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Published on March 4, 2009

Author: mitoztip

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DEVELOPMENT OF SYNTHETIC PROGESTINS IN COMBINED ORAL CONTRACEPTIVES : DEVELOPMENT OF SYNTHETIC PROGESTINS IN COMBINED ORAL CONTRACEPTIVES KENAN ERTOPÇU SSK EGE DOGUMEVI VE KADIN HASTALIKLARI EGITIM HASTANESI AILE PLANLAMASI KLINIGI Better Things for Better Living Through Chemistry : Better Things for Better Living Through Chemistry Slide 5: The discovery of ethinyl substitution and oral potency led (at the end of the 1930s) to the preparation of ethisterone, an orally active derivative of testosterone. Progestins derived from testosterone : Progestins derived from testosterone OH O Testosterone Progestins derived from testosterone : OH O C CH Progestins derived from testosterone Ethisterone Slide 8: In 1951, it was demonstrated that removal of the 19 carbon from ethisterone to form norethindrone did not destroy the oral activity, and most importantly, it changed the major hormonal effect from that of an androgen to that of a progestational agent. Progestins derived from testosterone : OH O C CH 19 Nor-Ethisterone Norethindrone Progestins derived from testosterone First combined oral contraceptive : First combined oral contraceptive In 1957, the U.S. Food and Drug Administration approved a combination of 9.85 mg of norethynodrel and 0.15 mg of mestranol (ENOVID) for use in menstrual disorders and, subsequently in 1960, as a contraceptive. Oral activity of synthetic estrogens and progestins : Oral activity of synthetic estrogens and progestins All the synthetic estrogens and progestins in OCs have an ethinyl group at position 17. the presence of this ethinyl group enhances the oral activity of these agents. Structures of the two estrogens used in combination oral contraceptives : Structures of the two estrogens used in combination oral contraceptives An overview of oral contraceptives : An overview of oral contraceptives ESTROGEN PROGESTOGEN 1960 2000 150 µg (mestranol) 10 mg (norethindrone) 0.06 mg (gestodene) 15 µg (ethinylestradiol) Slide 15: The synthetic progestins used so far for contraception are derived either from TESTOSTERONE (19-nortestosterone derivatives) or from PROGESTERONE (17-OH progesterone derivates and 19-norprogesterone derivatives) Synthetic progestins : Synthetic progestins Testosterone derivates Progesterone derivates ESTRANES GONANS FIRST GENERATION SECOND GENERATION Norethindrone dl norgestrel Norethynodrel Levonorgestrel Norethindrone Acetate THIRD GENERATION Ethynodiol Diacetate Gestodene Norethindrone enanthate Norgestimate Lynestrenol Desogestrel FOURTH GENERATION Dienogest 17-OH PROGESTERONE 19-NORPROGESTERONE (PREGNANS) Medroxyprogesteroneacetate Trimegestone 17?-Hydroxyprogesterone acetate Nomegestrol Megestrol acetate Nestoronee Siproteron acetate Klormadinon acetate Spirolactone Derivative Drospirenone Slide 17: Among the 19-nortestosterone derivates, the ESTRANE GROUP include norethisterone (NET) and its metabolites, and the GONANE group include levonorgestrel (LNG) and its derivates. Estrane progestins : Estrane progestins Gonane progestins : Gonane progestins Progestins derived from testosteronesecond generation : OH O C CH dlnorgestrel Progestins derived from testosteronesecond generation Progestins derived from testosteronesecond generation : OH O C CH Progestins derived from testosteronesecond generation Levonorgestrel Progestins derived from testosteronethird generation : OH O C CH Progestins derived from testosteronethird generation Levonorgestrel Progestins derived from testosteronethird generation : OH O C CH Gestodene Progestins derived from testosteronethird generation Progestins derived from testosteronethird generation : OH C CH Desogestrel Progestins derived from testosteronethird generation H2C Progestins derived from testosteronethird generation : OH C CH 3-keto-Desogestrel (11 methylene-levonorgestrel) Progestins derived from testosteronethird generation H2C O Active component of desogestrel Progestins derived from testosteronethird generation : OAcetate C CH Progestins derived from testosteronethird generation Norgestimate HON Oxime Progesterone and progestins : Progesterone and progestins PROGESTERONE AND PROGESTINS CANNOT BE CONSIDERED AS A SINGLE CLASS. THEY INTERACT NOT ONLY WITH THE PROGESTERONE RECEPTOR (PR), BUT ALSO WITH OTHER STEROID RECEPTORS, SUCH AS THE ANDROGEN RECEPTOR, THE GLUCOCORTICOID RECEPTOR, THE MINERALOCORTICOID RECEPTOR. A progestin’s potency : A progestin’s potency A progestin’s potency is determined largely by its ability to bind to progestin