Hormone Replacement Therapy – Is it Contraindicated in Patients with Polymorphisms in Clotting Factors?
Overview
We consider the use of hormone replacement therapy in patients who have risk factors for thrombosis due to genetic, or other risk factors. Estrogen therapy is often discouraged for those with genetic clotting risk factors due to putative increased blood clotting risk. However, the vast majority of studies looking at this connection have been cohorts of women using birth control, estrogen receptor modulators, estrogens with progestins, in vitro fertilization, or other non-natural forms of hormone therapy. Hormone therapy aimed at replacing physiologic doses of hormones has a much safer risk profile when used appropriately.
Copyright 2019 by Robert Stephens
Background
Hormone replacement therapy is widely used among perimenopausal and menopausal women for symptomatic relief of menopause symptoms, and possibly reducing age-related osteoporosis and cognitive decline. Concern has been raised about the possible increased risk of thrombosis and certain hormones, and whether HRT is contraindicated in patients with risk factors.
Venous Thrombosis Risk
Genetic testing allows consumers to access genetic data which may uncover risk factors to diseases. A few companies provide inexpensive saliva testing intended for ancestry use, and some websites reprocess the data to generate health reports for a small fee. Patients should be aware that these tests have non-trivial rates of errors, and the results may or may not be relevant.
With regards to thrombosis risk, the most common genetic risk factors include Factor 5 Leiden, and Factor 2 (G20210A). Additionally, MTHFR (C677T) may also lead to a hypercoagulable state, due to its influence on homocysteine metabolism.
Being (+/-) for G20210A results in a 2.8x increased risk of VTE (venous thromboembolism) compared to the general population, due to the production of excess prothrombin.
| Venous Thrombosis Risk | Heterozygous | Homozygous |
| Factor 5 (Leiden) | ≃4x increased risk of thrombosis | 11x increased risk |
| Factor 2 (G20210A) | 2.8x increased risk | 6.74x increased risk |
What are things that increase the risk of VTE?
• Age
• BMI
• Inflammation, Metabolic Syndrome (https://www.ahajournals.org/doi/abs/10.1161/atvbaha.109.184085)
• Being male
• Inactivity
• Active cancer
• Other medical conditions
• Pregnancy, especially c-section delivery.
• Surgeries
• Having a blood type other than O
Additional information
• Stroke is more likely with G20210A if a person also has PFO (Patent foramen ovale) https://www.ncbi.nlm.nih.gov/pubmed/22784820
• A poor diet may be a factor https://www.internationaljournalofcardiology.com/article/S0167- 5273(16)31861-7/fulltext and https://academic.oup.com/aje/article/175/2/114/82041
• Diet has little correlation, but drinking alcohol is protective against VTE in this questonnaire https://www.sciencedirect.com/science/article/pii/S0002870309002701
• This study says that diet is not a factor in VTE https://www.thieme- connect.com/products/ejournals/abstract/10.1160/TH11-11-0818
• Pfizer refers to the Women’s Health Initiative Study, claiming this as proof that estrogen increases risk of stroke and cancer (http://labeling.pfizer.com/showlabeling.aspx? id=132#S14.2). This seems fraudulent, because it fails to make a distinction between natural estrogen and a synthetic analog.
• If someone has already had a venous thromboembolism, oral birth control definitely increases risk of recurrent VTE. HRT might increase risk, but more research is needed. https://www.ncbi.nlm.nih.gov/pubmed/9236553 I don’t have access to the full text of this study, but presumably “HRT” refers to oral estrogen medications.
Synthetic vs. Natural
• Natural estrogen is safer than synthetic https://www.cedars-sinai.org/newsroom/study-different- hormone-therapy-formulations-may-pose-different-risks-for-heart-attack-and-stroke/
• Estrogen Reduces All-Cause Mortality https://jamanetwork.com/journals/jama/article- abstract/383611
• Estrogen is anti-inflammatory, preserves the integrity of the arteries, reduces the risk of stroke, heart attack, osteoporosis, and slows progression of calcium score. https://jamanetwork.com/journals/jama/article-abstract/385577 https://www.ncbi.nlm.nih.gov/pubmed/17582069/
• Equine estrogen reduces total mortality, heart disease, and cancer risk in recently postmenopausal women https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872992/
The following research indicates that hormones increase the risk of thromboembolism:
• The Women’s Health Initiative used oral conjugated equine estrogen (CEE) plus medroxyprogesterone acetate, vs placebo. Showed a significant increase in risk of venous thrombosis in the treatment group. Factor 5 Leiden enhanced the hormone-associated risk of thrombosis, but G20210A did not. https://jamanetwork.com/journals/jama/fullarticle/199531
• The effect of high circulating estradiol levels on thrombin generation during in vitro fertilization. In vitro fertilization is a risk factor for thromboembolic complications. Supraphysiological amounts of estradiol are observed to cause decreased antithrombin, increased factor VIII, and total tissue factor pathway inhibitor (TFPI). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804893/
• “These results indicate that ovarian stimulation for IVF may create a state of hypercoagulability” https://www.ncbi.nlm.nih.gov/pubmed/1761659
• A double-blind intervention using oral estradiol plus a progestin found that “…women who have previously suffered a VTE have an increased risk of recurrence on HRT. https://www.thieme- connect.com/products/ejournals/html/10.1055/s-0037-1614156
• In The Lancet, “The risk of idiopathic VTE is about three times higher among current users of replacement oestrogens than among non-users. However, the absolute risk is low…” https://www.ncbi.nlm.nih.gov/pubmed/8855853
• Also in the Lancet, “Current HRT use is associated with risk of VTE…” Presumably oral CEE, but not specified in the summary. https://www.sciencedirect.com/science/article/pii/S0140673696071139
• A population study done in Southern Europe found “Current users of hormone replacement therapy had 2.3 times higher risk of venous thromboembolism (95 percent confidence interval 1.0–5.3) compared with nonusers. The increased risk was restricted to the first year of treatment.” Published in 1998. [It’s not clear what type of estrogen was used] https://academic.oup.com/aje/article/147/4/387/84336
• A similar study in the United Kingdom found the same result https://www.bmj.com/content/314/7083/796.full
• In a study published by the American Heart Association in 2003, an intervention trial using various forms of HRT looked at resistance to activated protein C (APC), which could explain the increased thrombosis risk with hormone therapy. Groups included
◦ a placebo
◦ transdermal 17ß-estradiol
◦ oral 17ß-estradiol, or
◦ oral 17ß-estradiol plus a progestin. Resistance to activated protein C was seen in all treatment groups, but much more in groups using oral estradiol. Progestins increase resistance to activated protein C, which is considered to be a risk factor for venous thrombosis.
