Avances in Oral contraception
The Progestins: All similar?
Regine Sitruk-Ware, MD
Population Council & Rockefeller University, New York, USA
World Congress Pediatric & Adolescent Gynecology May 22-25 Montpellier, France
Overview
Pharmacology of Progestins Risks and benefits of current Progestins Prospects for research Conclusions
Classification of Progestins
Related to Progesterone Related to Testosterone
Dydrogesterone Medrogestone 17-OH Progesterone (Pregnanes) Medroxyprogesterone Ac Cyproterone Ac Chlormadinone Ac Megestrol Ac 19-nor progesterone Nestorone Nomegestrol ac Trimegestone
Estranes Norethisterone Dienogest (non-ethyl)
13-ethyl Gonanes Levonorgestrel Desogestrel (etonogestrel) Gestodene Norgestimate (norelgestromin) Spirolactone Drospirenone
Progestins Mechanism of Action
GR MR AR DNA
PR
P4
A B
Receptor
associated proteins & transcription factors SRC1 COa
A B
P4 PR
SMRT COr
Cytoplasm
Nucleus
Progestin Response Element (PRE)
Androgenic Potency
Progesterone Testosterone
Increase Prostate Growth (%)
LNG
DSG
Nestorone
NOMAc
100
10
NETA
Dienogest Trimegestone MPA Drospirenone
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 preferably combined with natural estradiol E2
Effect of EE on hepatic markers when given with non-androgenic Progestins
SHBG HDL
Angiotensinogen Modification of some clotting factors
Effects of OC with 30gEE and Drospirenone or LNG
25 20 15 10 5 0 -5 -10 -15 Weight KG DBP mm SHBG HDL % DRSP LNG
so
Oelkers W et al., JCEM 1995
NEW PROGESTINS FOR CONTRACEPTION Predominent effects
Drospirenone (DRSP) = antimineralocorticoid Dienogest (DNG) = antiandrogenic Nestorone (NES) = highest antiovulatory effect (non-oral) Nomegestrol (NOM Ac) = highly antigonadotropic Trimegestone (TMG)= highly progestational None is androgenic nor estrogenic
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
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
Overview
Pharmacology of Progestins Risks and benefits of current Progestins Prospects for research Conclusions
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
Coronary artery atherosclerosis in monkeys
Clarkson T.B., Anthony M.S. et al 1996
Plaque area (mm2)
0.23
0.10
0.10
Control
Estradiol
Estradiol +
Progesterone
Coronary Artery Diameter in atherosclerotic monkeys
15
OVX E E + NMA
2 2
% change from control
*
-150
-15
-8 -7 -6
ACH
ACH
ACH
NTG ACH=acetylcholine NTG=nitroglycerin E2=Estradiol NMA=Nomegestrol Acetate
Adapted from: Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. Am J Obstet Gynecol 1998; 179: 1288-94
Antimineralocorticoid effect of DRSP
E2 or EE Liver impact Angiotensinogen
AI A II
Aldosterone
Na & Water Retention Na & Water Excretion
Block MR DROSPIRENONE
Effect of Progestins on hemostasis
No changes in clotting factors when Progestin are given without estrogen, however: Progestins with glucocorticoid action potentiate the vascular procoagulant effects of thrombin (Herkert O 2001) No increased risk with CMA given alone (PluBureau G, 2004) Estrogenicity of COCs reflected by the increase of SHBG levels potentiate the risk of VTE
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, 5 years in the trial with CEE +MPA RR = 1.06 (n = 12,504)
MCF 7 cells grown without E2
35 30
DNA (g/well)
25 20 15 10 5 0 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5
Estradiol Gestodene Norgestrel MPAc
Catherino, Jeng and Jordan; 1993, Br J. Cancer, 67.945-952
Overview
Pharmacology of Progestins Risks and benefits of current Progestins Prospects for research Conclusions
Beneficial Role of P & some progestins in the neuronal tissue
Increase neuronal survival Increase synthesis of myelin specific proteins by oligodendrocytes 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
Conclusions
Different progestins have various interactions with the 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 modify hemostasis Potential benefits of P and some progestins on neuroprotection and myelin regeneration deserve further development