receptor, which is expressed in terms of its relative binding affinity (RBA). THE HIGHER THE PROGESTIN RBA, THE SMALLER THE DOSE THAT IS REQUIRED TO PRODUCE THE PROGESTATIONAL EFFECTS NECESSARY FOR CONTRACEPTION. A progestin’s androgenicity : A progestin’s androgenicity A progestin’s androgenicity is determined by its capacity to bind to androgen receptors and is represented by its androgenic RBA. PROGESTINS WITH HIGH ANDROGENIC RBA PRODUCE UNDESIRABLE SIDE EFFECTS. Slide 30: The progestational activity of the gonane progestins is higher than that of estranes in equivalent dosages; therefore, the gonanes maintain contraceptive efficacy at relatively low serum concentrations. The androgenicity of each of the gonanes differs according to its chemical structure, although desogestrel, gestodene, and norgestimate share the property of being less androgenic than estranes with equivalent progestational potency. Third-generation progestins : Third-generation progestins OH C CH Desogestrel H2C OAcetate C CH Norgestimate HON OH O C CH Gestodene Androgen (A) / Progestin (P) Biologic activity. Receptor binding and invivo activities of the new progestins : Androgen (A) / Progestin (P) Biologic activity. Receptor binding and invivo activities of the new progestins Upmalis et al. J Soc Obstet Gynecol Can 1991;13(suppl): 35-9.¹³ Low androgenic progestins and lipid metabolism : Low androgenic progestins and lipid metabolism Desogestrel, gestodene, and norgestimate have less androgenic activity than the older progestins and as such, when combined with an estrogen, would be expected to have less adverse effect on lipid metabolism than the older formulations. Lipid changes with oral contracetives : Lipid changes with oral contracetives PERCENTAGE CHANGE FROM BASELINE PROGESTIN N TG C LDL-C HDL-C Apo B Apo A-I ___________________________________________________________________________ Desogestrel 608 29.3 2.8 -2.1 12.9 10.5 11.3 Gestodene 296 38.3 3.8 -2.5 8.1 16.0 7.1 Norgestimate >2550 14.8 4.3 -0.2 9.9 5.3 7.3 ___________________________________________________________________________ TG, triglyceride; C, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; apo, apoprotein. From Speroff L, DeCherney A, and the Advisory Board for the New Progestins. Evaluation of a new generation of oral contraceptives. Obstet Gynecol 81:1034-1047, 1993. Venous thromboembolism and third-generation combined oral contraceptives. : Venous thromboembolism and third-generation combined oral contraceptives. In the period 1995-96, four epidemiological studies were published on the possible link between venous thromboembolism and third-generation combined oral contraceptives. Venous thromboembolism and third-generation combined oral contraceptives. : Venous thromboembolism and third-generation combined oral contraceptives. Four later studies 1997 to 1999 addressed bias and confounding by age and two further analyses were made of data from the Transnational Study. THESE SIX SUBSEQUENT STUDIES SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN THE RELATIVE RISKS OF VENOUS THROMBOEMBOLISM FOR SECOND-AND THIRD-GENERATION ORAL CONTRACEPTIVES. An overview of epidemiological studies on venous thromboembolism and combined oral contraceptives : An overview of epidemiological studies on venous thromboembolism and combined oral contraceptives Dienogest (Fourth-generation progestin) : Dienogest (Fourth-generation progestin) A hybrid progestin being derived from the gonane group with a 17?-cyanomethyl group. No androgenic effect but a partial antiandrogenic effect. Ülkemizdeki yüksek doz östrojenli (50µg Ethinyl Estradiol) OC’ler : Ülkemizdeki yüksek doz östrojenli (50µg Ethinyl Estradiol) OC’ler Anovlar 4.00 mg noretisteron asetat Eugynon 0.50 mg norgestrel Lyndiol 2.50 mg linestrenol Ovral 0.25 mg levonorgestrel Ovulen 1.00 mg etinadiol diasetat TÜRKIYE’ DEKI DÜSÜK DOZ MONOFAZIK OC’ LER : TÜRKIYE’ DEKI DÜSÜK DOZ MONOFAZIK OC’ LER Lo-Ovral = Microgynon =LoFemenal(hibe) 25.6.1980 18.9.1989 9.5.1985 ruhsatli 0.150 mg levonorgestrel 0.030 mg etinilestradiol içerirler. Ülkemizdeki trifazik preparatlar : Ülkemizdeki trifazik preparatlar Triquilar = Trinordiol levonorgestrel ethinilestradiol içerirler TÜRKIYE’ DEKI III. KUSAK PROGESTERONLU OC’LER : TÜRKIYE’ DEKI III. KUSAK PROGESTERONLU OC’LER DESOLETT 0.150 mg desogestrel 0.030 mg etinilestradiol Ruhsat tarihi 13.6.1985 GINERA 0. 075 mg gestoden 0.030 mg etinilestradiol Ruhsat tarihi 6.2.1991 MINULET 0. 