Deep Vein Thrombosis and Hormone Use

hormones

Deep Vein Thrombosis – Facts at a Glance

  • In the United States alone, deep vein thrombosis (DVT) is responsible for hundreds of thousands of hospitalizations and tens of thousands of deaths each year.
  • DVT can be caused by hormone therapy in transgender persons, especially those who take ethinyl estradiol orally.
  • Key risk factors include smoking, increased age, a sedentary lifestyle, and a genetic tendency towards high levels of clotting factors.
  • Symptoms of DVT include leg pain, swelling, an unusual warm area, shortness of breath, chest pain, and the symptoms of stroke.
  • DVT cannot be treated by yourself! Seek medical care immediately if you suspect you have DVT!
  • Overall, the incidence of DVT is declining among transgender persons as more of us are using transdermal hormones and 17-β estradiol.
  • With a healthy lifestyle and proper hormone use under a physician’s care, the risk of DVT in transgender persons is relatively low.

Description

Every transsexual person who is considering or has taken hormone therapy has heard of a potential side effect called deep vein thrombosis, or DVT. DVT is a condition where a blood clot forms in a deep vein within the body, very often in the legs but capable of occurring anywhere.

DVT is a dangerous and potentially life-threatening medical condition for two reasons. First, the primary clog can severely damage the tissues which are drained by the vein it clogs, leading to swelling, inflammation, and in the worst case, permanent injury and loss of the limb. Second, parts of the clot can break free from the blockage, traveling to the heart and then directly to the lungs. Once in the lungs, the clot can block the arteries which take oxygen. This condition is called a pulmonary embolism (PE), and can rapidly be fatal if untreated. If the clot travels to the arteries which supply the brain, the result can be a stroke. Sometimes the term venous thromboembolism (VTE) is used to describe DVT, PE, or DVT+PE. For reasons which are not known, blood clots in the legs are much more likely to lead to PE than clots which form elsewhere.

DVT_Diagram_1

Among the general United States population there are about 300,000-600,000 cases of DVT+PE per year for adults over age 18. On average nearly 10-30% of DVT+PE sufferers die within the first month. More than 20% of DVT+PE cases result in sudden death. (Beckman, CDC)

Symptoms

The symptoms of DVT can vary from mild to dramatic. It can present as simply an inexplicably warm area on your lower leg which persists for more than an hour, and can evolve to localized swelling, redness, and pain. Sometimes this can involve the entire leg. The photographs below show examples of a moderate and severe DVT presentation, respectively.

DVT_Real_2

DVT_Real_1

The impacts of pulmonary embolism and stroke cannot easily be seen from the outside, of course, but CT scans and MRIs can tell a chilling tale. In the photograph below we see brain imagery from a transsexual woman who suffered a devastating case of DVT, where blood clots traveled to her carotid artery and disrupted the blood supply to her brain. This is especially telling in the right-hand photograph, where you can see a large area of the forebrain on her left side which has suffered severe damage.

DVT_3

(From Mullins)

Treatment

DVT cannot be treated on your own, although in rare cases it will resolve itself without medical treatment. You should always seek medical care immediately if you suspect you are suffering from DVT. There is no proof that high-dose aspirin therapy at home will resolve symptoms. The standard treatment is hospitalization for the administration of anticoagulants. (Beckman) In some cases surgery may be required.

Primary Causes

Blood clots form for many reasons, but the primary causes are lack of exercise, long periods of immobility (such as long airline flights), an inherited tendency for increased blood clotting, or the influence of certain drugs – such as hormones used in transsexual hormone therapy. DVT can also form as a result of injuries, often as a result of broken bones but sometimes even a severe bruise has triggered an instance.

Race has a strong effect on DVT prevalence, with white and African American persons more likely than Hispanic persons to have DVT. People of Asian ethnicity have almost 1/5 the risk of developing DVT than average. (Beckman) Genetic males are about 18% more likely to develop DVT than genetic women. (Beckman) DVT has a moderate genetic component, so if you have blood relatives who suffered from it you can be as much as 10 times as likely to develop it. (Franco) This may be especially exacerbated in genetic men. (Glueck 2011)

SmokingWoman

Smoking and DVT

Smoking has been found to greatly increase the risk of DVT and pulmonary embolism, especially when oral estrogens are taken. A study of nearly 4,000 cisgender patients found that being a former smoker led to a 23% increase in the risk, and being a current smoker led to a 43% increase in the risk. (Pomp) Current smokers who smoked 1-9 cigarettes per day had a 23% increase in risk, those smoking 10-19 cigarettes per day had a 41% increase in risk, and those smoking 20 or more cigarettes per day had a 64% increase in risk. (Pomp) But here was where the really scary news came: cisgender women who took oral birth control pills (normally a mixture of estradiol and progesterone) had a very high risk of DVT. The worst case was for women who were current smokers and birth control pill users, who had an increased risk of 879% for developing DVT. (Pomp)

What About E-Cigarettes?

