The Safety of Transdermal Estrogen

by Jeffrey Dach MD

This article is Part One.For Part Two, Click Here.

Left Image: Red Arrow points to clot in deep vein, Ultrasound image, courtesy of wikimedia commons and (c) Nevit Dilmen.

A Case of Chronic Calf Swelling

Rebecca, a forty year old housewife came into the office to see me about various complaints related to mood, poor quality sleep and weight gain.  She had been on birth control pills for 20 years to “regulate her menstrual cycles” which prior to the BCP’s had been very irregular.   About two years ago after a long airplane flight, while shopping on vacation, she noticed her right calf was significantly larger than her left.  Shortly thereafter, she noticed an aching, heavy feeling in the enlarged calf,  When she returned home, she had ultrasound and CAT testing which was negative for acute deep venous thrombosis, and no treatment was offered.

I explained to Rebecca her calf swelling and discomfort are symptoms of a healed clot formation in the deep vein that has resolved causing incompetent valves and chronic venous insufficiency.  This is a complication of the birth control pills, the aftermath of an episode of deep venous thrombosis of the deep vein of the right calf vein.  The blood clot has dissolved, and the vein has recanalized, explaining why the imaging tests showed normal findings. As bad as this may be, it is actually a far better outcome than pulmonary embolus and stroke which may be caused by birth control pills, a far worse outcome.

Oral BCPs – Ninefold Increase in Stroke

One of the major adverse effects of oral birth control pills is the increased coagulation and blood clot formation which may cause DVT (deep venous thrombosis), pulmonary embolus and stroke.  Oral contraceptive use (BCPs) is associated with a ninefold increased risk of stroke (cerebral infarction) in women.(10)  Oral contraceptives (BCPs) alter platelet aggregation, enhance antithrombin III activity, decrease serum antithrombin levels, and increase the levels of certain coagulation factors, especially factor VII.(10)

Adverse Effect is a Reason to Discontinue BCP’s

An adverse effect such as clot formation is certainly a good reason to discontinue birth control pills and switch to a more natural alternative,  Treatment with cyclic progesterone capsules on days 12-26 of the menstrual cycle is one such alternate treatment which restores normal cycles.  Good thyroid function is required for regular ovulatory cycles, and this is also evaluated and addressed.

Transdermal Estrogen

You might ask, is there a safer way to take hormones, not associated with blood clot formation?  The answer is yes.  The  safer method of delivery is transdermal.  In this method, the hormone comes in a skin cream or skin patch as a topical preparation applied to the skin.

BMJ Study by Renoux

A well designed study  by Dr. Renoux in the 2010 BMJ compared oral and transdermal estrogen at both high and low dosage. Dr Renoux found no increased stroke with the low dose transdermal estrogen skin patches compared to non-users.  The oral estrogen pills at both low dose and high dose, as well as the the high dose transdermal estrogen patch were all associated with increased coagulation and stroke. (1,2)

Dr Speroff Speaks

As Dr Speroff points out in his editorial in Climacteric, the Renoux BMJ study is reassuring in that low dose topical estrogen was not associated with increased coagulation, clots and stroke.(1)  However, Dr. Speroff  advises caution with high dose topical estrogen preparations which showed similar tendency for increased coagulation as the oral estrogen pills.

We still don’t have these types of studies for commonly used topical hormone preparations containing combined hormone formulations such as Bi-Est which is 20% estradiol and 80 % estriol.  Until then we will have to rely on the Renoux study.  The Renoux study used topical patches as shown below:

Oral Estrogen Pills used in the BMJ Renoux Study:

Oral low dose products contained ≤0.625 mg of equine oestrogen (Premarin)
or ≤2 mg of estradiol.

Oral High dose products contained >0.625 mg of equine oestrogen
or >2 mg of estradiol;

Transdermal Preparations

Transdermal low dose products contained ≤50 μg of oestrogen.
Transdermal High dose products contained >50 μg of estrogen.

