Hormone Therapy and Safety

Sarah J. Lewis (Volunteer Researcher) sarah@transcience-project.org





Is hormone therapy safe? What are the risk factors? Are there any long term health implications? In this paper we will attempt to answer all these questions by examining several long term studies.

Important: This paper is a compiled subsection of the current medical knowledge available, it will be updated on a best-effort basis. It does not replace the advice of your consulting physician.

This paper will not explore the more commonly associated affects of hormone therapy e.g. increased breast growth in trans-women or deepening voice in trans-men.





Legend

Throughout this paper we have provided a legend to summarize the research into a particular risk. It should be read as follows:

- Studies have shown a marked increase in risk for the condition in transgender patients. Patients and doctors need to monitor for signs of the potential issue.

- Studies have shown no increased risk of the given condition in transgender patients.





Does hormone therapy work?

Before we dive into the safety of hormone therapy we should ask ourselves "does it work?", that is to say, does hormone therapy relieve or lessen gender dysphoria?

We are only aware of one study that specifically looked at quality of life in transgender patients; Gorin-Lazard et al[1] found that hormonal therapy was significantly associated with a higher quality of life in transgender patients.

There is also plenty of anecdotal evidence to support the above conclusion.





Overall Mortality

Current Status:

Many studies have looked at how transgender patients are affected by hormone therapy throughout their lives.

Kesteren et al[2] was the first to conduct a long term study into the mortality of transgender patients who has received hormonal therapy. They found that for both trans-men and trans-women there was no increased mortality compared to the general population. They found no evidence of increased cancer risk, but did find that patients treated with oral oestrogens had a higher rate of Venous thromboembolism.

Asscheman et al[3] conducted a study with similar sample sizes to Kesteren, however they found that transgender women had a 51% increase in mortality - this increase was mainly associated with the increased suicide rate in transgender patients. Asscheman also concluded that ethinyl estradiol may increase the risk of cardiovascular death. The study found no increase in risk for trans-men.

Dhejne et al[15] followed 324 transgender patients over the course of 30 years between 1973 and 2003. They found that transgender patients, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. One of the key reasons for this increased mortality was the increased suicide rate in patients. In the paper the authors suggest that the high suicide rate could be linked to worse surgical success in early surgeries (prior to 1989), and worse societal attitudes towards transgender persons in that time frame. For the group of patients operated on after 1989 there was no significant increase in suicide rate.

Asscheman et al (2014) [7] presenting at the Endocrine Society's 96th Annual Meeting noted the following "Our data show a very reassuring picture of side effects with cross-sex hormone treatment. Our observations are biased... Nevertheless our data confirm the reassuring data from studies with smaller numbers published in the last 10 years."

Causes of Death for transgender patients and controls reported by Dhejne et al(2011)

A small study by Wierckx et al[4] followed post-operative transgender patients. They, like previous studies, found no increased risk from hormone treatment in trans-men. On the other hand, a substantial number of trans-women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of trans-women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, oestrogen treatment, and lifestyle factors.

It would certainly seem that there are risks to taking hormone therapy. But that these risks are rare, and do not affect the overall mortality rate of transgender patients compared to the average population. We will now explore some of these potentials risks.





Potential Risk: Cardiovascular Disease and Deep Vein Thrombosis

Current Status:

Deep vein thrombosis, or deep venous thrombosis, (DVT) is the formation of a blood clot (thrombus) in a deep vein, predominantly in the legs.

The WPATH standards of care[10] lists that trans-women who are over age 40, smokers, highly sedentary, obese, and who have underlying thrombophilic disorders are at most risk.

Many of the studies[1][3][4] into the long term affects of hormone treatment have found an increased risk in both venous thromboembolism and other cardiovascular issues. However it is worth calling out that many of the discussion sections in these studies cite high rates of smoking and other risk factors as being a potential cause.

It is strongly recommended that trans-women maintain a healthy weight and exercise regularly and avoid smoking.





Potential Risk: Osteoporosis

Current Status:

Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture.

Schlatterer et al[5] conducted a small study (consisting of 10 trans-women and 10 trans-men), they concluded that the risk of developing osteoporosis as a result of hormone therapy was low.

Ruetsche et al[8] in their cross-sectional study found that bone mass density was preserved in trans-women, and increased in trans-men over a 12.5 year study. They did find that five trans women who did not comply with the recommended hormone regiment did develop osteoporosis.