I have found no compelling research that smoking e-cigarettes is less likely to contribute to DVT formation than ordinary tobacco smoking. However, e-cigarettes do have other health advantages which should encourage a switch to them from ordinary cigarettes.

Hormone Therapy and DVT

In cisgender women estradiol leads to changes in blood lipids which are often protective – such as reducing low-density lipoprotein (LDL, or “bad cholesterol”) and increasing high-density lipoprotein (HDL, or “good cholesterol”). It also can increase nitric oxide (NO) levels in the blood, which is thought to have a cardio-protective effect. Finally, estradiol can act as an antioxidant and reduce inflammation.

This is not the case for transgender women who take exogenous estradiol. Despite decades of study the effects of HT on transwomen are not entirely understood, and any potential cardio-protective effect is unlikely. A study of 38 transwomen, 25 of which were receiving estradiol, found there was not a statistically significant change in LDL or HDL levels, nor triglycerides. However, antioxidants and NO were significantly increased for those on estradiol. (Wilson 2006) A small study of 23 transwomen taking oral estrogen with 7 transwomen using a transdermal patch found that for the oral estrogen users their “bad” cholesterol and triglycerides increased significantly, while the level of “good” cholesterol decreased significantly. Those on transdermal estrogen experienced significant increases in their triglycerides, but no other blood lipids were affected. While no DVT was reported in the study, the authors did suggest that the action of the liver upon oral estrogens may be the root cause for creating small increases in inflammatory blood markers. (Wilson 2009)

Hormone therapy for transwomen causes increases in certain metabolic factors which lead to a risk of increased clotting. (Mullins) But not all hormones are created equal, nor are their delivery methods treated equally. A 2003 study examined the effects on thrombosis-causing factors in the blood and compared the effects of antiandrogens alone, antiandrogens plus transdermal 17-β estradiol, antiandrogens plus oral ethinyl estradiol, and antiandrogens plus oral 17-β estradiol. The results of the study found that antiandrogens plus oral ethinyl estradiol led to a much higher risk of thrombosis than any other regimen. (Toorians)

As a result, many researchers in the field of transsexual medicine recommend transdermal estrogen instead of oral estrogen, or the use of17-β estradiol orally. (see Asscheman 2011, and various)

OldHospital

Transsexuals and DVT – History

DVT was once a dread condition which was a serious contraindication for hormone therapy (HT). The earliest studies on the relationship between HT and DVT estimated that transsexuals were more than 50 times as likely as the general population to develop the condition. (Moore)

A study of transsexuals who sought treatment at a Netherlands clinic from 1975-1994 followed the health and welfare of a total of 1,433 patients, of which 816 transwomen and 293 transmen received hormone therapy for at least 2 months. This study found disturbingly high risks of DVT among the 816 transwomen, who were followed for a total of 7,734 patient-years of treatment. Before 1989 the transwomen were primarily treated with ethinyl estradiol, and after that date patients older than 40 years were advised to take transdermal estradiol. Looking at the group as a whole, transwomen were 20 times more likely to suffer from DVT than the general population. Most of the cases (36 of the 45) occurred in the first year of estradiol treatment. Only one DVT case occurred with transdermal estradiol. Of the 293 transmen who were followed over 2,418 patient-years of treatment, only one person suffered from DVT, and that occurred after an operation. (Kesteren)

Very interesting results were found from a long-term study of 966 transwomen and 365 transmen who had taken hormones over the period 1975-1996, and were followed-up until July 1, 2007 (or until they died). Data over 18,678 patient-years of follow-up were available for the transwomen, and over 6,866 patient-years of follow-up for the transmen. Over that time period 122 (12.6%) of the transwomen had died, which represented an increase of the relative risk of death compared to the general population of 51%. Ischemic heart disease was responsible for 18 deaths, at a relative rate which was 64% greater than that of the general population. The majority of these heart disease-related deaths were users of ethinyl estradiol. Four of the 18 who died from heart disease had also suffered from a DVT event. Five of the 122 transwomen died from stroke, with all of these victims being ethinyl estradiol users. Twelve of the 365 (3.4%) transmen died during the study, which represented an increase of the relative risk of death compared to the general population of 12% (which was not statistically significant). Only one died from cardiovascular disease, and he was 72 years old and had been using testosterone for 42 years. (Asscheman 2011)

Historical Summary

Prior to the 2000’s DVT was a serious risk for transsexual women. Transsexual men were not significantly affected by DVT.

