Download - The Progestins All Similar
-
8/13/2019 The Progestins All Similar
1/23
Avances in Oral contraception
The Progestins: All similar?
Regine Sitruk-Ware, MD
Population Council & Rockefeller University, New York, USA
World Congress Pediatric & AdolescentGynecology
May 22-25 Montpellier, France
-
8/13/2019 The Progestins All Similar
2/23
Overview
Pharmacology of Progestins
Risks and benefits of current Progestins
Prospects for research
Conclusions
-
8/13/2019 The Progestins All Similar
3/23
Classification of Progestins
Related to Progesterone
DydrogesteroneMedrogestone
17-OH Progesterone(Pregnanes)
Medroxyprogesterone Ac
Cyproterone Ac
Chlormadinone AcMegestrol Ac
Related to Testosterone
EstranesNorethisterone
Dienogest (non-ethyl)
13-ethyl Gonanes
Levonorgestrel
Desogestrel (etonogestrel)
19-nor progesterone
Nestorone
Nomegestrol ac
Trimegestone
Gestodene
Norgestimate (norelgestromin)Spirolactone
Drospirenone
-
8/13/2019 The Progestins All Similar
4/23
Progestins Mechanism of Action
GR MR AR
DNA
P4
PR
A AB B
P4 PR
Receptorassociated proteins
& transcription factors
SRC1COa
SMRTCOr
Progestin
Response
Cytoplasm Nucleus Element(PRE)
-
8/13/2019 The Progestins All Similar
5/23
-
8/13/2019 The Progestins All Similar
6/23
Androgenic Potency
Progesterone
Increase
Testosterone LNG DSG Nestorone
NOMAc
Prostate 100 10 0Growth
(%)
NETA
MPA
DienogestTrimegestone
Drospirenone
-
8/13/2019 The Progestins All Similar
7/23
Progestin androgenicity in
hormonal contraception with EE
EE given orally or via non-oral route has similar
impact on the liver
EE-related SHBG increase is opposed by an
androgenic progestin
Non-androgenic progestins should be preferablycombined with natural estradiol E2
-
8/13/2019 The Progestins All Similar
8/23
Effect of EE on hepatic markers when
given with non-androgenic Progestins
SHBG
HDLAngiotensinogen
Modification of some clotting factors
-
8/13/2019 The Progestins All Similar
9/23
soEffects of OC with 30gEE and
Drospirenone or LNG
25
20
15
10
5
0
-5-10
-15
DRSP
LNG
Weight KG DBP mm SHBG HDL %
Oelkers W et al., JCEM 1995
-
8/13/2019 The Progestins All Similar
10/23
NEW PROGESTINS FOR CONTRACEPTION
Predominent effects
Drospirenone (DRSP) =antimineralocorticoid
Dienogest (DNG) =antiandrogenic
Nestorone (NES) =highest antiovulatory effect
(non-oral)
Nomegestrol (NOM Ac) =highly antigonadotropicTrimegestone (TMG)=highly progestational
None is androgenic nor estrogenic
-
8/13/2019 The Progestins All Similar
11/23
Nomegestrol Acetate (NOMAc) for oral
contraception
High antigonadotropic action
No androgenic effect
Low antiandrogenic effect
No estrogenic effect
No glucocorticoid action
Making it highly suitable for oral contraceptive use
-
8/13/2019 The Progestins All Similar
12/23
Nestorone in non-oral contraceptives
Highest antiovulatory potency
high progestational potency
not active orally
not bound to SHBG
no androgenic or estrogenic effect
no glucocorticoid activity at contraceptive
doses
Making it highly suitable for non-oral delivery
-
8/13/2019 The Progestins All Similar
13/23
Overview
Pharmacology of Progestins
Risks and benefits of current Progestins
Prospects for research
Conclusions
-
8/13/2019 The Progestins All Similar
14/23
Clinical Benefits of Progestins
without androgenic activity
no weight gain
no acne
no adverse effect on Lipids
minimal impact on Glucose and Insulin
Should have less impact on the
vessels and vasomotion
-
8/13/2019 The Progestins All Similar
15/23
Coronary artery atherosclerosis in
monkeysClarkson T.B., Anthony M.S. et al 1996
Plaque area
(mm2)
0.23
Control
0.10
Estradiol
0.10
Estradiol +
Progesterone
-
8/13/2019 The Progestins All Similar
16/23
Coronary Artery Diameter in
atherosclerotic monkeys
15OVX
E2
% change
from control
-150
-15
*
*
E2+ NMA
ACH-8
ACH-7
ACH-6
NTG
Adapted from: Williams JK, Cline JM, Honore EK, Delansorne R, Paris J.ACH=acetylcholine
NTG=nitroglycerin
Am J Obstet Gynecol 1998; 179: 1288-94
.E2=Estradiol
NMA=Nomegestrol Acetate
-
8/13/2019 The Progestins All Similar
17/23
Antimineralocorticoid effect of DRSP
E2 or EE Liver impact
Angiotensinogen
AI A II Aldosterone
Block MR
DROSPIRENONE
Na & Water Retention
Na & Water Excretion
-
8/13/2019 The Progestins All Similar
18/23
Effect of Progestins on hemostasis
No changes in clotting factors when Progestin
are given without estrogen, however:
Progestins with glucocorticoid action potentiatethe vascular procoagulant effects of thrombin
(Herkert O 2001)
No increased risk with CMA given alone (Plu-
Bureau G, 2004)Estrogenicity of COCs reflected by the increase
of SHBG levels potentiate the risk of VTE
-
8/13/2019 The Progestins All Similar
19/23
Progesterone and progestin action on
breast cells differ
All progestins do not stimulate breast tissue
growth the same way (Wood CE, 2007 )
Progesterone either oral or vaginal stimulate
less than MPA (Wood C, 2007)Observational studies: no increase in BC risk
with progesterone
RCT-WHI :Non previous users of HRT, 5years in the trial with CEE +MPA RR = 1.06 (n
= 12,504)
-
8/13/2019 The Progestins All Similar
20/23
DNA
(g/well)
MCF 7 cells grown without E2
35
30
25Estradiol
20
15
10
5
0
Gestodene
Norgestrel
MPAc
-14 -13 -12 -11 -10 -9 -8 -7 -6 -5
Catherino, Jeng and Jordan; 1993, Br J. Cancer, 67.945-952
-
8/13/2019 The Progestins All Similar
21/23
Overview
Pharmacology of Progestins
Risks and benefits of current Progestins
Prospects for research
Conclusions
-
8/13/2019 The Progestins All Similar
22/23
Beneficial Role of P & some progestins in
the neuronal tissue
Increase neuronal survival
Increase synthesis of myelin specific proteins byoligodendrocytes
P & 19-nor P increase Bcl-2 expression preventing
cell death
Nilsen & Brinton, Endocrinology 2002, Nilsen et al Gynecol Endocrinol 2006,Ibanez C et al Neuropathol Appl Neurobiol 2004; 30: 80-9
-
8/13/2019 The Progestins All Similar
23/23
Conclusions
Different progestins have various interactions withthe steroid receptors, hence different side-effects
New Progestins are non-androgenic and should
preferably be used with E2
Androgenic Progestins can be combined with EE
Most Progestins when given alone do not modifyhemostasis
Potential benefits of P and some progestins on
neuroprotection and myelin regeneration deservefurther development