Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39555.441944.BE (Published 29 May 2008) Cite this as: BMJ 2008;336:1227All rapid responses
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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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests