Transdermal vs.
Oral Estrogen Part Two
by Jeffrey Dach MD
In part one,
we explored the studies which show that transdermal estrogen delivery
is preferable over the oral pill form of delivery. In part two of this
series, we will explore further the studies which explain why oral
estrogen pills are associated with a hypercoagulability and inflammation
causing the observed increase in clots, deep venous thrombosis,
pulmonary embolus, and stroke in young women on “the Pill” and in
post-menopausal women on oral HRT.(1,7) Transdermal estrogen on the
other hand does not cause such effects, making it the safer choice. (1)
Above
left image : Premarin and Prempro are the two most common oral estrogen
pills known to cause blood clot formation. Poster courtesy of Tuesday Horse Files.
Bioidentical HRT- Comparing Oral Vs. Transdermal Estrogen
In
1997, Dr. Scarabin studied bioidentical HRT in post menopausal women.
He compared oral to transdermal estrogen delivery in 45 post-menopausl
women in Paris France. The women were given either oral or transdermal
estradiol, along with natural progesterone, and various parameters of
the coagulation system were studied.
Dr Scarabin concluded: “that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis.” (1)
Avoiding Hepatic First Pass Metabolism
In a 2009 report, Dr Kopper speculates that transdermal is safer and more effective than oral. He says:
“Transdermal drug delivery may
mitigate some of these effects by avoiding gut and hepatic first-pass
metabolism. Advantages of transdermal delivery include the ability to
administer unmetabolized estradiol directly to the blood stream,
administration of lower doses compared to oral products, and minimal
stimulation of hepatic protein production.”(2)
CRP Goes Up with Oral Estrogen
Left Image Prempro pack known to cause blood clots, courtesy of Wyeth, Pfizer.
CRP is a non-specific inflammatory marker which increases risk for heart disease.
After 12 months, the Prempro treated women had a 64% increase in CRP. The Transdermal estradiol/provera combination had only 3% increase in CRP.(3)
A second report published in 2008 by the Milan Group on the same
patient group showed a significant effect on fibrinogen levels.(4) The
oral estrogen group had a 5-fold decrease in fibrinogen for oral pills
(Prempro) compared to transdermal estrogen, ( -5.7% vs, -1.1%)
Reduction in fibrinogen levels indicate activation of the clotting
system, with consumption of clotting factors faster than synthesis.(4)
More on CRP by Dr. Koh
Dr Koh published his observations in 2006 Cardiovascular Research in which he reviewed the medical literature and remarks:(6)
“Orally administered estrogens increase blood CRP levels and maintain sustained increases for up to 3 years .
By contrast, transdermal estradiol in healthy postmenopausal women
significantly lowers CRP levels, or remains unchanged. In premenopausal
women, CRP correlates inversely with blood estradiol concentrations
during the menstrual cycle.” (6)
Oral Estrogen Increased Markers of Hypercoagulability
Published in 2001, Dr Vehkavaarafrom Helsinki Finland studied 27
post-menopausal women on either oral or transdermal estrogen. They
found oral estrogen increased markers of hypercoagulability and CRP, while transdermal estrogen had no such effects.(5)
“oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters.”(5)
Conclusion:
There is overwhelming evidence in the medical literature that oral
estrogen increases markers of hypercoagilbility(7) and CRP, while
transdermal estrogen has no such deleterious effects.
Links and References:
Effects of oral and transdermal estrogen/progesterone regimens on
blood coagulation and fibrinolysis in postmenopausal women. A randomized
controlled trial. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P,
Agher R, Aiach M.
SourceINSERM-Cardiovascular Epidemiology Unit U258, Hôpital Broussais, Paris, France Abstract
Postmenopausal hormone replacement therapy is associated with a
reduction in the incidence of coronary heart disease. However,
inconclusive results have been reported with respect to the risk of
stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen.
There are surprisingly few interventional studies to assess the true
effects of estrogen-progestin regimens on blood coagulation and
fibrinolysis, and the impact of the route of estrogen administration on
hemostasis has not been well documented.
Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment.
Hemostatic variables were assayed at baseline and after a 6-month
period. Pairwise differences in the mean change between the three groups
were compared using nonparametric tests.
Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant.
The oral estrogen group was associated with a significant
decrease in both mean tissue-type plasminogen (t-PA) concentration and
plasminogen activator inhibitor (PAI-1) activity and a significant rise
in global fibrinolytic capacity (GFC) compared with the two other groups.
A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels.
There were no significant changes in mean values of fibrinogen, factor
VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen
between and within the three groups.
We conclude that oral estrogen/progesterone replacement therapy may
result in coagulation activation and increased fibrinolytic potential,
whereas opposed transdermal estrogen appears without any substantial
effects on hemostasis. Whereas these results may account for an
increased risk of venous thromboembolism in users of oral postmenopausal
estrogen, they emphasize the potential importance of the route of
estrogen administration in prescribing hormone replacement therapy to
postmenopausal women, especially to those at high risk of thrombotic
disease.
Drug Des Devel Ther. 2009 Feb 6;2:193-202.