The low dose transdermal estrogen patch was not associated with increaed coagulation and stroke.  The high dose patches and the oral pills, however, showed increased incidence of blood clots and stoke (1,2)

Inherited Thrombophilia –
A Contra-Indication Against Use of Birth Control Pills

Some women have a genetic mutation which increases the risk for blood clots.  This is called thrombophilia, and the two most common genetic mutations are the Leiden mutation of factor V and the G20210A mutation of prothrombin. (3)

Studies show that many of women suffering blood clots while on birth controls pills have an underlying genetic thrombophila, an inherited tendency to form clots, which places them at greater risk.  Obviously, these women should avoid birth control pills and any other medications that cause blood clot formation. One might argue the case for routine screening for inherited thrombophila in all young women before starting oral birth control pills. (3,4,5,6)

In addition, women suffering from DVT or blood clot formation while on BCP’s or any form of  HRT should have thrombophila screening testing.(4)

Dr Caprini from Northwestern reported on thrombophila screening in the 2005 European Journal of Vascular Endovascualr Surgery(4)  Dr. Caprini screened 166 women presenting with venous thrombosis, and found two thirds had abnormal findings on thromophila screening.  One quarter (23%) were positive for Factor V  Leiden (FVL) genetic mutation.

Dr. Caprini’s Thrombophilia Testing Panel included (4):
Factor V Leiden (FVL),
Prothrombin 20210A mutation (P2),
methylene tetrahydrofolate reductase deficiency (MTHFR),
fasting serum homocysteine (HC),
lupus anticoagulant (LA),
anticardiolipin antibodies (ACA),
antithrombin deficiency (AT),
protein S deficiency (PS), and
protein C deficiency (PC).”

Cerebral Vein Thrombosis Associated with Inherited Thrombophilia

Dr. Ida Martinelli reported in the 1998 NEJM on 40 patients with idiopathic cerebral-vein thrombosis.   Patients were screened for inherited thrombophilia.

20% of the patients with cerebral-vein thrombosis were carriers of the prothrombin-gene mutation, and 15% had the Factor V mutation.  Dr Martinelli advises against use of oral contraceptives in these patients.(9)

Articles with Related Interest:

This article is Part One.  For Part Two Click Here.

Author: Jeffrey Dach MD

Links and References

1) http://www.ncbi.nlm.nih.gov/pubmed/20670199

Climacteric. 2010 Oct;13(5):429-32.  Transdermal hormone therapy and the risk of stroke and venous thrombosis. Speroff L.  Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, USA.

Recent case-control and cohort studies have indicated that the transdermal administration of postmenopausal estrogen therapy is not associated with an increased risk of cardiovascular complications, specifically stroke and venous thrombosis. These studies have prompted the clinical promotion of transdermal treatment as ‘safer’. There are reasons, however, to be cautious regarding postmenopausal transdermal hormone therapy, especially in regard to stroke. Previous reports linking postmenopausal estrogen therapy and the risk of stroke have not yielded consistent results, finding it difficult to adjust for all confounding factors, including compliance with treatment. Age of the population studies may be a critical issue. Notably, the risk of stroke with oral estrogen was not increased in the Women’s Health Initiative when women with prior cardiovascular disease or those older than 60 years were excluded. There does appear to be a dose-response relationship with stroke, similar to that observed with estrogen-progestin contraceptives, and this may be a problem when studying standard doses of transdermal treatment, in that many women receiving transdermal estrogen display lower estrogen blood levels when compared with oral treatment. Clinicians should administer low doses of estrogen to women with risk factors for stroke, and the transdermal route of administration is indicated for women at high risk for venous thrombosis and for older postmenopausal women, especially for women with stroke risk factors. In a recent study, Renoux and colleagues from McGill University in Montreal performed a nested case-control study deriving the data from a cohort of women in the UK General Practice Research Database (GPRD).

