The use of progestins today

Controversialcomments

~ HERS 1996~ WHI 2002-2003~ MWS 2003-2004~ « witch-hunt »~ back to reasonable, adequate analyses, experience…

HRT – after HERS, WHI, MWS …

WEST (cont.)WHIMS

E3NKEEPS – ongoing

WEST – cont. = nothing new

E3N – advantage of natural progesterone

Studies:

STAR trialRUTH studyWISDOMPEPIHERSWHIMWSHOPENURSEMISSION…… etc.

DP – HORMOGIN Sao Paulo 2007

HRT use


2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

kg

HRT – after HERS, WHI, MWS …

HERS and WHI : study population too old

In spite of negative publication, positive messages for estrogens use

Latest results speak very positively about benefits of estrogens


Conclusions after WHI

• HT with Prempro (CEE+MPA) should not be used for prevention of CHD in women of this age group

• Other therapies, lower doses, other routes of delivery to be studied

• Shorter duration of treatment is advised (but for how long?)

IMS, Rome,June 2011IMS, Rome,June 2011

MISSION Study MISSION Study 3rd Follow up : The new results 3rd Follow up : The new results of a French National Cohort on of a French National Cohort on

coronary heart disease incidence coronary heart disease incidence in postmenopausal women in postmenopausal women

treated by HRT or nottreated by HRT or not

Progesterone

http://en.wikipedia.org/wiki/File:Progesterone-3D-vdW.png

http://en.wikipedia.org/wiki/File:Progesteron.svg

Progesterone – progestins

BIOAVAILABILITY

Dienoges

t

Nestorone

Drospir

Trimeges

MPA

Desog

Dienog

Cypro

LEVOGestod

Chlormad

NOMAC

Progestins

Related

to progest

erone

Related

to tes

tosterone

Drospirenone

Progesterone

17-OH-progesteronederivated

19-norprogesteronederivated

PREGNANES NOR-PREGNANESESTRANES- Hydroxyprogesterone

caproate- Hydroxyprogesterone heptanoate- Gestonorone caproate- Chlormadinone acetate- Medrogestone- Medroxyprogesterone acetate- Cyproterone acetate

- Nomegestrol acetate- Demegestone- Promegestone- Nestorone- Trimegestone

-Lynestrenol-Levonorgestrel-Norethisterone-Norethisterone acetate-Ethinodiol diacetate-Norgestrienone-Dienogest

GONANES

-Norgestrel-Desogestrel-Gestodene-Norgestimate

Dydrogesterone

androgenicity lipid metabolism glucocorticoids mineralocorticoids gonadotrophic action antiestrogenic properties

PROGESTINS

DP

THE ROLE OF PROGESTINS IN CARDIOVASCULAR PROTECTION BY HRT

Efficacy

Metabolicside effects

Androgenicity

Nomegestrol acetate

Trimegestone

DrospirenoneNestorone

MPA

Cyproterone acetate

Progesterone

Levonorgestrel

NETA

Lynestrenol

Ethinodiol

ACTIONS ON METABOLISM

HALF-LIFE & BIOAVAILABILITY

PROGESTINS

PARAMETER NET Noretisterone acetate (NETA)

Levonorgestrel (LNG)

Gestodene (GSD)

Desogestrel (DSG)

Drospirenone (DSRP)

NomAc

Bioavailability% oral dose

65 ~50* 100 100 75** ~76 63

Half-life (hours) 8 8* 16 12 12** 30 46

Volume of distribution (l)

240 240* 120 32 110** 4L/kg 1200

Progestational Potency

NES 100 > LNg 10 > Progesterone 1 NES 100 > LNg 10 > Progesterone 1

NES 30 > LNg 10 > Progesterone 1 NES 30 > LNg 10 > Progesterone 1

McPhail

Index

McPhail

IndexOvulation

Inhibition

Ovulation

Inhibition

DSG TMG

Norgestimate

DrospirenoneNET

Dienogest

DSG NOM Ac

MPA

Norgestimate

DrospirenoneNETTMG

CPA

R.Sitruk-Ware classification 2010

Androgenic Potency

100 0100 0

Increase

Prostate

Growth

(%)

Increase

Prostate

Growth

(%)

NETA

MPA Drospirenone

Dienogest

LNG DSG Nestorone

Progesterone

Testosterone

NOMAc

Trimegestone


AntiAndrogenic Potency

Decrease

Rat

Prostate

(%)

Decrease

Rat

Prostate

(%)

Progesterone

Drospirenone

NOM AcTMGCPA

DienogestChlormadinone

100 40 20 100 40 20


Minimal ovulation inhibition dose

• Gestodene: 40 mcg• Levonorgestrel: 50 mcg• Desogestrel: 60 mcg• Drospirenone: 3 mg• Ciproterone Acetate: 2 mg• Clormadinone Acetate: 2 mg• Nomegestrol Acetate: 1,5 mg• Dienogest: 2 mg

Progestins & hemostatic factors

• No variations in coagulation factors when progestins are administered without estrogens.

