Endometrial protection and progestins. Which, how much and for how long A reappraisal. Claire Bourgain

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1 Endometrial protection and progestins. Which, how much and for how long A reappraisal Claire Bourgain

2 Setting the problem Million Woman Study Standardized incidence for endometrial cancer/1000 woman 5y FU Lancet, 2005 QuickTime and a TIFF (LZW) decompressor are needed to see this picture. QuickTime and a TIFF (LZW) decompressor are needed to see this picture. Low incidence 2

3 Hormone replacement therapy Relieves menopauzal symptoms Increased risk for hormone-dependent malignancies Difference between ERT and HRT Difference in breast and endometrium Unopposed estrogen will increase the risk for endometrial hyperplasia and cancer Need for progesterone-protection of the endometrium 3

4 Hyperplasia-carcinoma progression 4

5 Dualistic pathogenic model of carcinoma Type I carcinoma Hyperplasia precursor QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. HRT concerns Type I Ca Low-grade Indolent Low incidence QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. 5

6 Estrogen metabolism DHEA 3ß-HSD Estrone sulphate EST-STS Androstenedione Estrone 17ß-HSD type 5 17ß-HSD type 1 17ß-HSD type 2 Testosterone 5æ reductase Estradiol DHT AR ER 6

7 Estrogen metabolism in endometrial CA Androstenedione STS Estrone Estronesulphate 17ß HSD 5 17ß HSD 2 Testosterone aromatase Estradiol Type-1 17ß HSD is not present in the endometrium Type-2 17ß HSD is present in normal endometrial glands, is decreased in hyperplasia to cancer is inversely correlated to intratumoral E2 7 Type-5 17ß HSD is present in normal endometrium and is increased in hyperplasia to cancer Ito, T J Exp Med, 2007

8 Progesterone effects on the endometrium Dynamic morphological transformation Glandular proliferation inhibition Secretory vacuole induction Induction of pinopods Induction of stromal edema Induction of decidual stroma transformation Induction of stromal proliferation Angiogenesis Immunomodulation 8

9 Progesterone effects on the endometrium Modulation of cytokines Increased PP12 Increased PP14 Increased calcitonine Production of prolactine Production of 17betaHSD-2 Production of 11betaHSD-1 Modulation of HOXA Down-regulation of estrogen receptors Down-regulation of COX Immunomodulation 9

10 Genomic effects of progesterone 10

11 Récepteurs de la progestérone rone Progesterone receptors Progesterone receptor isoforms PRB NH2 A/B DOMAIN C DOMAIN(DBD) D DOMAIN E/F DOMAIN(HBD) COOH PRA NH2 A/B DOMAIN C DOMAIN(DBD) D DOMAIN E/F DOMAIN(HBD) COOH 11 Vegeto et al, 1990

12 12

13 PR and endometrial cancer Mijamoto et al,

14 Non-genomic effects of progesterone Rapid effects that cannot be explained by nuclear transcription Posttranscriptional changes Subpopulation of receptors Allosteric regulation of unrelated receptors Activation of transmembrane receptors Poorly understood in the endometrium Gellersen et al,

15 Effects of progesterone 15

16 Effects of progesterone 16

17 Natural progesterone Metabolism incompletely understood Numerous metabolites Oral progesterone bacterial enzymes intestine first-pass hepatic metabolism Parenteral progesterone site of injection hepatic metabolism Vaginal progesterone no first-pass effect Low bioavailability except if micronized 17

18 Antiproliferative effects of progesterone Transdermal E2+200mg oral progesterone Moyer et al,

19 Oral micronized progesterone 19

20 Administration route of progesterone Delayed In phase Asynchronous P oral P I.M. P I.Vag. 300 P I.Vag. 600 Bourgain et al,

21 Vaginal natural progesterone 21

22 Progestins Micronized progesterone, dydrogesterone, medrogestone Synthetic progestins with a 2-C side chain Structurally related to progesterone Pregnane derivatives (MPA, MA, CPA) Acethylated Not acethylated 19-Norpregnane derivatives (TMG, noresterone, promegestrone) Acethylated Not acethylated Synthetic progestins without a 2-C side chain Structurally related to testosterone Ethylinated Estranes (norethisterone, NETA, lynestrol) 13-Ethylgonanes (second and third generation) Non-ethylinated Drospirinone 22

23 Progestins and receptor binding Schindler,

24 Progesterone therapy and endometrium 24

25 Oral dydrogesterone 25 Fatemi et al, 2006

26 Potency of different progestins Stanzcyk,

27 PEPI Trial, JAMA 1996 Randomized placebo-controlled trial 3-Year Placebo CEE 0,625 mg CEE 0,625 mg+10 mg MPA 12 d CEE 0,625 mg+2,5 mg MPA CEE 0,625 mg +200 mg MP 12d 27