Transdermal hormone therapy in postmenopausal women: a review of
metabolic effects and drug delivery technologies. Kopper NW, Gudeman J,
Thompson DJ.
Source KV Pharmaceutical, 2503 South Hanley Road, St. Louis, MO 63144, USA.
Abstract Vasomotor symptoms (VMS) associated with menopause can
cause significant discomfort and decrease the quality of life for women
in the peri-menopausal and post-menopausal stages of life. Hormone
therapy (HT) is the mainstay of treatment for menopausal symptoms and is
currently the only therapy proven effective for VMS. Numerous HT
options are available to treat VMS, including estrogen-only and
estrogen-progestogen combination products to meet the needs of both
hysterectomized and nonhysterectomized women. In addition to selecting
an appropriate estrogen or estrogen-progestogen combination,
consideration should be given to the route of administration to best
suit the needs of the patient. Delivery systems for hormone therapy
include oral tablets, transdermal patches, transdermal topical
(nonpatch) products, and intravaginal preparations. Oral is currently
the most commonly utilized route of administration in the United States.
However, evidence suggests that oral delivery may lead to some
undesirable physiologic effects caused by significant gut and hepatic metabolism. Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism.
Advantages of transdermal delivery include the ability to administer
unmetabolized estradiol directly to the blood stream, administration of
lower doses compared to oral products, and minimal stimulation of
hepatic protein production. Several estradiol transdermal delivery
technologies are available, including various types of patches, topical
gels, and a transdermal spray.
Circulation. 2002 Sep 3;106(10):1224-8.
Effect of transdermal estradiol and oral conjugated estrogen on
C-reactive protein in retinoid-placebo trial in healthy women. Decensi
A, Omodei U, Robertson C, Bonanni B, Guerrieri-Gonzaga A, Ramazzotto F,
Johansson H, Mora S, Sandri MT, Cazzaniga M, Franchi M, Pecorelli
S.Division of Chemoprevention, European Institute of Oncology, Milan,
Italy.
The increase in C-reactive protein (CRP) during
oral conjugated equine estrogen (CEE) may explain the initial excess of
cardiovascular disease observed in clinical studies. Because the effect
of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes
after 6 and 12 months of transdermal E2 and oral CEE in a randomized
2×2 retinoid-placebo trial.
METHODS AND RESULTS: A total of 189 postmenopausal women were randomized to 50 microg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 microg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE
and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo
(n=49) for 1 year. Sequential medroxyprogesterone acetate was added in
each group. Relative to baseline, CRP increased by 10% (95% CI -9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI -14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE.
CONCLUSIONS:
In contrast to oral CEE, transdermal E2 does not elevate CRP levels
up to 12 months of treatment. The implications for early risk of
coronary heart disease require further studies.
Ecancermedicalscience. 2008;2:67. Feb 6.
The effect of transdermal estradiol or oral conjugated oestrogen
and fenretinide versus placebo on haemostasis and cardiovascular risk
biomarkers in a randomized breast cancer chemoprevention trial. Lazzeroni
M, Macis D, Decensi A, Gandini S, Sandri MT, Serrano D,
Guerrieri-Gonzaga A, Johansson H, Mora S, Daldoss C, Omodei U, Bonanni
B.Source Cancer Prevention and Genetics, European Institute of Oncology,
20141 Milan, Italy.
Abstract BACKGROUND:We have previously reported the favourable
effect of transdermal estradiol (E2), relative to oral conjugated equine
oestrogen (CEE), on ultrasensitive C-reactive protein after 12 months
of treatment in a retinoid-placebo controlled two-by-two randomized
breast cancer prevention trial (Decensi A et al (2002) Circulation106 10
1224-8). Here, we investigate the changes in lipids and clotting profile in patients of the same trial.
METHODS AND RESULTS: Recent post-menopausal women were randomised
to either oral CEE 0.625 mg/day and placebo (n = 55), CEE and
fenretinide 200 mg/day (n = 56), transdermal E2 50 mg/day and placebo (n
= 59) or E2 and fenretinide 200 mg/day (n = 56). Sequential
medroxyprogesterone acetate 10 mg/day was given in each group.
After 12 months, there was a statistically significant effect of
the route of administration of hormone replacement therapy (HRT) on
fibrinogen levels; the median percentage change being -5.7% with CEE and
-1.1% with E2 (p = 0.012).
Total cholesterol decreased in all arms (p < 0.0001). HDL-C
decreased significantly with transdermal E2 (p = 0.006) compared to oral
CEE and with fenretinide relative to placebo (p<0.001).
Triglycerides exhibited an opposite modulation in the HRT route, with a
21.4% median increase with oral CEE and an 8.6% reduction with
transdermal E2 (p < 0.0001). Antithrombin-III showed a 4% borderline
significant reduction in the fenretinide arm relative to placebo,
irrespective of the HRT administration route (p = 0.055).
CONCLUSIONS: Our data indicate that transdermal E2 may be
preferable to oral CEE based on its safer cardiovascular risk profile.