Current use of oral and transdermal hormone therapy, based on recorded prescriptions, was compared to no use in 15 710 cases and 59 958 controls. The adjusted rate ratio (RR) for stroke for current use of transdermal estrogens, with or without a progestin, was not increased (RR 0.95; 95% confidence interval (CI) 0.75-1.20) compared with a significant increase associated with oral estrogen, with or without a progestin (RR 1.28; 95% CI 1.15-1.42). This would amount to an attributal risk of 0.8 additional strokes per 1000 women per year. There was an indication of a dose-response relationship; a significant increase in risk was observed with transdermal estrogen doses greater than 50 microg.

The case-control study by Renoux and colleagues is the first major analysis to compare transdermal and oral hormone therapy and conclude that, compared with an increased risk of stroke with oral therapy, there was no increased risk with transdermal treatment at a dose of 50 microg or less.

This report is about as strong an observational study as can be achieved.

Large numbers of cases (15 710) and controls (59 958) were available for analysis using the well-known UK GPRD. The use of this computerized database precludes selection bias by the investigators and recall bias by the women in the study. The results support the growing conventional wisdom that transdermal therapy at standard doses is free of the cardiovascular risks associated with oral therapy.

2) http://www.bmj.com/content/340/bmj.c2519?view=long&pmid=20525678
http://www.ncbi.nlm.nih.gov/pubmed/20525678
BMJ. 2010 Jun 3;340:c2519.
Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study.Renoux C, Dell’aniello S, Garbe E, Suissa S.
McGill Pharmacoepidemiology Research Unit, Center for clinical epidemiology, Jewish General Hospital, Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada H3T 1E2.

To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy.DESIGN:Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date.
RESULTS:

There were 15,710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. T

he risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)).

Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose.

CONCLUSIONS:  The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.

3) http://www.ncbi.nlm.nih.gov/pubmed/18501222

Am J Med. 2008 Jun;121(6):458-63. doi: 10.1016/j.amjmed.2007.10.042.
Should patients with venous thromboembolism be screened for thrombophilia?
Dalen JE.  University of Arizona, 1840 E River Road, Suite 120, Tucson, AZ 85718, USA.

In the mid-19th century, Virchow identified hypercoagulability as part of the triad leading to venous thrombosis, but the specific causes of hypercoagulability remained a mystery for another century. The first specific cause to be identified was antithrombin III deficiency. Many other causes of thrombophilia, both genetic and acquired, have been discovered since then. The 2 most common genetic causes of thrombophilia are the Leiden mutation of factor V and the G20210A mutation of prothrombin. The most common acquired cause is antiphospholipid syndrome. These factors increase the relative risk of an initial episode of venous thromboembolism (VTE) by a factor of 2 to 10, but the actual risk remains relatively modest. Therefore, thrombophilia screening to prevent initial episodes of VTE is not indicated, except possibly in women with a family history of idiopathic VTE who are considering oral contraceptive therapy. Some physicians screen for thrombophilia to aid decision making concerning the duration of anticoagulant therapy. However, several studies have demonstrated that, with the exception of antiphospholipid syndrome, thrombophilia does not significantly increase the risk of recurrent VTE. On the other hand, idiopathic VTE significantly increases the risk of recurrence in patients with or without thrombophilia.

4) http://www.ncbi.nlm.nih.gov/pubmed/16055356
http://www.ejves.com/article/S1078-5884%2805%2900371-0/fulltext
Eur J Vasc Endovasc Surg. 2005 Nov;30(5):550-5. Epub 2005 Aug 1.
Thrombophilia testing in patients with venous thrombosis.
Caprini JA, Goldshteyn S, Glase CJ, Hathaway K. Source Department of Surgery, Evanston Northwestern Healthcare, Evanston, IL 60201,

Routine thrombophilia testing is controversial because of the low yield of positive tests, costs involved, and debate about the clinical usefulness of the data obtained from testing. Laboratory investigations are rarely done for those with superficial venous thrombosis (SVT) or isolated calf vein thrombosis (CVT) which are often not treated with anticoagulants.

