Controversial comments HERS 1996 WHI 2002 2003 MWS

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

HRT – after HERS, WHI, MWS … WEST (cont. ) WHIMS E 3 N KEEPS – ongoing WEST – cont. = nothing new E 3 N – advantage of natural progesterone DP – HORMOGIN Sao Paulo 2007 Studies: STAR trial RUTH study WISDOM PEPI HERS WHI MWS HOPE NURSE MISSION… … etc.

HRT use kg M? M? 2000 DP – HORMOGIN Sao Paulo 2010 2001 2002 2003 2004 2005 2006 2007 2008 2009

HRT – after HERS, WHI, MWS … ØHERS and WHI : study population too old ØIn spite of negative publication, positive estrogens use messages f ØLatest results speak very positively about of estrogens benefits DP – HORMOGIN Sao Paulo 2007

Conclusions after WHI • HT with Prempro (CEE+MPA) should not be used for prevention of CHD in women of this age group • Otherapies, lower doses, other routes of delivery to be studied • Shorter duration of treatment is advised (but for how long? )

MISSION Study 3 rd Follow up : The new results of a French National Cohort on coronary heart disease incidence in postmenopausal women treated by HRT or not IMS, Rome, June 2011

Progesterone

Progesterone – progestins BIOAVAILABILITY

od Gest O est Dienog ad V LE m Chlor g Deso Nestorone Trimeges NOMAC Drospir ro p y C n Die og MPA

Progestins

Progesterone 17 -OH-progesterone derivated PREGNANES - Hydroxyprogesterone caproate - Hydroxyprogesterone heptanoate - Gestonorone caproate - Chlormadinone acetate - Medrogestone - Medroxyprogesterone acetate - Cyproterone acetate Dydrogesterone 19 -norprogesterone derivated NOR-PREGNANES - Nomegestrol acetate - Demegestone - Promegestone ne - Nestorone o r ste - Trimegestone e og r op t ted a l Re Drospirenone ESTRANES GONANES -Lynestrenol -Norgestrel -Levonorgestrel -Desogestrelone ter -Norethisterone -Gestodene s o est -Norethisterone -Norgestimate t to d acetate l e -Ethinodiol diacetate R -Norgestrienone -Dienogest

PROGESTINS ~ androgenicity ~ lipid metabolism ~ glucocorticoids ~ mineralocorticoids ~ gonadotrophic action ~ antiestrogenic properties

THE ROLE OF PROGESTINS IN CARDIOVASCULAR PROTECTION BY HRT Efficacy Nomegestrol acetate Trimegestone Nestorone Drospirenone Cyproterone acetate MPA Progesterone Androgenicity NETA Levonorgestrel Lynestrenol Ethinodiol Metabolic side effects DP ACTIONS ON METABOLISM

PROGESTINS HALF-LIFE & BIOAVAILABILITY PARAMETER NET Noretisterone acetate (NETA) Levonorgestrel (LNG) Gestodene (GSD) Desogestrel (DSG) Drospirenone (DSRP) Nom. Ac Bioavailability % oral dose 65 ~50* 100 75** ~76 63 Half-life (hours) 8 8* 16 12 12** 30 46 Volume of distribution (l) 240* 120 32 110** 4 L/kg 1200

Progestational Potency TMG DSG MPA Norgestimate NET NOM Ac Drospirenone Mc. Phail Index NES 100 > LNg 10 > Progesterone 1 Ovulation NES 30 > LNg 10 > Progesterone 1 Inhibition DSG TMG NET Drospirenone Norgestimate CPA Dienogest R. Sitruk-Ware classification 2010

Androgenic Potency Progesterone Testosterone LNG Nestorone NOMAc Increase Prostate DSG 100 0 Growth (%) NETA Dienogest Trimegestone MPA Drospirenone R. Sitruk-Ware classification 2010

Anti. Androgenic Potency Dienogest CPA Chlormadinone TMG NOM Ac Decrease Rat 100 40 20 Prostate (%) Progesterone Drospirenone R. Sitruk-Ware classification 2010

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

Variations in (%) of SHBG: in monophasic OCs E 2: 17βestradiol EE: ethinylestradiol NOMAc: nomegestrol acetate LNG: levonorgestrel NMG: norgestimate tv: transvaginal ETN: etonorgestrel GSD: gestodene NOMAc+E 2 LNG+EE NMG+EE td: transdermal NMGG: norelgestromine DSG: desogestrel DRSP: drospirenone DNG: dienogest CPA: cyproterone ac. tv ETN+ EE GSD+EE td NMGG+EE DSG+EE DRSP+EE Modified from ODLIND V et al. , Acta Obstet Gynecol Scand, 2002; 81: 482 -90. DNG+EE CPA+EE

Clinical benefits of progestins with no androgenic activity è no weight gain no acne no side-effects on lipids è minimal impact on glucose and insulin è less impact on vasomotor system

Use of progestins in OC • different progestins have different interactions with steroid receptors (thus different effects) • non androgenic progestins can preferably be used with E 2 • androgenic progestins can be combined (and often are) with EE • most of the progestins does not modify coagulation

