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26-06-2013

Role of for the Thromboembolic Risk of Hormonal Contracepves

Professor Dr. Dr. h.c. Adolf E. Schindler Vising Professor Krasnoyarsk State Medical University, Director Instute for Medical Research and Educaon, Essen, Germany Former Chairman Dept. Obstetrics and Gynecology, University Essen Email: [email protected]

Golden Madonna, Münster, Essen Oldest known statue of Mary Medical School and Clinics, University Duisburg-Essen in the world, created 990 AD A.E. Schindler 1 Kopenhagen 2013 A.E. Schindler 2

Definion of a One has to take into account that the progestogens are not equal: • with progestogenic acvity at the 1. Difference in structure endometrium 2. Difference in acon profile • But: Progestogens – besides the progestogenic 3. Difference in organ effects acon – have different paral other biological effects, which are of clinical relevance.

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Classification of progestogens To illustrate the importance of my presentaon I am demonstrang this by a most recent publicaon. Journal: Climacteric 2012 Oct. 9 (Epub ahead of print)

Title of the paper:“Progesterone increases resistence of ophthalmic and central renal arteries in climacteric women“. 17-OH-progesterone 19-norprogesterone 19-nortestosterone Derivates Derivaves Derivaves In the text it is 5 mg of acetate (MPA) p.o. PREGNANE NOR-PREGNANE daily, which resulted in a vasoconstricve effect in postmenopausal - Hydroxyprogesterone - Nomegestrole Acetate GONANES women in the ophthalmic and central renal arteries. caproate - - Indeed, MPA has an elevated thromboembolic effect (seeWHI 2002) - Hydroxyprogesterone - - - heptanoate - Nestorone - - compared to progesterone and dydrogesterone . - - - -Norethisterone Progesterone as well as Dydrogesterone – in contrast – dilate - Acetate Acetate -Norgesmate arterial vessels resulng in a lowering of the blood pressure. - -Ethinodiol Diacetate De Souza et al. Climacteric 2012 Oct. 9 ( Epub ahead of print) - Medroxyprogesterone - Acetate - - Acetate According to R. Druckmann Kopenhagen 2013 5 Kopenhagen 2013 A.E. Schindler 6 A.E. Schindler

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Paral effect paern of Progestogens

Progestogene Progestogenic Androgenic Anandrogenic Estrogenic Anestrogenic Glucocorcoid Anmineralo- corcoid

Progesterone + - (+) - + (+) +

Dydrogesterone + - - - + - (+)

MPA + (+) - - + + -

Norethisterone + + - + + - -

Nomegestrol + - (+) - + - -

Drospirenone + - + - + - +

Modified according to Schindler et al Maturitas 46, S1, S 7 2003 7 Maturitas 61, 171, 2008 Kopenhagen 2013 A.E. Schindler 7 Kopenhagen 2013 A.E. Schindler 8

Hemostasis

1. Coagulaon 2. Fibrinolysis

Normally this system is in balance

Winkler et al Adv. in Contracept. 7 (Suppl.3), 273, 1991

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Thromboembolism Thrombosis • The venous thromboembolism (VET) 1. Venous comprises deep vein thrombosis and pulmonary embolism. 2. Arterial • This is an essenal negave factor for the premenopausal (/ progestogen combinaon = pill) and postmenopausal HRT.

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Risk factors for thromboembolism I Risk factors for thromboembolism II 1. Increasing age 2. Increasing body weight 3. / post partum 4. Pill as estrogen/ progestogen combinaon a) Type of estrogen (EE, E2, E2V) 6. Genec predisposion, which influences hemostasis b) Estrogendosis 7. Family and personal history regarding thrombosis c) Type of progestogen d) Length of use 8. Immobility (operaon, accident) 5. HRT as estrogen/progestogen combinaon a) Type of estrogen 9. Long distance air travel b) Estrogen dosis 10. Smoking c) Type of progestogen d) Length of use

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The risk of venous thrombosis while taking the pill The absolute risk of venous thrombosis • It is known since the sixes that oral estrogen/ per 10.000 women years progestogen combinaon are associated with an elevated thromboembolic risk. – without pill 3,01 – • The thromboembolic risk is related to type and with pill 6,29 dose of the estrogen component. The role of thrombosis decreases with length of pill use – less than 1 year = 4,17 • In the ninees debate started that different – 1-4 years = 2,98 progestogens are associated with a different – more than 4 years = 2,76 thromboembolic risk. The rate is also lower with lower estrogen dosis

Lidegaard et al BMJ 339, 2890, 2009

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Comparison of oral, hormonal contracepves with 30 µg and 20µg EE Frequency of venous thrombosis and 150µg desogestrel (n=1633)

1. Non users of COC´s have a risk of 4-5/10.000 women years Hemostasis parameter 30 µg 20 µg

2. COC-user have a rate of 9-10/10.000 women years Thrombinfragment 1+2 +72,0% +61,1% 3. Pregnancy has a rate of 29/10.000 women years D-dimer +42,4% +36,0% Dinger Contracepon 75, 328 + 344, 2007 4. Postpartum 300-400/ 10.000 women years Protein C acvity +6,1% +4,6% Thromb.Hemostasis 6, 632, 2004 Anthrombin III -6,3% -5,3%

Protein S acvity -19,7% -16,0%

Winkler et al Gynecol. Endocrinol. 10, 266, 1996

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HRT increases thromboembolic risk up to three mes.

