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

n Pharmacology of Progestins
n Risks and benefits of current Progestins
n Prospects for research
n Conclusions
 Classification of Progestins

Related to Progesterone Related to Testosterone

Dydrogesterone 9 Estranes
Medrogestone
Norethisterone
9 17-OH Progesterone (Pregnanes)
Dienogest (non-ethyl)
Medroxyprogesterone Ac
Cyproterone Ac
9 13-ethyl Gonanes
Chlormadinone Ac
Megestrol Ac Levonorgestrel
Desogestrel (etonogestrel)
9 19-nor progesterone Gestodene
Norgestimate (norelgestromin)
Nestorone
9 Spirolactone
Nomegestrol ac
Drospirenone
Trimegestone
 Progestins – Mechanism of Action

GR MR AR
DNA

PR
A A
P4
B B

Receptor
associated proteins
P4 PR & transcription factors

SRC1 SMRT
COa COr
Progestin
Response
Cytoplasm Nucleus Element
(PRE)
 Androgenic Potency
Progesterone

Testosterone LNG DSG Nestorone

NOMAc
Increase
Prostate 100 10 0
Growth
(%)

NETA Dienogest
Trimegestone
MPA Drospirenone
 Progestin androgenicity in
hormonal contraception with EE

n EE given orally or via non-oral route has similar

impact on the liver

n EE-related SHBG increase is opposed by an

androgenic progestin

n Non-androgenic progestins should be preferably

combined with natural estradiol E2
Effect of EE on hepatic markers when
given with non-androgenic Progestins

n Å SHBG
n Å HDL
n Å Angiotensinogen
n Modification of some clotting factors
 so
Effects of OC with 30µgEE and
Drospirenone or LNG
25
20
15
10
5 DRSP
0 LNG

-5
-10
-15
Weight KG DBP mm SHBG HDL %

Oelkers W et al., JCEM 1995

NEW PROGESTINS FOR CONTRACEPTION
Predominent effects

n Drospirenone (DRSP) = antimineralocorticoid

n Dienogest (DNG) = antiandrogenic
n Nestorone (NES) = highest antiovulatory effect
(non-oral)
n Nomegestrol (NOM Ac) = highly antigonadotropic
n Trimegestone (TMG)= highly progestational

n 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

n Highest antiovulatory potency

n high progestational potency
n not active orally
n not bound to SHBG
n no androgenic or estrogenic effect
n no glucocorticoid activity at contraceptive
doses
Making it highly suitable for non-oral delivery
 Overview

n Pharmacology of Progestins
n Risks and benefits of current Progestins
n Prospects for research
n Conclusions
Clinical Benefits of Progestins
without androgenic activity

Î no weight gain
Î no acne
Î no adverse effect on Lipids
Î minimal impact on Glucose and Insulin
Î 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

Estradiol Estradiol +
Control Progesterone
 Coronary Artery Diameter in
atherosclerotic monkeys
15
OVX
E2

% change E + NMA
2

from control

*
-15
0

-15
-8 -7 -6

ACH ACH ACH NTG

ACH=acetylcholine
Adapted from: Williams JK, Cline JM, Honore EK, Delansorne R, Paris J. NTG=nitroglycerin
Am J Obstet Gynecol 1998; 179: 1288-94 . E2=Estradiol
NMA=Nomegestrol Acetate
Antimineralocorticoid effect of DRSP

E2 or EE Liver impact

Angiotensinogen Ç

AI Ç J A II Ç Aldosterone Ç

Block MR Na & Water Retention

Na & Water Excretion

DROSPIRENONE
Effect of Progestins on hemostasis

n No changes in clotting factors when Progestin

are given without estrogen, however:
n Progestins with glucocorticoid action potentiate
the vascular procoagulant effects of thrombin
(Herkert O 2001)
n No increased risk with CMA given alone (Plu-
Bureau G, 2004)
n Estrogenicity of COCs reflected by the increase
of SHBG levels potentiate the risk of VTE
 Progesterone and progestin action on
breast cells differ
n All progestins do not stimulate breast tissue
growth the same way (Wood CE, 2007 )
n Progesterone either oral or vaginal stimulate
less than MPA (Wood C, 2007)
n Observational studies: no increase in BC risk
with progesterone
n 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 (μg/well)

25
Estradiol
20 Gestodene
15 Norgestrel
MPAc
10
5
0
-14 -13 -12 -11 -10 -9 -8 -7 -6 -5

Catherino, Jeng and Jordan; 1993, Br J. Cancer, 67.945-952

 Overview

n Pharmacology of Progestins
n Risks and benefits of current Progestins
n Prospects for research
n Conclusions
Beneficial Role of P & some progestins in
the neuronal tissue
n Increase neuronal survival

n Increase synthesis of myelin specific proteins by

oligodendrocytes

n 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
n Different progestins have various interactions with
the steroid receptors, hence different side-effects
n New Progestins are non-androgenic and should
preferably be used with E2
n Androgenic Progestins can be combined with EE
n Most Progestins when given alone do not modify
hemostasis
n Potential benefits of P and some progestins on
neuroprotection and myelin regeneration deserve
further development