In contrast, Wierckx et al[4] as stated above did find a marked increase in osteoporosis at the lumbar spine and distal arm.

Sex hormones play a key role in maintaining healthy bones. One of the main suffers of osteoporosis are post-menopausal women, it shouldn't be a surprise that older trans-women are also at risk, if hormone therapy is not consistent, or levels are too low.





Potential Risk: Breast Cancer

Current Status:

Gooren et al[6] conducted a very large study (more than 2000 trans-women and 795 trans-men that had received between 5 and (more than) 30 years of hormone therapy). They found "Breast carcinoma incidences in both groups are comparable to male breast cancers. Cross-sex hormone treatment of [transgender] subjects does not seem to be associated with an increased risk of malignant breast development."

Wiley et al[10] mentions that a few cases have been seen, but that there is nothing to indicate that the cases were the result of hormonal therapy.

It is recommended for everyone to check their breast tissue on a regular basis.





Potential Risk: Prostate Cancer

Current Status:

There is currently little to no evidence of an increased risk of prostate cancer in trans-women or trans-men. Coleman et al[9] in the 7th version of the WPATH Standards of Care paper didn't even mention it.

Wiley et al[10] mentions that a few cases have been seen, but that there is nothing to indicate that the cases were the result of hormonal therapy. They err on the side of caution and recommend that patients be monitored for signs of prostate cancer.





Potential Risk: Type II Diabetes

Current Status:

Many of standards of care guides mention that hormone therapy can potentially increase the risk of type II diabetes. Hormones as certainly a factor in the prevalence of type II diabetes, however, with the exception of a few case studies[11] we can find no studies which provide evidence to support an increased risk in type II diabetes in transgender patients undertaking hormonal therapy.

The WPATH standards of care states that "Feminizing hormone therapy, particularly estrogen, may increase the risk of type 2 diabetes, particularly among patients with a family history of diabetes or other risk factors for this disease" and that "Testosterone therapy does not appear to increase the risk of type 2 diabetes among trans-men patients overall, unless other risk factors are present."[9]





Potential Risk: Cervical, Ovarian, Endometrial Cancer

Current Status:

Testosterone therapy in trans-men patients does not increase the risk of cervical cancer, although it may increase the risk of minimally abnormal Pap smears due to atrophic changes.[9]

Analogous to persons born with female genitalia with elevated androgen levels, testosterone therapy in trans-men patients may increase the risk of ovarian cancer[12], although evidence is limited.[9]

Testosterone therapy in trans-men patients may increase the risk of endometrial cancer, although evidence is limited.[9]





Potential Risk: Polycythemia

Current Status:

Polycythemia (also known as polycythaemia or polyglobulia) is a disease state in which the proportion of blood volume that is occupied by red blood cells increases. It is a rare complication from androgen therapy in biological males[14]

The WPATH standards of care states that "Masculinizing hormone therapy involving testosterone or other androgenic steroids increases the risk of polycythemia (hematocrit > 50%), particularly in patients with other risk factors."[9]

However, other papers, for example Jacobeit et al[13] have found that while hemocrit levels did rise in trans-men patients, the levels were, almost without exception, in the normal physiological range.





Citations

[1] Gorin-Lazard, A., Baumstarck, K., Boyer, L., Maquigneau, A., Gebleux, S., Penochet, J.-C., Pringuey, D., Albarel, F., Morange, I., Loundou, A., Berbis, J., Auquier, P., Lançon, C. and Bonierbale, M. (2012), Is Hormonal Therapy Associated with Better Quality of Life in Transsexuals? A Cross-Sectional Study. Journal of Sexual Medicine, 9: 531–541. doi: 10.1111/j.1743-6109.2011.02564.x



[2] Kesteren, Paul J. M. Van, Henk Asscheman, Jos A. J. Megens, and Louis J. G. Gooren. "Mortality and Morbidity in Transsexual Subjects Treated with Cross-sex Hormones." Clinical Endocrinology 47.3 (1997): 337-43.



[3] Asscheman, H., E. J. Giltay, J. A. J. Megens, W. De Ronde, M. A. A. Van Trotsenburg, and L. J. G. Gooren. "A Long-term Follow-up Study of Mortality in Transsexuals Receiving Treatment with Cross-sex Hormones." European Journal of Endocrinology 164.4 (2011): 635-42.



