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  Pregnant Mares and HRT – The Bad News Keeps on Coming Posted on Nov 19, 2010 by Jane Allin Written Chief Research Analyst

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 writes:

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)

In 2018, Dr. Scarabin did an updated meta-analysis of the medical literature on this question finding when comparing oral route to transdermal route, the oral estrogen carries a 48 percent increased risk of venous thromboembolism (VTE), with the relative risk (RR) 1.48. The added progestogen agent (progesterone vs MPA) also makes a difference in VTE risk. The transdermal estradiol combined with progesterone is the safest, with no increased risk of VTE. However, when synthetic progestins such as MPA are added to oral estrogen as in the Prempro pill (CEE +MPA) the risk of VTE goes up almost 3-fold. (RR 2.77). Dr. Scarabin writes:

Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE risk, there is also increasing evidence that progestogens may modulate the estrogen-related VTE risk. This review updates previous meta-analyses of VTE risk in HT users, focusing on the route of estrogen administration, hormonal regimen and progestogen type. Among women using estrogen-only preparations, oral but not transdermal preparations increased VTE risk (relative risk (RR) 1.48, 95% confidence interval (CI) 1.39-1.58; RR 0.97, 95% CI 0.87-1.09, respectively). In women using opposed estrogen, results were highly heterogeneous due to important differences between the molecules of progestogen. In transdermal estrogen users, there was no change in VTE risk in women using micronized progesterone (RR 0.93, 95% CI 0.65-1.33), whereas norpregnane derivatives were associated with increased VTE risk (RR 2.42, 95% CI 1.84-3.18). Among women using opposed oral estrogen, there was higher VTE risk in women using medroxyprogesterone acetate (RR 2.77, 95% CI 2.33-3.30) than in those using other progestins. These clinical findings, together with consistent biological data, emphasize the safety advantage of transdermal estrogen combined with progesterone and support the current evidence-based recommendations on HT, especially in women at high VTE risk. (14)

In 2020, Dr. Pierre-Yves Scarabin responded to an editorial by Dr Felice Gersh, repeating the transdermal route avoids first pass through the liver, is not associated with clot formation, and is the safest way to administer estrogen. Delivery of estrogen by oral pills is associated with first pass through the liver and increases thrombogenicity (clot formation). Dr Scarabin says women should be encouraged to use estrogen and progesterone as the preferred hormones, and transdermal as the preferred route of delivery, writing:

Oral but not trans-dermal estrogens result in a hepatic first- pass effect that may induce reversible prothrombotic changes in haemostatic variables,2 including resistance to activated protein C. Thrombotic process plays a critical role in the development of both venous and arterial diseases. European studies have clearly shown the advantage of transdermal oestrogens with respect to the risk of venous thrombo-embolism and probably also stroke. The type of progestogens has also emerged as an important determinant of thrombosis. Progesterone has no effect on blood coagulation, and it is the safest progestogen with respect to thrombosis. Since thrombosis is one main serious adverse effect of hormone therapy, women should be encouraged to use transdermal oestrogens combined with progesterone. (8) (13-14)

Avoiding Hepatic First Pass Metabolism

In a 2009 report, Dr. Kopper speculates that transdermal is safer and more effective than oral estrogen.  Dr. Kopper writes:

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 (Premarin/MPA) manufactured by Wyeth,Displayed for educational purposes. Boxed Warning.  courtesy of Drugs.com Pill Identifier. 

Published in 2002 in Circulation, Dr Decensi from Milan, Italy studied changes in CRP in 189 postmenopausal women randomized to either oral CEE(Premarin)/provera or to transdermal Estradiol/provera.(3)

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)

Fibrinogen Levels 5 Times Lower with Oral Estrogen

In 2008, Dr. M. Lazzeroni from Milan, Italy studied post-menopausal women given either oral or transdermal estrogen, oral CEE (Premarin) vs placebo, and transdermal estradiol (E2, 50 mcg/day) vs. placebo. Sequential MPA (medroxyprogesterone10 mg/day) was also given to each treatment group. 55 women were randomized in each group. The oral estrogen group (CEE + MPA) had a 5-fold decrease in fibrinogen compared to the transdermal estradiol group, ( -5.7% vs, -1.1%)  A decrease in fibrinogen levels indicates activation of the clotting system with consumption of clotting factors. This indicates increased clot formation. Obviously this is a bad thing leading to deep venous thrombosis. Dr. M. Lazzeroni  concludes that transdermal estrogen is safer and preferable to oral estrogen, writing:

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)…Our data indicate that transdermal E2 may be preferable to oral CEE based on its safer cardiovascular risk profile. (4)

Above Left Image Prempro (Premarin + MPA  medroxyprogesterone) pack known to cause blood clots, courtesy of drugs.com. Displayed for educational purposes. Boxed Warning.