CurrentResearch

Transsexuals and DVT – Current Research

Transsexual health, both mental and physical, has undergone radical changes since the era of Christine Jorgensen. By the middle of the 2000’s the risk factor for developing DVT as a result of HT was assumed to be about 20-times that of the general population, with an expectation that 2-6% of transwomen would develop it over their lifetime. (Mullins) As we can see from the studies below, the risk of DVT has plummeted among transsexuals who take HT.

  • A study of 192 transwomen and 50 transmen over a total of 1,380 patient-years of follow-up found 5 cases of DVT, all of them in transwomen. However, in 2 of those cases the DVT occurred while the patients were taking unprescribed hormones, in one case oral contraceptives. No patients taking 17-β estradiol developed DVT over the study. (Leinung)
  • A 10-year study of 50 transsexual women on hormones found that 3 suffered from DVT, with two of those cases leading to a blood clot in the brain. None of the DVT patients were taking 17-β estradiol. (Wierckx)
  • A study of 101 transsexual women in New York found that only 2 had suffered from DVT. In one case the subject had used hormones without a prescription, and in another case the use of Premarin (conjugated equine estrogens) was suspected as the cause. However, this study did not perform a detailed study of individuals, relied upon personal health interviews, and did not track the total years of hormone use. (Sanchez)
  • Two reviews and meta-analyses of the risk of DVT in cisgender women who were taking estrogen replacement therapy found that the pooled risk of DVT for transdermal estrogen use was 0-20% more risk, and for oral estrogen use was up to 2.5 times as high as women not taking estrogen. (Asscheman 2014)
  • A study which examined 162 transwomen and 89 transmen over the period 1995-2007 to determine not only the prevalence of DVT, but the potential risk factors which were responsible for it occurring. All subjects were taking the appropriate cross-sex hormones for their gender. A total of 13 transwomen and 5 transmen out of the 251 subjects developed DVT over the examination period, which represents 8.0% of the transwomen and 5.6% of the transmen. All 18 tested positive as having activated protein C (aPC) resistance, which is a familial indicator for blood clotting irregularities. Of the 13 transwomen with DVT, 4 were current smokers, 2 had hypertension, and one was a type 1 diabetic. Five of the 13 transwomen with DVT had self-treated with ethinyl estradiol. Only one transman had a contributing familiar clotting factor. (Ott)DVT_4(From Ott – the 13 transsexual women who suffered from DVT)DVT_5(From Ott – the 5 transsexual men who suffered from DVT)

One of the best recent reports I’ve read was the results of a recent meta-study by a noted researcher of transsexual medicine, and indicated that the rate of DVT has fallen dramatically over the last 40 years, but is still higher than that seen in the general population. This meta-study listed the results of 10 other studies from 1989-2012, and found that among those studies carried out before 2000, DVT was seen in 64 of 1,257 patients after starting hormone therapy. This represents an absolute risk of 5.1%. However, the total number of patient-years among these studies was 9,348. Meaning that the gross annual risk of DVT was about 0.7%. (Asscheman 2014) However, if we look at all studies in the meta-study which were conducted at the year 2000 and later, we see that DVT was seen in 4 of 334 patients after starting hormone therapy. This represents an absolute risk of 1.2%. However, the total number of patient-years among these studies was 1,668. Meaning that the gross annual risk of DVT was about 0.24%. (Asscheman 2014)

DVT_1

(From Asscheman – profiles of studies which were reviewed)

Current Research Summary

When recent studies are examined, the risk of DVT is much lower than the historical risk. All studies which were reviewed agree that smoking while on HT greatly increases the risk of DVT. One complicating factor is that the age at which transsexuals have started HT has been declining over recent years. Younger persons are generally much more resistant to developing DVT, and so it’s possible that this has slightly skewed the results showing a decreasing prevalence of DVT over time.

DVT_2

(From Leinung)

What About Transmen?

DVT is an uncommon side effect of hormone treatment in transmen. In the Ott study (see above) transmen were found to develop DVT, but at a rate lower than that of transwomen. In the Leinung study (see above) none of the 50 transmen who were studied developed DVT. In fact, one 2003 study found that testosterone acted as an anti-clotting agent, providing some protection against DVT. (Toorians) One study of cisgender men found that testosterone therapy encouraged blood clots from both patch and intramuscular delivery, although in that study an inherited tendency was thought to be behind the occurrences. (Glueck 2011) In some cases testosterone from HT can also be aromatized (transformed) into estrogens, which can then lead to DVT. (Glueck 2013)

How Can I Prevent DVT?