[4] Wierckx, Katrien, Sven Mueller, Steven Weyers, Eva Van Caenegem, Greet Roef, Gunter Heylens, and Guy T'sjoen. "Long-Term Evaluation of Cross-Sex Hormone Treatment in Transsexual Persons." The Journal of Sexual Medicine 9.10 (2012): 2641-651



[5] Schlatterer, K., D. Auer, A. Yassouridis, K. Von Werder, and G. Stalla. "Transsexualism and Osteoporosis." Experimental and Clinical Endocrinology & Diabetes 106.05 (1998): 365-68.



[6] Gooren, L. J., van Trotsenburg, M. A.A., Giltay, E. J. and van Diest, P. J. (2013), Breast Cancer Development in Transsexual Subjects Receiving Cross-Sex Hormone Treatment. Journal of Sexual Medicine, 10: 3129–3134.



[7] Asscheman, Henk, Guy G. T'Sjoen, and Louis J. Gooren. "OR42-3: Morbidity in a Multisite Retrospective Study of Cross-Sex Hormone-Treated Transgender Persons." (2014).



[8] Ruetsche, Adrian G., Renato Kneubuehl, Martin H. Birkhaeuser, and Kurt Lippuner. "Cortical and Trabecular Bone Mineral Density in Transsexuals after Long-term Cross-sex Hormonal Treatment: A Cross-sectional Study." Osteoporosis International 16.7 (2005): 791-98.



[9] Coleman, E., W. Bockting, M. Botzer, P. Cohen-Kettenis, G. Decuypere, J. Feldman, L. Fraser, J. Green, G. Knudson, W. J. Meyer, S. Monstrey, R. K. Adler, G. R. Brown, A. H. Devor, R. Ehrbar, R. Ettner, E. Eyler, R. Garofalo, D. H. Karasic, A. I. Lev, G. Mayer, H. Meyer-Bahlburg, B. P. Hall, F. Pfaefflin, K. Rachlin, B. Robinson, L. S. Schechter, V. Tangpricha, M. Van Trotsenburg, A. Vitale, S. Winter, S. Whittle, K. R. Wylie, and K. Zucker. "Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7." International Journal of Transgenderism 13.4 (2012): 165-232.



[10] Wylie, Kevan Richard, Robert Fung, Claudia Boshier, and Margaret Rotchell. "Recommendations of Endocrine Treatment for Patients with Gender Dysphoria." Sexual and Relationship Therapy 24.2 (2009): 175-87.



[11] Feldman, Jamie. "New Onset of Type 2 Diabetes Mellitus with Feminizing Hormone Therapy: Case Series". The International Journal of Transgenderism. 6.2 (2002).







[13] Jacobeit, J. W., L. J. Gooren, and H. M. Schulte. "Safety Aspects of 36 Months of Administration of Long-acting Intramuscular Testosterone Undecanoate for Treatment of Female-to-male Transgender Individuals." European Journal of Endocrinology 161.5 (2009): 795-98.



[14] Moore, E. "Endocrine Treatment of Transsexual People: A Review of Treatment Regimens, Outcomes, and Adverse Effects." Journal of Clinical Endocrinology & Metabolism 88.8 (2003): 3467-473.



[15] Dhejne, Cecilia, Paul Lichtenstein, Marcus Boman, Anna L. V. Johansson, Niklas Långström, and Mikael Landén. "Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden." Ed. James Scott. PLoS ONE 6.2 (2011): E16885.