Evidence that hormones do not increase the risk of thromboembolism:
• “Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens.” https://www.maturitas.org/article/S0378-5122(08)00204-1/fulltext
• A cohort of 489,105 women in Finland using estradiol-based hormone therapy (HT) found that, “Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older.” https://www.ncbi.nlm.nih.gov/pubmed/25803671
• “This case-control study of older women, unselected for other thrombotic risk factors, does not support the commonly held assumption that replacement estrogen increases the risk of venous thrombosis.” Published in 1992 in the American Journal of Medicine https://www.sciencedirect.com/science/article/pii/000293439290077O
• “Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone.” https://www.tandfonline.com/doi/abs/10.3810/pgm.2009.01.1949
• The British Medical Journal did a meta-analysis of published studies to compare oral estrogen vs. transdermal. Various types of estrogens were used. “Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism”. https://www.bmj.com/content/336/7655/1227?eaf
• A literature review concludes that bioidentical hormone replacement is more efficacious and has fewer harmful effects https://www.tandfonline.com/doi/abs/10.3810/pgm.2009.01.1949
• “The transdermal route of estrogen administration avoids excess venous thromboembolic and ischemic stroke events.” “…estradiol might also be superior to conjugated equine estrogens (CEE) in terms of global cardiovascular health. The most valid evidence presently suggests that CEE-only treatment does not increase the risk of breast cancer and even may reduce it.” “…a synthetic progestogen …. seems to be primarily associated with an increased incidence of breast cancer…” “Though not yet proven in a randomized, controlled trial, MHT continuously combining oral micronized progesterone with transdermal estradiol can presently be considered as the optimal MHT.” https://www.tandfonline.com/doi/full/10.1080/13697137.2017.1291607
• “Oral HRT is associated with an increased risk of venous thromboembolism (VTE), … [which] can be prevented by the use of the transdermal route of estradiol administration” https://www.tandfonline.com/doi/full/10.3109/13697137.2013.808563
• “…unlike oral estrogens, transdermal estradiol does not increase the risk of venous thromboembolism, probably due to its lack of effect on the coagulation cascade, including thrombin generation and resistance to activated protein C, and does not increase the risk of stroke.” https://www.tandfonline.com/doi/full/10.3109/13697137.2012.669624
• “…the use of transdermal estradiol and micronized progesterone could reduce or possibly even negate the excess risk of VTE, stroke, cholecystitis, and possibly even breast cancer associated with oral HRT use.” https://www.tandfonline.com/doi/full/10.3109/13697137.2012.669332
Summary and recommendations for an individual with clotting factor mutations
• Stay active. Don’t sit for long periods of time.
• Eat a healthy diet (the relevance of diet is disputed in the literature)
• Get frequent blood tests to evaluate coagulation risk and inflammation (ETP? INR? CRPhs?)
• Hormone replacement therapy (either static or rhythmic) would likely have benefit. However, recommend:
◦ Use only appropriate amounts of hormones.
◦ Blood testing to make sure doses are physiologic, and not excessive
◦ Estrogen should be given as a transdermal cream, not taken orally.
◦ Bioidentical forms of hormones have a lower risk profile.
◦ In most cases, estrogen should be balanced with progesterone.
• Menaquinone (Vitamin K2) is a regulator and stabilizer of the clotting cascade. In patients with elevated levels uncarboxylated osteocalcin, supplementation of low-dose Vitamin K2 is indicated to activate vitamin K dependent anti-clotting factors. (https://patents.google.com/patent/US20160310445A1/en and https://www.sciencedirect.com/topics/medicine-and-dentistry/vitamin-k-dependent-protein ) Menaquinone also has positive effects on reducing the risk of coronary artery disease, cancer, and stroke (Kate Rheaume-Bleue, 2013)
Notes: Being heterozygous for G20210A means that you have a 2.8x increased risk of venous thromboembolism (compared to the general public). https://www.snpedia.com/index.php/I3002432 But the risk of embolism in an otherwise healthy person is not very high. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624298 )