• Progestins with glucocorticoid action increase the procoagulant effects of thrombin (Herkert O 2001)

• Estrogenicity of COC, indicate an increase of SHBG, and potentialize the risk of DVT.

Modified from ODLIND V et al., Acta Obstet Gynecol Scand, 2002;81:482-90.

0

50

100

150

200

250

300

me

an

ch

an

ge

vs

ba

sa

l of

SH

BG

(%

)

NOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EE td NMGG+EE td NMGG+EE DSG+EE DRSP+EE DNG+EE CPA+EE DSG+EE DRSP+EE DNG+EE CPA+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EENOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EE td NMGG+EE td NMGG+EE DSG+EE DRSP+EE DNG+EE CPA+EE DSG+EE DRSP+EE DNG+EE CPA+EE

E2: 17E2: 17ββestradiolestradiol td: transdermal td: transdermalEE: ethinylestradiol EE: ethinylestradiol NMGG: norelgestromine NMGG: norelgestromineNOMAc: nomegestrol acetate DSG: desogestrelNOMAc: nomegestrol acetate DSG: desogestrelLNG: levonorgestrelLNG: levonorgestrel DRSP: drospirenone DRSP: drospirenone NMG: norgestimateNMG: norgestimate DNG: dienogest DNG: dienogest tv: transvaginaltv: transvaginal CPA: cyproterone ac. CPA: cyproterone ac.ETN: etonorgestrelETN: etonorgestrelGSD: gestodeneGSD: gestodene

E2: 17E2: 17ββestradiolestradiol td: transdermal td: transdermalEE: ethinylestradiol EE: ethinylestradiol NMGG: norelgestromine NMGG: norelgestromineNOMAc: nomegestrol acetate DSG: desogestrelNOMAc: nomegestrol acetate DSG: desogestrelLNG: levonorgestrelLNG: levonorgestrel DRSP: drospirenone DRSP: drospirenone NMG: norgestimateNMG: norgestimate DNG: dienogest DNG: dienogest tv: transvaginaltv: transvaginal CPA: cyproterone ac. CPA: cyproterone ac.ETN: etonorgestrelETN: etonorgestrelGSD: gestodeneGSD: gestodene

Variations in (%) of SHBG: in monophasic OCs

no weight gain

no acne

no side-effects on lipids

minimal impact on glucose and insulin

less impact on vasomotor system

Clinical benefits of progestins with no androgenic activity

Use of progestins in OC

• different progestins have different interactions with steroid receptors (thus different effects)

• non androgenic progestins can preferably be used with E2

• androgenic progestins can be combined (and often are) with EE

• most of the progestins does not modify coagulation

BP

Increased progestative and antigonadotrophic action , clinicaly insignificant interaction with androgenic receptors

Minimal interaction with glucocorticoid, but noted adhaerence with mineralcorticoid receptor, which can che determine an competitive inhibition with aldosterone, although in doses used in OC it does not seems relevant

Cinetics similar to levonorgestrel, bioavailability close to 100%, binding to SHBG above 50%.

After oral administration, plasmatic pic is reached within 1 hour (increasing with repeated intake to 12-18 hours)

Gestodene

EE + Gestodene

Pharmacological form / C.name

Ethynilestradiol mcg

Gestodene mg Note

Ginoden (Bayer)Minulet (Wyeth)Kipling (Effik Italia)Gestiodol (EG)

30 0,075 MONOPHASIC21 CPS (A)

Fedra (Bayer)Harmonet (Wyeth)Estinette (Effik Italia)

20 0,075 MONOPHASICLow dose21 CPS

Arianna (Bayer)Minesse (Wyeth)

15 0,060 MONOPHASICLow dose 24 CPS + 4 PLB

Milvane (Bayer)Triminulet (Wyeth)

304030

0,050,070,1

TRIPHASIC21 CPS (A)

High progestative and antigonadotrophic power caracterised by a minimal antiestrogenic action.

No estrogenic, gluco and mineralocorticoid effects and low affinity for androgen receptors.

Desogestrel is a prodrug, rapidly trasformed on hepatic level to an active compound (citochrome P450; 3-Ketodesogestrel, etonorgestrel - ETG)

Binding to SHBG is above 30%, and 58% to albumins. Bioavailability is 76%.

Desogestrel

EE + Desogestrel

Pharmacological form/name

Ethynilestradiol mcg Desogestrel mg Note

Planum (Menarini)Practil 21 (Organon Italia)

30 0,15 MONOPHASIC21 CPS (A)

Mercilon (Organon)Securgin (Menarini)Novynette (Finderm)


Dueva (Menarini)Gracial (Organon Italia)

4030

0,0250,125

BIPHASICO22 CPS

Lucille (Organon Italia) 353030

0,050,100,15

TRIPHASICA21 CPS

Cyproterone Acetate Cyproterone Acetate

Progestin with antiandrogenic activity, thus blocking the action of testosterone in tissues.

It is stocked on adipose level, with some residual glucocorticoid activity.

Coadjuvant in hirsutism treatment (EE 35mcg/CPA 2mg).