BP

Gestodene 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)

EE + Gestodene Pharmacological form / C. name Ethynilestradiol mcg Gestodene mg Note Ginoden (Bayer) Minulet (Wyeth) Kipling (Effik Italia) Gestiodol (EG) 30 0, 075 MONOPHASIC 21 CPS (A) Fedra (Bayer) Harmonet (Wyeth) Estinette (Effik Italia) 20 0, 075 MONOPHASIC Low dose 21 CPS Arianna (Bayer) Minesse (Wyeth) 15 0, 060 MONOPHASIC Low dose 24 CPS + 4 PLB Milvane (Bayer) Triminulet (Wyeth) 30 40 30 0, 05 0, 07 0, 1 TRIPHASIC 21 CPS (A)

Desogestrel 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 P 450; 3 Ketodesogestrel, etonorgestrel - ETG) Binding to SHBG is above 30%, and 58% to albumins. Bioavailability is 76%.

EE + Desogestrel Pharmacological form/name Ethynilestradiol mcg Desogestrel mg Note Planum (Menarini) Practil 21 (Organon Italia) 30 0, 15 MONOPHASIC 21 CPS (A) Mercilon (Organon) Securgin (Menarini) Novynette (Finderm) 20 0, 15 MONOPHASIC Low dose 21 CPS Dueva (Menarini) Gracial (Organon Italia) 40 30 0, 025 0, 125 BIPHASICO 22 CPS Lucille (Organon Italia) 35 30 30 0, 05 0, 10 0, 15 TRIPHASICA 21 CPS

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 35 mcg/CPA 2 mg). «Not used in USA; high estrogen content and collateral hepatic risks; antiacne effect incostante. » .

EE + Cyproterone Acetate Pharmacological form/name Diane (Bayer) Ethynilestradiol mcg Cyproterone Acetate mg 35 2 Note MONOPHASIC 21 CPS

Chlormadinone 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%.

EE + Chlormadinone Acetate Pharmacological form/name Ethynilestradiol mcg Chlormadinone Acetate mg Note Belara (Formenti) Lybella (Alfa Wasserman) 30 2 MONOPHASIC 21 CPS

Drospirenone is an 17 -alfa-spirolactone derivative. Antimineralocorticoid activity of drospirenone, similar to the one progesterone, is linked to the action in renin-angiotensinealdosterone 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.

EE + Drospirenone Pharmacological form/name Ethynilestradiol mcg Drospirenone mg Note Yasmin (Bayer) 30 3 MONOPHASIC 21 CPS Yasminelle (Bayer) 20 3 MONOPHASIC Low dose 21 CPS Yaz (Bayer) 20 3 MONOPHASIC Low dose 28 CPS (24+4 PLB)

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 Pharmacological form/name Ethynilestradiol mcg Levonorgestrel mg Note Novogyn 21 (Bayer)* Microgynon (Bayer) 50 50 0, 250 0, 125 MONOPHASIC Rarely used 21 CPS (A) (*Morning after pill Yuzpe) Egogyn 30 (Bayer) 30 0, 150 MONOPHASIC 21 CPS Loette (Wyeth) Miranova (Bayer) Lestronette (Theramex) 20 0, 100 MONOPHASIC Low dose 21 CPS

E 2 V+Dienogest Quadriphasic (+2 placebo; 26+2) (Qlaira)

E 2+Nomegestrol Acetate (Nom. Ac) Monophasic (+4 placebo; 24+4) (Zoely)

od Gest O est Dienog ad V LE m Chlor g Deso Nestorone Trimeges NOMAC Drospir ro p y C n Die og MPA

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 !

Progesterone Dydrogesterone Nom. Ac 17 -OH-progesterone derivated PREGNANES - Hydroxyprogesterone caproate - Hydroxyprogesterone heptanoate - Gestonorone caproate - Chlormadinone acetate - Medrogestone - Medroxyprogesterone acetate - Cyproterone acetate 19 -norprogesterone derivated Nestorone Trimegestone Drospirenone NOR-PREGNANES - Nomegestrol acetate - Demegestone - Promegestone ne - Nestorone o r ste - Trimegestone e og r op t ted a l Re Drospirenone ESTRANES GONANES -Lynestrenol -Norgestrel -Levonorgestrel -Desogestrelone ter -Norethisterone -Gestodene s o est -Norethisterone -Norgestimate t to d acetate l e -Ethinodiol diacetate R -Norgestrienone -Dienogest

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. ORAL E/P Conducted at nine national sites Approximately 720 recently menopausal women ages 42 to 58 is being recruited TD E/P Study participants will be divided into three groups and will receive either transdermal estrogen (via skin patch), oral estrogen or placebo Women who are receiving active estrogen will also receive progesterone (the bio-identical human progestin) for 12 days per month. Placebo Study Start Date: Estimated Study Completion September 2005 Fall 2011

USE OF HORMONES 1890’s 2010’s The concepts change with time…