of Transdermal Estrogen
by Jeffrey Dach MD
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.
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
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 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
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
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
Author: Jeffrey Dach MD
Links and References
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,
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
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.
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
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.
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
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.
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
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
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
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.
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
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.
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
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
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
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
7450 Griffin Road, Suite 190
Davie, Fl 33314
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