More on CRP by Dr. Koh

Dr Koh published his observations in 2006 Cardiovascular Research in which he reviewed the medical literature and writes:

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 Increases Markers of Hypercoagulability

In 2001, Dr Vehkavaara from from 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, writing:

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)

Using Oral Contraceptive Pills to Manage Menopause

Treatment with oral contraceptive pills is not recommended as hormone therapy (HT) in post-menopausal (PM) women because it causes blood clots and hypertension. In 2021, Dr. Felice Gersh writes:

Of note, oral contraceptives contain ethinyl oestradiol and various progestins, are thrombophilic [induces blood clots] and predispose to hypertension…Oral contraceptives are not recommended as HT in PM women and must be used cautiously, with individualised risk management, during the menopausal transition. (9-11)

Conclusion: There is overwhelming evidence in the medical literature that transdermal route for delivery of estrogen is the safest with no increase in VTE. Also the choice of added progestagen plays an important role. Adding natural micronized progesterone to the transdermal estradiol is safe with no increased risk of VTE. However, adding MPA to oral estrogen (CEE) increases risk for venous thromboembolism by almost three-fold. (1-14) Note: VTE=Venous Thromboembolism, MPA=medroxyprogesterone.

Articles with related interest:

The Safety of Transdermal Estrogen Part One

All articles on Bio-Identical Hormones by Jeffrey Dach MD

Jeffrey Dach MD
7450 Griffin Road, Suite 180
Davie, Fl 33314
954-792-4663

Links and References:

1) Scarabin, Pierre-Yves, et al. “Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women: a randomized controlled trial.” Arteriosclerosis, thrombosis, and vascular biology 17.11 (1997): 3071-3078.

Source INSERM-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.

2) Kopper, Nathan W., Jennifer Gudeman, and Daniel J. Thompson. “Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies.” Drug design, development and therapy (2009): 193-202.

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.

3) Decensi, Andrea, et al. “Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women.” Circulation 106.10 (2002): 1224-1228.

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.

4) Lazzeroni, M., et al. “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.” ecancermedicalscience 2 (2008).

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.

5) Vehkavaara, Satu, et al. “Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.” Thrombosis and haemostasis 85.04 (2001): 619-625.

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.

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) Koh, Kwang Kon, and Byung-Koo Yoon. “Controversies regarding hormone therapy: Insights from inflammation and hemostasis.” Cardiovascular research 70.1 (2006): 22-30.

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) Høibraaten, Else, et al. “The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism–results from a randomized, double-blind, clinical trial.” Thrombosis and haemostasis 85.05 (2001): 775-781.

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.

8) Scarabin, Pierre-Yves, et al. “Menopause and hormone therapy in the 21st century: why promote transdermal estradiol and progesterone?.” Heart 106.16 (2020): 1278-1.

Oral but not trans-dermal oestrogens result in a hepatic first- pass effect that may induce reversible prothrombotic changes in haemostatic variables,2 including resistance to acti-vated protein C (figure 1). Thrombotic process plays a critical role in the develop-ment of both venous and arterial diseases. European studies have clearly shown the advantage of transdermal oestrogens with respect to the risk of venous thrombo-embolism3 and probably also stroke. The type of progestogens has also emerged as an important determinant of thrombosis. Progesterone has no effect on blood coag-ulation,2 and it is the safest progestogen with respect to thrombosis.4 Since throm-bosis is one main
serious adverse effect of hormone therapy, women should be encouraged to use transdermal oestrogens combined with progesterone.

9) Gersh, Felice L., James H. O’Keefe, and Carl J. Lavie. “Postmenopausal hormone therapy for cardiovascular health: the evolving data.” Heart 107.14 (2021): 1115-1122.

Of note, oral contraceptives contain ethinyl oestradiol and various progestins, are thrombophilic w4 and predispose to hypertension…Oral contraceptives are not recommended as HT in PM women and must be used cautiously, with individualised risk management, during the menopausal transition.

10) Liu, Hui, et al. “Association between duration of oral contraceptive use and risk of hypertension: a meta‐analysis.” The Journal of Clinical Hypertension 19.10 (2017): 1032-1041.

