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