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


2/23

Overview

Pharmacology of Progestins

Risks and benefits of current Progestins

Prospects for research

Conclusions


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


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)


5/23


6/23

Androgenic Potency

Progesterone

Increase

Testosterone LNG DSG Nestorone

NOMAc

Prostate 100 10 0Growth

(%)

NETA

MPA

DienogestTrimegestone

Drospirenone


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


8/23

Effect of EE on hepatic markers when

given with non-androgenic Progestins

SHBG

HDLAngiotensinogen

Modification of some clotting factors


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


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


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


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


13/23

Overview




Conclusions


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


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


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


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


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


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)


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


21/23

Overview




Conclusions


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


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

Documents

The Progestins All Similar