11) Cameron, Natalie A., Ciantel A. Blyler, and Natalie A. Bello. “Oral contraceptive pills and hypertension: a review of current evidence and recommendations.” Hypertension 80.5 (2023): 924-935.

12) Abdelhafez, Mohsen MA, et al. “Menopausal hormone therapy and risk of venous thromboembolism: The story so far.” African journal of reproductive health 28.3 (2024): 122-129.

13) Scarabin P-Y, Oger E, Plu-Bureau G, et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–32.

Background: Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk.

Methods: We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999-2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment.

Findings: Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3.5 (95% CI 1.8-6.8) and 0.9 (0.5-1.6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4.0 (1.9-8.3).

Interpretation: Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.

14) Scarabin P-Y. Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric 2018;21:341–5.

Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE risk, there is also increasing evidence that progestogens may modulate the estrogen-related VTE risk. This review updates previous meta-analyses of VTE risk in HT users, focusing on the route of estrogen administration, hormonal regimen and progestogen type. Among women using estrogen-only preparations, oral but not transdermal preparations increased VTE risk (relative risk (RR) 1.48, 95% confidence interval (CI) 1.39-1.58; RR 0.97, 95% CI 0.87-1.09, respectively). In women using opposed estrogen, results were highly heterogeneous due to important differences between the molecules of progestogen. In transdermal estrogen users, there was no change in VTE risk in women using micronized progesterone (RR 0.93, 95% CI 0.65-1.33), whereas norpregnane derivatives were associated with increased VTE risk (RR 2.42, 95% CI 1.84-3.18). Among women using opposed oral estrogen, there was higher VTE risk in women using medroxyprogesterone acetate (RR 2.77, 95% CI 2.33-3.30) than in those using other progestins. These clinical findings, together with consistent biological data, emphasize the safety advantage of transdermal estrogen combined with progesterone and support the current evidence-based recommendations on HT, especially in women at high VTE risk.

=================================================

15) Canonico, Marianne, et al. “Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen.” Stroke 47.7 (2016): 1734-1741.

We set up a nested case–control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01–2.49) in oral estrogen users and 0.83 (0.56–1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49–1.26), pregnanes (OR, 1.00; 95% CI, 0.60–1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62–2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05–4.81).

16) Stephenson, Kenna, Pierre F. Neuenschwander, and Anna K. Kurdowska. “The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women.” International journal of pharmaceutical compounding 17.1 (2013): 74-85.

Menopause impacts 25 million women world wide each year, and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030. Menopause has been associated with symptoms of hot flashes, night sweats, dysphoric mood, sleep disturbance, and conditions of cardiovascular disease, depression, osteoporosis, osteoarthritis, depression, dementia, and frailty. Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women’s Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors. Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long-term studies of this treatment model are lacking. The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol, estradiol, progesterone, DHEA, and testosterone on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality-of-life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. A prospective, cohort, closed-label study received approval from the Human Subjects Committee. Recruitment from outpatient clinics at an academic medical center and the community at large resulted in three hundred women giving signed consent. Seventy-five women who met strict inclusion/exclusion criteria were enrolled. Baseline hormone evaluation was performed along with baseline experimental measures. Following this, women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and/or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women. The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic, ischemic, or neuronal injury. Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of androgens of DHEA and Testosterone if indicated. Experimental subjects were monitored for 36 months. Baseline, 2-month, and annual values were obtained for: blood pressure, body mass index, fasting glucose, Homeostasis Metabolic Assessment of Insulin Resistance (HOMA-IR), fasting triglycerides, total Factor VII, Factor VIII, fibrinogen, Antithrombin III, Plasminogen Activator Inhibitor1(PAL-1), C-reactive protein (CRP), Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Tumor Necrosis Factor-alpha (TNF), Insulin-like Growth Factor (IGF-1), and sex steroid levels. Psychosocial measures included: Greene Climacteric Scale, Visual Analog Pain Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Holmes Rahe Stress Scale, Job Strain, and Home Strain. Health outcome measures included the number of prescribed medications used, number of co-morbidities, and endometrial thickness in postmenopausal women with intact uteri. Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co-morbidities and a number of prescribed medications. Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition.

=========================================

http://commons.wikimedia.org/wiki/File:Estrogen_patch.jpg

http://tuesdayshorse.files.wordpress.com/2010/10/expandable_poster.png
http://www.horsefund.org/pmu-faq.php

Last updated on September 29th, 2024 by Jeffrey Dach MD