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The use of progestins today

The use of progestins today. Dražen Postružnik. Monaco. Brijuni, rujan 2011. 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 E3N

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The use of progestins today

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  1. The use of progestins today Dražen Postružnik Monaco Brijuni, rujan 2011.

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

  3. HRT – after HERS, WHI, MWS … • WEST (cont.) • WHIMS • E3N • KEEPS – ongoing • WEST – cont. = nothing new • E3N – advantage of natural progesterone Studies: STAR trial RUTH study WISDOM PEPI HERS WHI MWS HOPE NURSE MISSION… … etc. DP – HORMOGIN Sao Paulo 2007

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

  5. 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 DP – HORMOGIN Sao Paulo 2007

  6. 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?)

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

  8. Progesterone

  9. Progesterone – progestins BIOAVAILABILITY

  10. Dienogest Gestod LEVO Chlormad Desog MPA Nestorone Trimeges NOMAC Drospir Cypro Dienog

  11. Progestins

  12. CLASSIFICATION OF PROGESTINS PROGESTERONE RETROPROGESTERONE Progesterone Dydrogesterone PROGESTERONE DERIVATED TESTOSTERONE DERIVATED 17-OH-progesterone derivated 19-norprogesterone derivated PREGNANES NOR-PREGNANES - Hydroxyprogesterone caproate - Hydroxyprogesterone heptanoate - Gestonorone caproate - Chlormadinone acetate - Medrogestone - Medroxyprogesterone acetate - Cyproterone acetate - Nomegestrol acetate - Demegestone - Promegestone - Nestorone - Trimegestone ESTRANES GONANES -Lynestrenol -Levonorgestrel -Norethisterone -Norethisterone acetate -Ethinodiol diacetate -Norgestrienone -Dienogest -Norgestrel -Desogestrel -Gestodene -Norgestimate Related to testosterone Related to progesterone SPIRONOLACTONE DERIVATED Drospirenone

  13. PROGESTINS • androgenicity • lipid metabolism • glucocorticoids • mineralocorticoids • gonadotrophic action • antiestrogenic properties

  14. 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 ACTIONS ON METABOLISM DP

  15. PROGESTINS HALF-LIFE & BIOAVAILABILITY

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

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

  18. AntiAndrogenic Potency Dienogest Chlormadinone CPA TMG NOM Ac Decrease Rat Prostate (%) 10040 20 Progesterone Drospirenone R.Sitruk-Ware classification 2010

  19. 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

  20. 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.

  21. Variations in (%) of SHBG: in monophasic OCs E2: 17βestradiol td: transdermal EE: ethinylestradiol NMGG: norelgestromine NOMAc: nomegestrol acetate DSG: desogestrel LNG: levonorgestrel DRSP: drospirenone NMG: norgestimate DNG: dienogest tv: transvaginal CPA: cyproterone ac. ETN: etonorgestrel GSD: gestodene NOMAc+E2 LNG+EE NMG+EE tv ETN+ EE GSD+EE td NMGG+EE DSG+EE DRSP+EE DNG+EE CPA+EE Modified from ODLIND V et al., Acta Obstet Gynecol Scand, 2002;81:482-90.

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

  23. Use of progestins in OC different progestins have different interactions with steroid receptors (thus different effects) non androgenic progestins can preferably be used withE2 androgenicprogestins can be combined (and often are) withEE most of the progestins does not modify coagulation

  24. BP

  25. Increased progestative and antigonadotrophic action , clinicalyinsignificant interaction withandrogenic receptorsMinimalinteraction withglucocorticoid, but notedadhaerence with mineralcorticoid receptor, which can che determine an competitive inhibition with aldosterone, although in doses used in OC it does not seems relevantCinetics 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

  26. EE + Gestodene 

  27. High progestative and antigonadotrophic power caracterised by aminimal antiestrogenic action. No estrogenic, gluco and mineralocorticoid effects andlow 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

  28. EE + Desogestrel 

  29. Cyproterone Acetate Progestin withantiandrogenic 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.».

  30. EE + Cyproterone Acetate

  31. Chlormadinone Acetate It hasantiandrogenic activity (cca 20% of that one from Ciproterone Acetate) and binding strengthfor 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%.

  32. EE + Chlormadinone Acetate

  33. Drospirenone  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 caracteristicsis blocking the androgenic receptor (1/3 activity of ciproterone acetate). Does not have androgenic, estrogenic, glucocorticoid or antiglucocorticoide actions.

  34. EE + Drospirenone  

  35. Levonorgestrel  Has a very efficientprogestative activity, high antigonadotrophic action, strong antiestrogenic activity anda weak androgenic and anabolic activity Thanks to thestrong 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.

  36. EE + Levonorgestrel 

  37. E2V+DienogestQuadriphasic (+2 placebo; 26+2) (Qlaira)

  38. E2+Nomegestrol Acetate (NomAc)Monophasic (+4 placebo; 24+4) (Zoely)

  39. Dienogest Gestod LEVO Chlormad Desog MPA Nestorone Trimeges NOMAC Drospir Cypro Dienog

  40. Progestins (use): • HT

  41. Progestins (use): • HT • DUB

  42. Progestins (use): • HT • DUB • OC (COC, POP)

  43. Progestins (use): • HT • DUB • OC (COC, POP) • Endometriosis

  44. Progestins (use): • HT • DUB • OC (COC, POP) • Endometriosis • Oncology (rare) • …..

  45. Progestins (use): • HT • DUB • OC (COC, POP) • Endometriosis • Oncology (rare) • ….. SPRMs !

  46. CLASSIFICATION OF PROGESTINS PROGESTERONE RETROPROGESTERONE Progesterone Dydrogesterone NomAc Nestorone Trimegestone Drospirenone PROGESTERONE DERIVATED TESTOSTERONE DERIVATED 17-OH-progesterone derivated 19-norprogesterone derivated PREGNANES NOR-PREGNANES - Hydroxyprogesterone caproate - Hydroxyprogesterone heptanoate - Gestonorone caproate - Chlormadinone acetate - Medrogestone - Medroxyprogesterone acetate - Cyproterone acetate - Nomegestrol acetate - Demegestone - Promegestone - Nestorone - Trimegestone ESTRANES GONANES -Lynestrenol -Levonorgestrel -Norethisterone -Norethisterone acetate -Ethinodiol diacetate -Norgestrienone -Dienogest -Norgestrel -Desogestrel -Gestodene -Norgestimate Related to testosterone Related to progesterone SPIRONOLACTONE DERIVATED Drospirenone

  47. 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. ORAL E/P 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 placebo Women who are receiving active estrogen will also receive progesterone (the bio-identical human progestin) for 12 days per month. TD E/P Placebo

  48. 1890’s 2010’s USE OF HORMONES The concepts change with time…

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