Unfortunately there are not many things which one can do to reduce the risk of or prevent DVT. Reducing the risk of DVT is largely a function of healthier living, combined with proper hormone type and use. If you smoke or use tobacco of any kind, stop. Leg exercise generally greatly reduces the risk of leg DVT, but it’s not a cure-all. As reported above, transdermal estradiol or using only 17-β estradiol orally seem to have greatly reduced the risk of developing DVT. Aspirin therapy is often recommended for transsexuals over the age of 40 who undergo HT, but this can be contraindicated in those who are at risk for or have a history of stomach bleeding.

Shoes

What About High-Heeled Shoes?

There is much “common sense” wisdom on the internet which claims that it’s “proven that wearing high-heeled shoes can cause DVT.” However, I performed numerous searches in medical databases and was unable to find compelling proof that high heel use had any impact on the propensity for DVT development. It is proven that high heels can be rougher on your feet and legs in general than flats or athletic shoes, and it’s also true that wearing high heels leads to a lack of mobility and exercise while wearing them. But other than those coincidental factors, there is no solid proof that high heel use contributes to DVT.

References

Asscheman, H. et al. “A Long-term Follow-up Study of Mortality in Transsexuals Receiving Treatment with Cross-sex Hormones” European Journal of Endocrinology 164 (2011): 635–642.

Asscheman, H. et al. “Venous Thrombo-Embolism As A Complication Of Cross-Sex Hormone Treatment Of Male-To-Female Transsexual Subjects: A Review” Andologia 46 (2014): 791-795.

Beckman, Michele G., et al. “Venous Thromboembolism: A Public Health Concern.” American Journal of Preventive Medicine 38.4 (2010): S495-S501.

Centers for Disease Control (CDC). Morbidity and Mortality Weekly Report (MMWR). “Venous Thromboembolism in Adult Hospitalizations — United States, 2007–2009” Weekly 61.22 (June 8, 2012): 401-404.

Franco, Rendrik F. and Reitsma, Pieter H. “Genetic Risk Factors of Venous Thrombosis” Hum Genet 109 (2001): 369-384.

Glueck, Charles J. et al. “Thrombotic Events After Starting Exogenous Testosterone In Men With Previously Undiagnosed Familial Thrombophilia” Translational Research 158.4 (October, 2011): 225-236.

Glueck, Charles J. et al. “Testosterone, Thrombophilia, and Thrombosis” Clinical and Applied Thrombosis/Hemostasis Published online 23 April, 2013.

Kesteren, Paul J. M. van et al. “Mortality and Morbidity in Transsexual Subjects Treated with Cross-sex Hormones” Clinical Endocrinology 47 (1997): 337-342.

Leinung, Matthew C. et al. “Endocrine Treatment of Transsexual Persons: Extensive Personal Experience” Endocrine Practice 19.4 (July/August, 2013): 644-650.

Moore, Eva et al. “Endocrine Treatment of Transsexual People: A Review of Treatment Regimens, Outcomes, and Adverse Effects” The Journal of Clinical Endocrinology & Metabolism 88.8 (2003): 3467–3473.

Mullins, G.M. et al. “Venous and Arterial Thrombo-Embolic Complications of Hormonal Treatment in a Male-to-Female Transgender Patient” Case Report / Journal of Clinical Neuroscience 15 (2008): 714–716.

Ott, Johannes et al. “Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy” Fertility and Sterility 93.4 (2010): 1267-1272.

Pomp, Elisabeth R. et al. “Smoking Increases The Risk Of Venous Thrombosis And Acts Synergistically With Oral Contraceptive Use” American Journal of Hematology 83 (2008): 97–102.

Sanchez, Nelson F. et al. “Health Care Utilization, Barriers to Care, and Hormone Usage Among Male-to-Female Transgender Persons in New York City” American Journal of Public Health 99.4 (2009): 713-719.

Toorians, A.W.F.T et al. “Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People” The Journal of Clinical Endocrinology & Metabolism 88.12 (2008): 5723–5729.

Wierckx, Katrien et al. “Long-Term Evaluation of Cross-Sex Hormone Treatment in Transsexual Persons” J Sex Med 9 (2012): 2641–2651.

Wilson, R. et al. “The Effect Of Oestrogen On Cytokine And Antioxidant Levels In Male To Female Transsexual Patients” Maturitas 55 (2006): 14–18.

Wilson, R. et al. “Effects Of High Dose Oestrogen Therapy On Circulating Inflammatory Markers” Maturitas 62 (2009): 281–286.

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