OBJECTIVE:  To identify the incidence of markers of thrombophilia in patients with deep vein thrombosis (DVT), SVT, isolated CVT or a history of thrombosis in a referral practice.

METHODS:  One hundred and sixty-six patients were referred to our thrombosis unit for consultation, including patients with SVT, DVT, and preoperative patients with a previous history of SVT or DVT. Patients underwent thrombophilia screening and patients with a diagnosis of SVT or DVT were confirmed by bilateral duplex ultrasonography of all lower limb veins. Thrombophilia testing included factor V Leiden (FVL), prothrombin 20210A mutation (P2), methylene tetrahydrofolate reductase deficiency (MTHFR), fasting serum homocysteine (HC), lupus anticoagulant (LA), anticardiolipin antibodies (ACA), antithrombin deficiency (AT), protein S deficiency (PS), and protein C deficiency (PC).
RESULTS:  The incidence of any significant abnormality in patients with DVT was 27/44 (61%; 95% Confidence interval [CI], 47-76%) and 10 of these patients were positive for FVL (23%; 95% CI, 10-35%).

Twelve patients with isolated CVT were seen and five had at least one abnormality (42%; 95% CI, 14-70%) including one with FVL (8%; 95% CI, 0-24%). Thirty-nine patients with isolated SVT were seen including 14 with at least one abnormality (36%; 95% CI, 21-51%) and five of these patients with SVT had FVL (13%; 95% CI, 2-23%). Nine patients with recurrent DVT were seen and five of these had at least one abnormal test (56%; 95% CI, 23-88%). Finally, 18 of the 166 patients had more than one abnormality (11%; 95% CI, 6-16%).

CONCLUSION: The presence of one or more markers of thrombophilia was significantly higher in this patient population compared to reports from other centres. This study identified 18/166 (10.8%; 95% CI, 6-16%) with more than one defect where life-long anticoagulation might be considered. The results in this subset of patients as well as the serious defects found in some patients with provoked DVT, isolated CVT or isolated SVT demonstrate the value of this screening program to both these patients and their blood relatives. On the other hand, this is a small series from a referral practice where the incidence of these defects is greater than one would expect in the general population. These studies are preliminary and it is not recommended that all VTE patients should be screened on the basis of the current report.

5) http://www.ejves.com/medline/record/ivp_14248832_32_315
Pathophysiol Haemost Thromb ; 32:315-7.
Thrombophilia in young women candidate to the pill: reasons for and against screening.   Cosmi B, Coccheri S

Screening for thrombophilia in women candidate to the pill is still a matter of debate. Oral contraceptives may trigger venous thromboembolic events in carriers of common inherited thrombophilic defects.  General screening is not cost-effective from an epidemiological point of view if the objective is to prevent death due to venous thromboembolism during oral contraception (OC).
However, clinicians deal with single patients and personal and/or family history for venous thromboembolism have limited value for identifying those women at risk of VTE complications during OC. A pharmacogenetics approach in prescribing OC on the basis of each woman’s genetic make-up could increase drug safety. A proper evaluation of the cost-effectiveness, the medical,psychosocial and legal consequences is needed before general screening with genetic testing for inherited thrombophilia can be recommended before OC.

6) http://www.ncbi.nlm.nih.gov/pubmed/16681418
Clin Chem Lab Med. 2006;44(5):514-21.
Factor V Leiden, prothrombin G20210A substitution and hormone therapy: indications for molecular screening. Andreassi MG, Botto N, Maffei S.
Laboratory of Cellular Biology and Genetics, CNR-Institute of Clinical Physiology, G. Pasquinucci Hospital, Via Aurelia Sud-Montepepe, 54100 Massa, Italy.

Venous thromboembolism is a well-known complication of oral contraception and hormonal replacement therapy. Inherited thrombophilia is viewed as an important determinant in modulating the effects of estrogens on thrombotic risk. An increasing number of kits for thrombophilic mutations [factor V Leiden, G20210A prothrombin and methylenetetrahydrofolate reductase (MTHFR) C677T genes] are becoming commercially available, and screening for inherited thrombotic risk is among the most requested genetic tests in molecular diagnostic laboratories. However, the question of routine genetic screening for thrombophilia before prescribing hormones is still a matter of debate. The purpose of this article is to discuss the usefulness and practical applications of thrombotic genetic testing to identify which women should be tested to improve both the safety and efficacy of individualized estrogen therapy.

7) http://www.ncbi.nlm.nih.gov/pubmed/16113779
Thromb Haemost. 2005 Jul;94(1):17-25.
Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.
Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P, Greaves M, Walker ID, Brenkel I, Regan L, Greer IA.  Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy.

For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41).

For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.\

8) Thrombosis of GSV and tributaries 2012     Nevit Dilmen
Image: © Nevit Dilmen found at Wikimedia commons
http://commons.wikimedia.org/wiki/File:Great_saphenous_vein_thrombosis_05091312009.jpg

9) http://www.nejm.org/doi/full/10.1056/nejm199806183382502
High Risk of Cerebral-Vein Thrombosis in Carriers of a Prothrombin-Gene Mutation and in Users of Oral Contraceptives
Ida Martinelli, M.D., Ph.D., Elisabetta Sacchi, M.D., Gianluca Landi, M.D., Emanuela Taioli, M.D., Francesca Duca, B.Sc., and Pier Mannuccio Mannucci, M.D. N Engl J Med 1998; 338:1793-1797

The risk of venous thrombosis of the lower extremities is increased by factors that cause hypercoagulability or venous stasis, such as the use of oral contraceptives, pregnancy or the postpartum state, surgery, trauma, and prolonged immobilization. The risk of venous thrombosis is also increased by hypercoagulable states due to inherited abnormalities of the coagulation system, such as the G1691A mutation in the factor V gene, which causes resistance to activated protein C, and deficiencies of antithrombin, protein C, or protein S. Acquired abnormalities such as the presence of antiphospholipid antibodies are also associated with an increased risk of venous thrombosis.1 The recent discovery of a transition from guanine to adenine at position 20210 in the sequence of the 3′ untranslated region of the prothrombin gene has widened the spectrum of inherited thrombophilia.2 Next to the mutation in the factor V gene,3,4 the prothrombin-gene mutation is the most common genetic determinant of deep-vein thrombosis of the lower extremities.2 Cerebral-vein thrombosis is a frightening event because of the severity of the clinical manifestations and the high mortality rate, estimated to be 5 to 30 percent.5-7 Clinically, cerebral-vein thrombosis presents with a wide range of symptoms, including headache, focal deficits (motor or sensory), dysphasia, seizures, and impaired consciousness. Idiopathic cerebral-vein thrombosis (i.e., that occurring in the absence of infection, trauma, tumors, or autoimmune disease) represents a large proportion of cases (approximately 30 percent).6

10) http://www.ncbi.nlm.nih.gov/pubmed/2309261
Stroke. 1990 Mar;21(3):382-6. Stroke in young adults. Bevan H, Sharma K, Bradley W.  Department of Neurology, University of Vermont, Burlington.
The use of oral contraceptives is associated with a ninefold increased risk of cerebral infarction in women.15 The Collaborative Group for the Study of
Stroke in Young Women found that the risk of stroke with the use of oral contraceptives rose sharply in women with hypertension or migraine and those who were heavy smokers.1516 Oral contraceptives alter platelet aggregation, enhance antithrombin III activity, decrease serum antithrombin levels, and increase
the levels of certain coagulation factors, especially factor VII.9

 

Jeffrey Dach MD
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