075 mg gestoden 0.030 mg etinilestradiol Ruhsat tarihi 19.12.1989 GINERA=MINULET Ülkemizdeki en düsük dozlu OC’ler : Ülkemizdeki en düsük dozlu OC’ler MYRALON 0.150 mg desogestrel 0.020 mg etinilestradiol Ruhsat tarihi 9.5.1990 MIRANOVA 0.10 mg levonorgestrel 0.02 mg etinilestradiol Ruhsat tarihi 16.08.2000 Pregnanes (C21 Progestines) : Pregnanes (C21 Progestines) Pregnanes are derived from 17-hydroxyprogesterone The most widely used pregnane is medroxyprogesterone acetate Pregnan progestins : Pregnan progestins Pregnan progestin in OC : Pregnan progestin in OC 19-norprogesterone derivates : 19-norprogesterone derivates The 19-norprogesterone derivates appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptors. 19-norprogesterone derivates : 19-norprogesterone derivates This category includes, Trimegestone, Nomegestrol acetate Nestoronee’ Nestorone’ is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Drospirenone : Drospirenone Drospirenone and spironolactone : O Testosterone OH Drospirenone and spironolactone Drospirenone and spironolactone : O Spirolactone O O Drospirenone and spironolactone Drospirenone and spironolactone : Drospirenone and spironolactone O Spironolactone O O S O CH3 Drospirenone and spironolactone : Drospirenone and spironolactone O Spironolactone O O S O CH3 O O O Drospirenone Sex hormones and renin,angiotensin, aldosterone system (RAAS) : Sex hormones and renin,angiotensin, aldosterone system (RAAS) Estrogens strongly stimulate the production of renin substrate (angiotensinogen), leading to increased levels of angiotensin and aldosteron, and sodium retention. Progesterone is a potent aldosterone antagonist, which acts on the mineralocorticod receptor to prevent sodium retention. Slide 55: Steady state: EVC normal, serum K+ and blood pressure normal Renin substrate(= angiotensinogen) Renin Angiotensin II Na+/ water retention (= weight gain) K+ elimination Aldosterone KIDNEY ADRENAL GLAND LIVER Combined oral contraceptives and renin,angiotensin, aldosterone system (RAAS) : Combined oral contraceptives and renin,angiotensin, aldosterone system (RAAS) In combined oral contraceptives, progestogens devoid of antimineralocorticoid and activity are unable to counteract the sodium-retaining effect of the ethinylestradiol component. As a consequence, these preparations may increase fluid retention, and promote related symptoms such as edema and body weight. Drospirenone and RAAS : Drospirenone and RAAS Drospirenone is a new progestogen, derived from 17?-spirolactone, and the relationship between its progestogenic and its antimineralocorticoid potency is almost identical to that of natural progesterone. The effect of both hormones on the mineralocorticoid receptor is inhibitory, while that on the progesterone receptor is agonistic. Pharmacological profile of drospirenone and other progestogens : Pharmacological profile of drospirenone and other progestogens Progesterone + – – (+) + Drospirenone + – – + + Cyproterone + (+) – + – acetate Desogestrel* + – (+) – – Dienogest + – – + – Gestodene + – (+) – (+) Levonorgestrel + – (+) – – Norgestimate** + – (+) – – +, effect; (+), negligible at therapeutic dosages; –, no effect Progestogenic Glucocorticoid Androgenic Antiandrogenic Antimineralocorticoid activity activity activity activity activity Foidart et al., 2000 Drospirenone : Drospirenone Antimineralocorticoid + Antiandrogenic activity activity Progesterone-like effects on sodium and water retention breast tension edema body weight some premenstrual symptoms Blockage of androgen receptor acne seborrhea Effects of drospirenone on sodium and aldosterone excretion : 2 mg/day drospirenone 1 2 3 4 5 6 7 8 9 10 100 80 60 40 20 0 130 110 90 70 50 Placebo Day Aldosterone excretion (nmol/day) Sodium excretion (mmol/day) ? Na excretion cumul. 84 mmol } * * * ** Treatment Oelkers et al., 1991 *p < 0.05; **p < 0.01 Effects of drospirenone on sodium and aldosterone excretion Effects of drospirenone/ethinylestradiolon body weight : 3 6 7 3 mg DRSP/30 µg EE (Yasmin) 3 mg DRSP/20 µg EE 3 mg DRSP/15 µg EE 150 µg LNG/30 µg EE Months of trial Mean body weight change (kg) 1.0 0.5 0 -0.5 -1.0 -1.5 -2.0 0 Follow-up Oelkers et al., 1995 Effects of drospirenone/ethinylestradiolon body weight Effect of drospirenone on acne and seborrhea : Effect of drospirenone on acne and seborrhea Boschitsch et al., 2000 Compared to baseline, * p < 0.0001 Ülkemizde 4.Kusak progesteron içeren OC : Ülkemizde 4.Kusak progesteron içeren OC 30 µg. Etinilestradiol 3 mg. Drospirenon YASMIN Slide 64: A progestogen with pharmacologic properties which more resemble those of ‘natural’ progesterone may enhance ‘well-being’ and be better tolerated Slide 65: TESEKKÜR EDERIM ESTRAN GONAN PREGNAN DROSPIRENONE 19-NORPROGESTERON

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