Fenretinide modified some cardiovascular risk biomarkers and confirmed a
safer profile compared to other retinoids.
Thromb Haemost. 2001 Apr;85(4):619-25.
Effects of oral and transdermal estrogen replacement therapy on
markers of coagulation, fibrinolysis, inflammation and serum lipids and
lipoproteins in postmenopausal women. Vehkavaara S, Silveira A,
Hakala-Ala-Pietilä T, Virkamäki A, Hovatta O, Hamsten A, Taskinen MR,
Yki-Järvinen H.
Department of Medicine, University of Helsinki, Finland.Abstract
We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations.
We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations.
Oral therapy increased the plasma concentrations of factor VII
antigen (FVIIag) and activated factor VII (FVIIa), and the plasma
concentration of the prothrombin activation marker prothrombin fragment
1+2 (F1+2).
Oral but not transdermal estradiol therapy significantly lowered
plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type
plasminogen activator (tPA) antigen concentrations and PAI-1 activity,
and increased D-dimer concentrations, suggesting increased fibrinolysis.
The concentration of soluble E-selectin decreased and serum
C-reactive protein (CRP) increased significantly in the oral but not in
the transdermal or placebo groups. In the oral but not in the
transdermal or placebo estradiol groups low-density-lipoprotein (LDL)
cholesterol, apolipoprotein B and lipoprotein (a) concentrations
decreased while high-density-lipoprotein (HDL) cholesterol,
apolipoprotein AI and apolipoprotein All concentrations increased
significantly. LDL particle size remained unchanged.
In summary, oral estradiol increased markers of
fibrinolytic activity, decreased serum soluble E-selectin levels and
induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations.Transdermal estradiol or placebo had no effects on any of these parameters.
6) http://www.ncbi.nlm.nih.gov/pubmed/16412400
Cardiovasc Res. 2006 Apr 1;70(1):22-30. Epub 2006 Jan 17.
Controversies regarding hormone therapy: Insights from inflammation and hemostasis. Koh KK, Yoon BK. Source Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Medical Center, Gachon Medical School, Incheon, Korea.
Abstract Many observational studies and experimental and animal studies have demonstrated that estrogen therapy (ET) or hormone therapy (HT) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials and the Nurses’ Health Study in secondary prevention demonstrate trends toward an increased risk of cardiovascular events rather than a reduction of risk from HT. HT has both anti-inflammatory and pro-inflammatory effects, and it activates coagulation and improves fibrinolysis. These effects depend on the route of administration, doses of estrogen, age of women, and the presence of coronary artery disease or the coexistence of other risk factors for hypercoagulability. In this review, we discuss effects of HT on markers of inflammation, hemostasis, and fibrinolysis that may link endothelial dysfunction in cardiovascular diseases. We also briefly discuss effects of lower doses of HT and tibolone in postmenopausal women.
Cardiovasc Res. 2006 Apr 1;70(1):22-30. Epub 2006 Jan 17.
Controversies regarding hormone therapy: Insights from inflammation and hemostasis. Koh KK, Yoon BK. Source Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Medical Center, Gachon Medical School, Incheon, Korea.
Abstract Many observational studies and experimental and animal studies have demonstrated that estrogen therapy (ET) or hormone therapy (HT) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials and the Nurses’ Health Study in secondary prevention demonstrate trends toward an increased risk of cardiovascular events rather than a reduction of risk from HT. HT has both anti-inflammatory and pro-inflammatory effects, and it activates coagulation and improves fibrinolysis. These effects depend on the route of administration, doses of estrogen, age of women, and the presence of coronary artery disease or the coexistence of other risk factors for hypercoagulability. In this review, we discuss effects of HT on markers of inflammation, hemostasis, and fibrinolysis that may link endothelial dysfunction in cardiovascular diseases. We also briefly discuss effects of lower doses of HT and tibolone in postmenopausal women.
7) http://www.ncbi.nlm.nih.gov/pubmed/11372667
Thromb Haemost. 2001 May;85(5):775-81.
The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism–results from a randomized, double-blind, clinical trial. Høibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. Source Department of Hematology, Ullevål University Hospital, Oslo, Norway.In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69).
Thromb Haemost. 2001 May;85(5):775-81.
The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism–results from a randomized, double-blind, clinical trial. Høibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. Source Department of Hematology, Ullevål University Hospital, Oslo, Norway.In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69).
HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation
was higher in those women who subsequently developed recurrent
thrombosis, but was similar in carriers and non-carriers of the factor V
Leiden mutation. HRT had no effects on fibrinogen and factor VIII.
Activated factor VII, but not factor VII antigen, decreased
significantly on HRT as compared with placebo. The coagulation
inhibitors antithrombin, protein C, and TFPI, but not protein S, all
showed significant sustained decreases in the HRT group as
compared with placebo. Antithrombin and protein C decreased by 8-12% on
HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by
29-30%. In multivariate analysis, only TFPI activity was a significant
predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.
Images:
http://commons.wikimedia.org/wiki/File:Estrogen_patch.jpg
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http://www.horsefund.org/pmu-faq.php
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