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RESEARCH: Marianne Canonico, Geneviève Plu-Bureau, Gordon D O Lowe, and Pierre-Yves Scarabin Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis BMJ 2008; 336: 1227-1231 [Abstract] [Full text]

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HRT increases mortality from thrombosis and cancers

Ellen CG Grant   (26 May 2008)

Quality of life and use of menopausal hormone therapy

Martina Dören, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany   (27 May 2008)

HRT and prothrombotic state

Filip Konecny   (7 June 2008)

HRT, quality of life and mortality

Marianne Canonico, Geneviève Plu-Bureau, Gordon DO Lowe, and Pierre-Yves Scarabin   (10 June 2008)

Concerned women must be immediately informed

Edith Schuligoi   (13 June 2008)

Concepts of Quality of life

Martina Dören   (23 June 2008)

HRT increases mortality from thrombosis and cancers 26 May 2008
Ellen CG Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU, UK Send response to journal: Re: HRT increases mortality from thrombosis and cancers	Marianne Canonico and colleagues are wrong to state that it is a known fact that HRT improves the quality of life for women.1 This is untrue. Neither combined progestogen plus oestrogen HRT, nor oestrogen- only HRT, improved women’s quality if life in the Women’s Health Initiative randomised clinical trials.2,3 They are also wrong to state that, “progestogens have recently emerged as a determinant of the risk of venous thromboembolism”. I proved in 1969 that the risk of thrombosis varied with different balances and doses of progestogens and oestrogens when given in progestogen-dominant combinations for oral contraception.4 It was also evident then that the risk increased with longer use. This suggests that an apparent greater risk during the first 12 months in more recent studies could be due to confounding by selections and drop outs or increased sensitivity due to past hormone use for other reasons. Most women who had a Pill thrombosis should have been warned not to take HRT. The authors found that transdermal oestrogen increased the thrombosis risk particularly in women with other risk factors. Why are further trials needed? Exogenous oestrogens and progestogens, whether taken as oral contraceptives or as HRT, are classified by the International Agency for Cancer Research (WHO) as highest level Group 1 carcinogens in animals and humans. The MWS found increased risk of breast cancer and death with use of both oral and transdermal HRT.5 The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1.32 [1.21-1.45]; 1.24 [1.11-1.39]; and 1.65 [1.26-2.16], respectively; all p<0.0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. Cancer is the biggest cause of death in women taking hormones. It is a great concern that transdermal hormones are widely promoted and sold via the internet without records being kept of adverse effects including increases in cancers and thrombosis. Salivary oestradiol levels from 5 to more than 50 times higher than normal postmenopausal levels are being obtained in women supplemented with oestrogen pills, patches creams or gels. Repeated applications of progesterone cream frequently elevate salivary progesterone levels to more than 100 times normal. These very high concentrations of progesterone take months to fall to normal levels during which time symptoms continue in my experience. How could exogenous hormones which increase death by causing thrombosis, vascular and mental illnesses and breast, cervical, ovarian and endometrial cancers improve life for anyone other than those profiting financially from such exposures? 1 Canonico M, Plu-Bureau G. Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ, doi:10.1136/bmj.39555.441944.BE (published 20 May 2008) 2 Hays J, Okene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG; Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003 May 8;348(19):1839-54. Epub 2003 Mar 3 Brunner RL, Gass M, Aragaki A, Hays J, Granek I, Woods N, Mason E, Brzyski R, Ockene J, Assaf A, LaCroix A, Matthews K, Wallace R; Women's Health Initiative Investigators. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial. Arch Intern Med 2005 Sep 26;165(17):1976-86 4 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;4:73- 77. 5 Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362(9382):419-27. Competing interests: None declared
Quality of life and use of menopausal hormone therapy 27 May 2008
Martina Dören, Professor of Women´s Health Charité-Universitätsmedizin Berlin,, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany Send response to journal: Re: Quality of life and use of menopausal hormone therapy	It appears questionable whether hormone replacement therapy indeed improves quality of life (QoL), as mentioned in the introduction of a new meta-analysis assessing the risk of venous thromboembolism (1). Not the least another systematic review and meta-analysis, also providing data on thromboembolism, cancer,cardiovscular risks, stroke, and mortality in associating with menopausal hormone use, could not confirm that menopausal hormones increases QoL (2); consistent with one HTA report (3). Although women may report vasomotor symptom relief once they use menopausal hormones, this does not necessaryily result in an improvement of specific domains of physical or phsychological well-being. 1 Canonico M, Plu-Bureau G. Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ, doi:10.1136/bmj.39555.441944.BE (published 20 May 2008) 2 Farquhar CM, Marjoribanks J, Lethaby A et al, and the Cochrane HT Study Group. Long-term hormone therapy for perimenopausal and postmenopausal women (Review). Cochrane Database Syst Rev 2005;(3):CD004143 3 Nelson HD et al. Management of menopause-related symptoms. Evidence Report / Technology Assessment No. 120. AHRQ Publication No. 05-E016-2. Rockville, MD, 2005 http://www.ahrq.gov/downloads/pub/evidence/pdf/menopause/menopaus.pdf Competing interests: None declared
HRT and prothrombotic state 7 June 2008
Filip Konecny, post-doctoral researcher TGH, Toronto Send response to journal: Re: HRT and prothrombotic state	Combined oral contraceptives have long been recognized as causative factors in the pathogenesis of venous thromboembolism (VTE) (1). Hormone replacement therapy (HRT), exposing women to exogenous estrogen, was not for long time linked to VTE (2). The direct mechanism of how HRT initiate an increased risk of VTE is very vaguely described in literature; moreover the involvedness of factors that comes into play is even more complex. In this research review compiled by Canonico et al. (3) I could not find any definitive or clinically related material of how the oral estrogen therapy, compared to transdermal HRT causes the prothrombotic state. If we look at the venous thromboembolism, one of the risk factors of pulmonary embolism (PE), is the HRT influence more the platelets or the prothrombin generation, or both? And further if the first pass effect makes difference compared to transdermal, what byproducts or receptor activity most likely influence this prothrombotic state? As we know the pulmonary embolism is life threatening, since silently develops usually in the lower limb blood vessel system. Fluctuating level of estrogens (as in pregnancy and etc.) are considered as one of many risk factors of PE. Could this be a link to HRT? (the direct receptor effect of estrogens or its first pass effect). As was reported by Wallen in 2006 (4), HRT are not influencing platelet P-selectin expression, platelet fibrinogen binding, or platelet- leukocyte aggregate formation either in the absence or presence of agonist stimulation. In addition, circulating platelet- platelet aggregates were similar during placebo and HRT treatment (4). Results supports previous study by Michelson where no significant effects of HRT treatment on either platelet P-selectin expression (platelet secretion), fibrinogen binding (aggregability), circulating platelet micro-aggregates (aggregability in vivo), plasma βTG (secretion in vivo), soluble P-selectin (endothelial activation in vivo), or platelet-leukocyte aggregation (including platelet-monocyte aggregates), a sensitive marker of platelet activation was observed (5). Williams et al reported similar results at 2005 (6). Moreover even the long-term HRT does not appear to cause increased platelet activation and aggregation. In terms of prothrombin generation the pathway, which final product is thrombin is upregulated during HRT (7, 8). In contrast, HRT produces a reduction in fibrinogen and factor VII activation such as antithrombin, von Willebrand’s factor and enhances fibrinolysis. In addition, an acquired resistance to activated protein C has been documented in users of oral oestrogen (11, 12), but two recent randomised trials indicated that these results did not apply to users of transdermal oestrogen (9). Citing the article form 1997 that liver metabolism of oral doses of estrogen and how exactly it impairs the balance between procoagulant factors and antithrombotic mechanisms is waiting to be answered (7). As reported, oral but