The icons used in this paper were provided by Hage, J., Dekker, J., Karim, R., Verheijen, R., & Bloemena, E. (2000). Ovarian cancer in female-to-male transsexuals: Report of two cases. Gynecologic Oncology, 76(3), 413–415. (Paperdex)Jacobeit, J. W., L. J. Gooren, and H. M. Schulte. "Safety Aspects of 36 Months of Administration of Long-acting Intramuscular Testosterone Undecanoate for Treatment of Female-to-male Transgender Individuals." European Journal of Endocrinology 161.5 (2009): 795-98. (Paperdex)Moore, E. "Endocrine Treatment of Transsexual People: A Review of Treatment Regimens, Outcomes, and Adverse Effects." Journal of Clinical Endocrinology & Metabolism 88.8 (2003): 3467-473. (Paperdex)Dhejne, Cecilia, Paul Lichtenstein, Marcus Boman, Anna L. V. Johansson, Niklas Långström, and Mikael Landén. "Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden." Ed. James Scott. PLoS ONE 6.2 (2011): E16885. (Paperdex)The icons used in this paper were provided by Centigrade [12] Gorin-Lazard, A., Baumstarck, K., Boyer, L., Maquigneau, A., Gebleux, S., Penochet, J.-C., Pringuey, D., Albarel, F., Morange, I., Loundou, A., Berbis, J., Auquier, P., Lançon, C. and Bonierbale, M. (2012), Is Hormonal Therapy Associated with Better Quality of Life in Transsexuals? A Cross-Sectional Study. Journal of Sexual Medicine, 9: 531–541. doi: 10.1111/j.1743-6109.2011.02564.x (Paperdex)Kesteren, Paul J. M. Van, Henk Asscheman, Jos A. J. Megens, and Louis J. G. Gooren. "Mortality and Morbidity in Transsexual Subjects Treated with Cross-sex Hormones." Clinical Endocrinology 47.3 (1997): 337-43. (Paperdex)Asscheman, H., E. J. Giltay, J. A. J. Megens, W. De Ronde, M. A. A. Van Trotsenburg, and L. J. G. Gooren. "A Long-term Follow-up Study of Mortality in Transsexuals Receiving Treatment with Cross-sex Hormones." European Journal of Endocrinology 164.4 (2011): 635-42. (Paperdex)Wierckx, Katrien, Sven Mueller, Steven Weyers, Eva Van Caenegem, Greet Roef, Gunter Heylens, and Guy T'sjoen. "Long-Term Evaluation of Cross-Sex Hormone Treatment in Transsexual Persons." The Journal of Sexual Medicine 9.10 (2012): 2641-651 (Paperdex)Schlatterer, K., D. Auer, A. Yassouridis, K. Von Werder, and G. Stalla. "Transsexualism and Osteoporosis." Experimental and Clinical Endocrinology & Diabetes 106.05 (1998): 365-68. (Paperdex)Gooren, L. J., van Trotsenburg, M. A.A., Giltay, E. J. and van Diest, P. J. (2013), Breast Cancer Development in Transsexual Subjects Receiving Cross-Sex Hormone Treatment. Journal of Sexual Medicine, 10: 3129–3134. (Paperdex)Asscheman, Henk, Guy G. T'Sjoen, and Louis J. Gooren. "OR42-3: Morbidity in a Multisite Retrospective Study of Cross-Sex Hormone-Treated Transgender Persons." (2014). (Paperdex)Ruetsche, Adrian G., Renato Kneubuehl, Martin H. Birkhaeuser, and Kurt Lippuner. "Cortical and Trabecular Bone Mineral Density in Transsexuals after Long-term Cross-sex Hormonal Treatment: A Cross-sectional Study." Osteoporosis International 16.7 (2005): 791-98. (Paperdex)Coleman, E., W. Bockting, M. Botzer, P. Cohen-Kettenis, G. Decuypere, J. Feldman, L. Fraser, J. Green, G. Knudson, W. J. Meyer, S. Monstrey, R. K. Adler, G. R. Brown, A. H. Devor, R. Ehrbar, R. Ettner, E. Eyler, R. Garofalo, D. H. Karasic, A. I. Lev, G. Mayer, H. Meyer-Bahlburg, B. P. Hall, F. Pfaefflin, K. Rachlin, B. Robinson, L. S. Schechter, V. Tangpricha, M. Van Trotsenburg, A. Vitale, S. Winter, S. Whittle, K. R. Wylie, and K. Zucker. "Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7." International Journal of Transgenderism 13.4 (2012): 165-232. (Paperdex)Wylie, Kevan Richard, Robert Fung, Claudia Boshier, and Margaret Rotchell. "Recommendations of Endocrine Treatment for Patients with Gender Dysphoria." Sexual and Relationship Therapy 24.2 (2009): 175-87. (Paperdex)Feldman, Jamie. "New Onset of Type 2 Diabetes Mellitus with Feminizing Hormone Therapy: Case Series". The International Journal of Transgenderism. 6.2 (2002). (Paperdex)