«Not used in USA; high estrogen content and collateral hepatic risks; antiacne effect incostante.».

EE + Cyproterone Acetate EE + Cyproterone Acetate

Pharmaco-logical form/name


Cyproterone Acetate mg Note

Diane (Bayer) 35 2 MONOPHASIC21 CPS

Chlormadinone AcetateChlormadinone Acetate

It has antiandrogenic activity (cca 20% of that one from Ciproterone Acetate) and binding strength for Progesterone receptor (PR) 1/3 superior to the one of P and a weak binding with glucocorticoid receptors.

17-OH-progesterone derivated.

Scarse effect of the first hepatic passage with bioavailability close to 100%.



Chlormadinone Acetate mg

Note

Belara (Formenti)Lybella (Alfa Wasserman)

30 2 MONOPHASIC21 CPS

EE + Chlormadinone AcetateEE + Chlormadinone Acetate

Drospirenone is an 17-alfa-spirolactone derivative.

Antimineralocorticoid activity of drospirenone, similar to the one progesterone, is linked to the action in renin-angiotensine-aldosterone system. Better control of body weight and of hydric retention.

Antiandrogenic caracteristics is blocking the androgenic receptor (1/3 activity of ciproterone acetate).

Does not have androgenic, estrogenic, glucocorticoid or antiglucocorticoide actions.

Drospirenone

EE + Drospirenone



Drospirenone mg Note

Yasmin (Bayer) 30 3 MONOPHASIC21 CPS

Yasminelle (Bayer) 20 3 MONOPHASICLow dose21 CPS

Yaz (Bayer) 20 3 MONOPHASICLow dose28 CPS (24+4PLB)

Levonorgestrel

Has a very efficient progestative activity, high antigonadotrophic action, strong antiestrogenic activity and a weak androgenic and anabolic activity

Thanks to the strong antiestrogenic activity of LNG, increase of SHBG, in connection to OC use, is lower than other progestins; but after 1-3 cycles this effects dissapears.

LNG is considered as progestin with minor risks of venous tromboembolism (Lidegaard O, 2009 – van Hylckama A, 2009), and is a gold standard in comparison with other progestins in the issue of coagulation profile.

EE + Levonorgestrel



Levonorgestrel mg Note

Novogyn 21 (Bayer)*Microgynon (Bayer)

5050

0,2500,125

MONOPHASICRarely used 21 CPS (A) (*Morning after pill Yuzpe)

Egogyn 30 (Bayer) 30 0,150 MONOPHASIC21 CPS

Loette (Wyeth)Miranova (Bayer)Lestronette (Theramex)


E2V+Dienogest

Quadriphasic (+2 placebo; 26+2)

(Qlaira)

E2+Nomegestrol Acetate (NomAc)

Monophasic (+4 placebo; 24+4)

(Zoely)

Dienoges

t

Nestorone

Drospir

Trimeges

MPA

Desog

Dienog

Cypro

LEVOGestod

Chlormad

NOMAC

Progestins (use):

• HT

Progestins (use):

• HT• DUB

Progestins (use):

• HT• DUB• OC (COC, POP)

Progestins (use):

• HT• DUB• OC (COC, POP)• Endometriosis

Progestins (use):

• HT• DUB• OC (COC, POP)• Endometriosis• Oncology

(rare)• …..

Progestins (use):

• HT• DUB• OC (COC, POP)• Endometriosis• Oncology

(rare)• …..

SPRMs !

Related

to progest

erone

Related

to tes

tosterone

Drospirenone

Progesterone

17-OH-progesteronederivated

19-norprogesteronederivated

PREGNANES NOR-PREGNANESESTRANES- Hydroxyprogesterone

caproate- Hydroxyprogesterone heptanoate- Gestonorone caproate- Chlormadinone acetate- Medrogestone- Medroxyprogesterone acetate- Cyproterone acetate

- Nomegestrol acetate- Demegestone- Promegestone- Nestorone- Trimegestone

-Lynestrenol-Levonorgestrel-Norethisterone-Norethisterone acetate-Ethinodiol diacetate-Norgestrienone-Dienogest

GONANES

-Norgestrel-Desogestrel-Gestodene-Norgestimate

Dydrogesterone

NomAc Nestorone TrimegestoneDrospirenone

KEEPS is designed to test this theory by recruiting 720 healthy, recently menopausal women for a randomized, placebo-controlled, double-blinded trial of HT for four years.

Five-year, randomized, placebo-controlled, double-blinded study, each participant will be evaluated for four years.

Conducted at nine national sites

Approximately 720 recently menopausal women ages 42 to 58 is being recruited

Study participants will be divided into three groups and will receive either transdermal estrogen (via skin patch), oral estrogen or placeboWomen who are receiving active estrogen will also receive progesterone (the bio-identical human progestin) for 12 days per month.

Study Start Date: September 2005Estimated Study Completion

Fall 2011

ORALE/P

TDE/P

Placebo

USE OF HORMONES

The concepts change with time…

1890’s 2010’s

Documents

The use of progestins today