Winkler et al Adv. in Contracept. 7 (Suppl.3), 273, 1991

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Risk factors for VTE in menopause

1. Changes in body composion (such as increase in visceral adipose ssue) • Thromboembolic risk will be modified using 2. Proatherogenic changes of the lipid COC or HRT by the type and dose of the estrogen (EE,E2, E2V) and by the used 3. Worsening of the carbohydrate metabolism progestogen through the paern of paral (increased diabetes risk and manifestaon) effects of each progestogen. 4. Increasing rate of women with metabolic syndrome

Gaspard Gynecol. Forum 17, 17, 2012 Kopenhagen 2013 A.E. Schindler 21 Kopenhagen 2013 A.E. Schindler 22

• The extend of the individual progestogen on • There can be increase or decrease on liver the hemostac system is dependent on the protein synthesis by progestogen acon extend of modificaon of the total estrogen reflected by the level of SHBG, CBG and TBG. effect in the body - mainly in the liver.

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• Progestogens induce through different paral SHBG-levels using different EE/progestogen effects such as androgenic, anandrogenic, combinaons estrogenic, anestrogenic the estrogen acon regarding the hemostasis system. • In addion, there are other risk factors such as • Increase in SHBG genecally induced changes of the hemostasis • EE/CPA ˃ EE/DRSP ˃ EE/Desogestrel inhibitors (Anthrombin III, Protein C, Protein S) or a hereditary resistance of the Faktor Leiden V against acvated Protein C (APC-resistance).

Bhaacharya et al Fert. Steril. 98, 2012

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• Progestogens with a glucocorcoid paral effect • COC´s with desogestrel and gestoden (3rd (i.e. MPA, CPA) regulate the thrombin receptor generaon progestogens) increase the risk of and smulate the procoagulatory acvity at the thrombosis by 70% compared to COC´s with vessel wall. levonorgestrel (2nd generaon progestogen). • Smulatory progestogens are MPA, CPA, gestoden, 3-ketodesogestrel and drospirenone. This is not the case with levonorgestrel or Mueck et al Therapeut. Umschau 2009 norgesmate. Clinically this is relevant only together with an acve estrogen (i.e. EE).

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BMJ publicaons

• In August 2009, the BMJ published the results of two retrospecve epidemiological studies that assessed the risk of • An elevated risk of gestoden or desogestrel – VTE in users of hormonal contracepves1,2 containing COC´s is accompanied by a higher • The results of these studies suggested that COCs were associated with a differenal risk of VTE based upon their SHBG concentraon compared with LNG- progesn component containing COC´s. • The risk of VTE was reportedly lower in women using LNG- containing COCs versus so-called ‘third-generaon’ COCs and COCs containing DRSP Van Vliet et al Human Reprod. 20, 569, 2005 1van Hylckama Vlieg, et al. BMJ 2009;339b2921; 2Lidegaard, et al. BMJ 2009;339b2890

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Thromboc risk of COC´s with different progestogens Comparison of incidences of venous thrombosis compared with COC´s and levonorgestrel in DRSP- or LNG- containing COC´s per 100.000 women years

Norethisterone 0,98 • Drospirenone: 23,0; 95% CI 13,4-36,9 Norgesmate 1,19 • Levonorgestrel: 9,1; 95%CI 6,6-12,2 Desogestrel 1,82 Gestoden 1,86 • Incidence raon: 2,7; 95%CI 1,5-4,7 Drospirnone 1,64 1,88 Parkin et al BMJ 342, 2139, 2011 (Australian Study)

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Comparison of incidences of venous thrombosis in DRSP- or LNG- containing COC´s VET and COC´s per 100.000 women years • The safest COC´s related to VET are the COC´s • Drospirenone: 30,8; 95% CI 26,6-36,8 with levonorgestrel and norgesmate. • Levonorgestrel: 12,5; 95%CI 9,6-15,9 • The VET risk is lower than for desogestrel, • Incidence raon: 2,8; 95%CI 2,1-3,8 gestoden, DRSP and CPA.