not transdermal oestrogen increases plasma concentrations of prothrombin fragment F 1+2 (8, 9), a marker for in vivo thrombin generation. In other study, 12 patients who received HRT for 3.8 months, there was no significant effect of HRT on levels of F1+2, thrombin -antithrombin complexes, or the APC ratio (13). However HRT use showed the maximum effect on PAI-1 activity compared to other coagulation parameters, this blood parameter was found to be statistically insignificant. A lower antithrombin concentration has also been shown in women using oral estrogen, but not in those using transdermal oestrogens (10). Thus transdermal estrogen seems to have less effect on coagulation (the first pass effect activates thrombin by different still unknown mechanisms). In recent study by Johnson in 2008, both contraceptives (transdermal, oral) were tested with significant declines in free and total protein S and antithrombin with increases in fibrinogen and C-reactive protein (14). Thus, liver seems to be responsible for certain side metabolic steps after oral estrogen dose e.g. lowering cholesterol levels and LDL and raising HDL and sometimes hypertriglyceridemia. All byproduct further metabolize, and some influence< for example >the plasminogen activator inhibitor-1 activity (13). I think in future rather then to examine of how transdermal oestrogen compared with placebo increases thrombotic risk, as was outlined in the Canonico review (3), the actual estrogen effect (direct or first pass) on either platelets or plasma has to be researched. 1. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD.Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case control study. BMJ 1996; 312: 83–8. 2. Carter C. Pathogenesis of thrombosis. In: Greer IA, Turpie AGG, Forbes CD, editors. Haemostasis and Thrombosis in Obstetrics and Gynaecology. London: Chapman Hall; 1992. p. 229–56.32 3. Canonico M, Plu-Bureau G. Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ, doi:10.1136/bmj.39555.441944.BE (published 20 May 2008) 4. Håkan Wallén N, Li N, Eriksson-Berg M, Landgren BM, Schenck- Gustafsson K, Hjemdahl P. No effect of oral hormone replacement therapy on platelet function in postmenopausal women with coronary artery disease. Thromb Haemost. 2006 Dec; 96(6): 862-3. 5. Michelson AD, Barnard MR, Krueger LA, et al. Circulating monocyte- platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533–7. 6. Williams MS, Vaidya D, Kickler T, Ouyang P. Long-term hormone replacement therapy does not cause increased platelet activation. Am Heart J. 2005 Sep; 150(3): 434-8. 7. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071-8. 8. Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671-6. 9. Lowe GD, Upton MN, Rumley A, McConnachie A, O’Reilly DS, Watt GC. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein—a cross- sectional population survey. Thromb Haemost 2001;86:550-6 10. Conard J, Samama M, Basdevant A, Guy-Grand B, de Lignieres B. Differential AT III-response to oral and parenteral administration of 17 beta-estradiol. Thromb Haemost 1983;49:252 11. Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036-40. 12. Hoibraaten E, Mowinckel MC, de Ronde H, Bertina RM, Sandset PM. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001;115:415-20 13. Douketis JD, Gordon M, Johnston M, Julian JA, Adachi JR, Ginsberg JS. The effects of hormone replacement therapy on thrombin generation, fibrinolysis inhibition, and resistance to activated protein C: prospective cohort study and review of literature. Thromb Res. 2000 Jul 1;99(1):25-34. 14. Johnson JV, Lowell J, Badger GJ, Rosing J, Tchaikovski S, Cushman M. Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial. Obstet Gynecol. 2008 Feb;111(2 Pt 1):278-84. Competing interests: None declared
HRT, quality of life and mortality 10 June 2008
Marianne Canonico, Postdoctoral research fellow Villejuif, France (94807), Geneviève Plu-Bureau, Gordon DO Lowe, and Pierre-Yves Scarabin Send response to journal: Re: HRT, quality of life and mortality	The letters by Doctors Grant and Doren deal with the effect of HRT on quality of life and mortality. While HRT use did not result in a better quality of life among older women without menopausal symptom included in the WHI trials 1 2, there is evidence that HRT is highly effective in relieving vasomotor symptoms 3. HRT can therefore improve health-related quality of life through decreased hypo-estrogenic symptoms as mentioned in the introduction of our review 4. However, there is a lack of consensus on the impact of HRT on overall quality of life. With regard to the effect of HRT on mortality, a recent WHI trials combined analysis has shown no change in total death among HRT users 5. In addition, the suggestion of reduced total mortality and risk of coronary heart disease among women who initiated HRT closer to menopause provides reassurance that hormones remain a reasonable option for short term treatment of menopausal symptoms 5. 1. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348(19):1839-54. 2. Brunner RL, Gass M, Aragaki A, Hays J, Granek I, Woods N, et al. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial. Arch Intern Med 2005;165(17):1976- 86. 3. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol 1993;168(3 Pt 1):824-30. 4. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Bmj 2008;336(7655):1227-31. 5. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Jama 2007;297(13):1465-77. Competing interests: None declared
Concerned women must be immediately informed 13 June 2008
Edith Schuligoi, leader of support group for women without ovaries Austria Send response to journal: Re: Concerned women must be immediately informed	I am leader of the first support group in Austria for women without ovaries. These Women do need hormones, because oophorectomy makes them loose their own hormonal production by the ovaries. So they would loose their quality of life by loosing the ovaries. And it is really surprising, that some countries in Europe, as FRANCE, always for years have chosen the way to subscribe transdermal oestrogens, and micronised prosgesteron, and the number of oophorectomies is low - and in other countries as in Germany and in Austria this is NOT the case. Many women loose their ovaries and receive oral oestrogens and they don't know anything about these studies!And many gynecologists do still ignore the harm of women in the so called "surgical menopause". Now it seems to be proven that the transdermal way to give hormones is the less harmful one- and so also the concerned women in ALL countries must be immediately informed about this knowledge! I want also respond to Dr. Martina Dören about her rapid response, concerning the loss of quality of life in menopause. She denies in this response the possible loss of quality of life- and she apparently does not know about the great impact of the total loss of the ovaries. These women loose oestrogen, progesteron and androgen production from one minute to the other. The concerned women have to deal with a lot of harmful consequences and these women DO need good, modern hormon therapy, whith the little side effects as possible. So I wish strongly that the results of these studies will be realized as soon as possible for the well being of the concerned women! Edith Schuligoi- support group "femica" Competing interests: None declared
Concepts of Quality of life 23 June 2008
Martina Dören, Professor of Women´s Health Charité-Universitätsmedizin Berlin, D-12200 Berlin Send response to journal: Re: Concepts of Quality of life	The relationships between the use of menopaual hormones and the consecutive reduction of flushes are very well documented by many randomized placebo controlled trials (RCTs), systematic reviews including meta-analyses and health technology assessment (HTA)reports. Hence, quality of life (QoL), depending on outcomes and definitions, does not necessarily improve. Current concepts of QoL, which are neither internationaly agreed upon nor beyond discussion and moreover consensus in the area of research into the menopause, do not include that the reduction of vasomotor symptoms "automatically" result in an improvement of general or health-related QoL. In particular the extensive HTA report by Heidi Nelson´s group (1, 2) states that "Some, but not all trials evaluating sleep, mood and depression, sexual function, and quality of life outcomes also report benefit with estrogen compared to placebo." (quotation). Hence, there is obviously a large variability how QoL is conceptualized. Therefore we should challenge the often heard statement that a reduction in flushes is equal to an improved general? and or health-related? QoL. (1)Nelson HD et al. Management of menopause-related symptoms. Evidence Report / Technology Assessment No. 120 AHRQ Publication No. 05- E016-2. Rockville, MD, 2005 http://www.ahrq.gov/downloads/pub/evidence/pdf/menopause/menopaus.pdf (Chapter 3, Results, pp 28-29) (2)National Institutes of Health State-of-the-Science Conference Statement: Management of menopause-related symptoms. Ann Int Med 2005;142:1003-13 Competing interests: None declared