wasserman)
30 2 MONOPHASIC21 CPS
EE + Chlormadinone AcetateEE + Chlormadinone Acetate
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.
Drospirenone
EE + Drospirenone
Pharmacological form/name
Ethynilestradiol mcg
Drospirenone mg Note
Yasmin (Bayer) 30 3 MONOPHASIC21 CPS
Yasminelle (Bayer) 20 3 MONOPHASICLow dose21 CPS
Yaz (Bayer) 20 3 MONOPHASICLow dose28 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)
5050
0,2500,125
MONOPHASICRarely used 21 CPS (A) (*Morning after pill Yuzpe)
Egogyn 30 (Bayer) 30 0,150 MONOPHASIC21 CPS
Loette (Wyeth)Miranova (Bayer)Lestronette (Theramex)
20 0,100 MONOPHASICLow dose21 CPS
Related
to progest
erone
Related
to tes
tosterone
Drospirenone
Progesterone
17-OH-progesteronederivated
19-norprogesteronederivated
PREGNANES NOR-PREGNANESESTRANES- Hydroxyprogesterone
caproate- Hydroxyprogesterone heptanoate- Gestonorone caproate- Chlormadinone acetate- Medrogestone- Medroxyprogesterone acetate- Cyproterone acetate
- Nomegestrol acetate- Demegestone- Promegestone- Nestorone- Trimegestone
-Lynestrenol-Levonorgestrel-Norethisterone-Norethisterone acetate-Ethinodiol diacetate-Norgestrienone-Dienogest
GONANES
-Norgestrel-Desogestrel-Gestodene-Norgestimate
Dydrogesterone
NomAc Nestorone TrimegestoneDrospirenone
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.
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 placeboWomen who are receiving active estrogen will also receive progesterone (the bio-identical human progestin) for 12 days per month.
Study Start Date: September 2005Estimated Study Completion
Fall 2011
ORALE/P
TDE/P
Placebo