28 PEPI Trial, JAMA 1996 Finding Placebo CEE CEE+ CEE+ CEE+ Total MPA cyclic MPA cc MP Normal SH CH AH CA Total No difference in the progesterone groups 28

29 Cochrane data, Furness et al,

30 Cochrane data, Furness et al,

31 Cochrane data, Furness et al, 2009 Unopposed estrogen is associated with increased risk for endometrial hyperplasia At 2 and 3 years at all dosages Dose-related relationship LD E at 1 year is not statistically different from placebo Unopposed estrogen is associated with increased odds of endometrial carcinoma compared to E+P 31

32 Cochrane data, Furness et al, 2009 Progesterone continuus combined Reduction of hyperplasia at 1 year all dosages >1 Y Reduction of hyperplasia at 2 years LD E2+1,5 or 2,5mg MPA Insufficient data for LD E2+0,2 or 1mg NETA 32

33 Cochrane data, Furness et al, 2009 Progesterone sequentially combined Reduction of hyperplasia No difference with continuus combined (1,2,3 years) Progesterone needs to be given for 10 days Long-cycle sequentially combined 2mgE2 + 1mg NETA 10d every 3 month 0,25mgE mg MP 7,5% hyperplasia no difference 33

34 Intra-uterine progesterone Lack of systematic trials Boon et al, mg E2 + levonorgestrel IUD 20µg/24h VS 1mg cyclic NETA 10d Wildemeersch et al, ,5mg E2 + levonorgestrel IUD 14µg/24h 34

35 Prevention of estrogen induced endometrial cancer in post menopausal women: micronized progesterone may not be as potent as other progestins EMAS meeting London May 20, 2009 Nathalie Chabbert-Buffet 1,2 *, Alban Fabre 3,4*, Zohra Rahy 3, Sylvie Mesrine 3, Philippe Bouchard 2,5, Serge Uzan 1, Marie- Christine Boutron-Ruault 3,4, Agnès Fournier 3,4, Françoise Clavel-Chapelon 3,4 35

36 The E3N Cohort Study Etude Epidémiologique de femmes de la MGEN Main objective: investigate cancer risk factors E3N cohort women aged years in 1990 Main factors under study: use of hormonal treatments diet reproductive factors Follow-up of the E3N cohort : self-administered questionnaires files from the MGEN insurance plan: addresses, vital status, 36 hospitalisations, prescribed drugs

37 MHT and endometrial cancer risk: n=219 cases among 66,324 non hysterectomized post menopausal women (585,199 PY) 2 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0, [ ] 1.26 [ ] non users oral transdermal administration of the estrogen 37

MHT and endometrial cancer risk depending on the progestin used: global risk, ever vs never users 2.22 [1.23-4.01] 1.80 [1.22-2.68] 0.

38 MHT and endometrial cancer risk depending on the progestin used: global risk, ever vs never users 2.22 [ ] 1.80 [ ] 0.77 [ ] 0.78 [ ] p: E vs E+DG = E vs E+other Prog = E vs E+ P = Chabbert-Buffet N et al, submitted

39 Endometrial bleeding patterns in HRT Irregular bleeding in HRT is associated with a specific expression of TIMP-1 Hickey et al, 2006 Steroid receptor expression is not different in the endometrium of women with and without unscheduled bleeding Vani et al, 2008 Hypothesis in Levonorgestrel IUD: Binding to AR and PR leads to initial rise in 17ßHSD2, conversion of estradiol to estrone and functional intracellular E2 deficiency and vascular fragility. Intermittent antiprogestin may control bleeding Critchley et al,

40 Conclusions Unopposed estrogen increases the risk of endometrial hyperplasia and cancer Progestins are equally effective to obtain an antiproliferative effect Progestins combined continuus and combined sequentially (10d) are equally effective to decrease endometrial hyperplasia and cancer risk The lowest safe dose of progesterone is dependent on the type of progestin and estrogen type and dose 40

Hormones. Synthetic. Bioidentical. vs. SPECIAL REPORT. for Menopause. by Dr. Mark Stengler

Hormones. Synthetic. Bioidentical. vs. SPECIAL REPORT. for Menopause. by Dr. Mark Stengler SPECIAL REPORT Synthetic vs. Bioidentical Hormones for Menopause by Dr. Mark Stengler www.markstengler.com All rights reserved. This program, or parts thereof, may not be reproduced in any form without