Marnez et al Eur.J. Contracept, Reprod. Health Care 17,7, 2012

Jick, Hernandez BMJ 342, 2151, 2011 (American Study)

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VET and COC´s Newest recommendaons

COC´s with EE/LNG and EE/NET are COC´s of first choice. • For women, who start COC´s it is recommended to use pills with 20 µg EE combined with NET, LNG or norgesmate. Ri Curr. Opin. Obstet. Gynecol. 24, 235, 2012

Lidegaard et al Acto Obstet. Gynecol. Scand. 91, 169, 2012

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Sex binding globulin as a marker of thromboc risk of hormonal contracepves • Users of hormonal contracepves with a high risk of VTE such as combined hormonal contracepves containing desogestrel, cyproterone acetate or Non-oral route of EE administraon seems to be drospirenone and the transdermal patch had higher more thrombogenic than oral route. SHBG levels than users of combined hormonal contracepves containing levonorgestrel. • SHBG-levels were posively associated with the risk Plu-Bureau et al best Pract. Res. Clin. Endocrinol. Metab. 27, 25, 2013 of VTE. Raps et al J. Thromb. Hemost. 2012

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Comparison of progestogen-only contracepves

LNG/NET 0,59 Progestogen-only OC´s such as minipill do not increase VET risk. Desogestrel 1,12

LNG-IUS 0,90

Mueck et al Therapeut. Umschau 2009 Lidegaard et al BMJ 339, 2890, 2009

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Combined oral hormonal contracepves increase the risk of VTE New E2-containing hormonal contracepves and should be avoided in women, who are already at increased VET-risk. 1. E2-valerate/DRSP PO-preparaons an are alternave 2. E2-17β/ opon. Bianco-Molina et al J. Fam. Plann. Reprod. Health Care 129, 257, 2012

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Type of estrogen and VET • Oral E2 has no first pass effect at the liver in contrast to EE because of the metabolisaon of E2 aer oral applicaon to /estrone • E2-17β/ E2V are less thrombogenic than EE. sulfate and . • Less effect on elevaon of SHBG. • The recirculang E2-levels are relave low and explain the low liver effect compared with EE and therefore E2 has a lower thromboembolic risk potenal.

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Qlaira – E2V 3 mg for 2 days – E2V 2 mg /DNG 2 mg for 5 days • The profibrinolyc effect of androgenic – E2V 1 mg /DNG 2 mg for 17 days – E2V 1 mg for 2 days progestogens of importance for the favourable – Plazebo for 2 days effects on hemostasis (coagulaon and Microgynon fibrinolysis) in hormonal contracepon and HRT. – EE 0,03mg/LNG and 0,150 mg Levonorgestrel for 21 days • A possible way of acon: – Placebo for 7 days Reducon of fibrinolyc inhibion by PAI-1 and Lp (a). For Qlaira the VET risk was similar or lower compared with Microgynon.

Klipping et al Drugs 11, 659, 2011 Winkler Maturitas 24, 147, 1996

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VET risk in postmenopausal women in relaon to the used progestogen • Basically, the use of an estrogen/progestogen combinaon has a higher VET risk than estrogen alone. • HRT RR 2,07; 95% CI 1,86-2,31 • E2 RR 1,42; 95% CI 1,25-1,66 • Transdermal estrogen RR 0,82; 95% CI 0,64- 1,06

Sweetland et al J. Thromb.Hemost. 2012

MacLennan Climacteric 14, 409, 2011 Kopenhagen 2013 A.E. Schindler 47 Kopenhagen 2013 A.E. Schindler 48

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Relaonship between VET and used VET risk of HRT in relaonship to the HRT over 5 years used progestogen No medicaon 1:650

Oral estrogen alone 1:475 • HRT with MPA RR 2,67; 95% CI 2,25-3,17 Estrogen/progestogen combinaon • HRT with other progestogens RR1,91; 95%CI 1,67-2,17 (Norethisterone/Norgestrel) 1:390 Difference stascally highly significant p ˂ 0.0007 Estrogen/progestogen combinaon (MPA) 1.250

Sweetland et al J. Thromb.Hemost. 2012 Sweetland et al J. Thromb.Hemost. 2012

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• Progesterone and dydrogesterone appear not to increase VET in combinaon with estrogen in postmenopausal women.

Canonico et al Maturitas 70, 354, 2001

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Summary

1. Progestogens can influence the VET risk in combinaon with estrogen (pill, HRT). • Norpregnanes such as Nomegestrol and 2. This effect appears to be related to the Promegeston are associated with a high VET paern of paral effects of each incidence, when used in postmenopausal HRT. progestogen. 3. Progestogens with androgenic effects lead in Canonico et al Artherioscler. Thromb.Vas. Biol. 30, 340, 2010 Canonico et al Circulaon 115, 840, 2007 COC´s or HRT to a reducon of VET-risk.

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Conclusion

• The VTE-risk is the interplay of the paern of the paral effects of each progestogen with the type and dose of the used estrogen and possibly type of applicaon.

Greengs from the City of Essen

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