Oestrogen and Liver Metabolism

Oestrogen is the essential component of feminising hormone treatment for many trans women. There is sometimes concern raised about the effect of oestrogen on liver metabolism. This brief article can hopefully allay this concern with reference to clinical evidence on the effect of oestrogen and the liver.

Liver metabolism

The liver is a large organ on the right side of the upper abdomen which performs a variety of activities. These include (1) metabolising and excreting medications and toxins, (2) aiding with fat digestion by secreting bile, (3) synthesising bodily components such as proteins, and (4) storing sugar in the form of glycogen.

Liver health can be assessed with a blood test for various components produced by the liver. The most sensitive of these are the enzymes alanine transaminase (ALT) and aspartate transaminase (AST). If the blood test shows these to be elevated above the recommended reference ranges, then this could indicate that there is some injury to the liver.

The effect of oestrogen on the liver

Oestrogen can sometimes be associated with slight elevations of liver enzymes such as ALT and AST. However, these elevations are typically within or close to the recommended reference ranges and are temporary. They tend to occur upon commencing oestrogen and then resolve on their own without any intervention. Furthermore, these mild elevations are not associated with any clinically significant problems.

A recent study showed that trans women who were taking oestrogen did not exhibit any elevations in liver enzymes after twelve months of treatment (Hashemi et al., 2021). Therefore, there is no evidence that the use of oestrogen in feminising hormone treatment causes liver injury.

Nonetheless, there is some reason to think that oestrogen might be associated with a slightly increased lifetime risk of gallstones. This would account for why the lifetime risk of gallstones is higher in cis women than in cis men and also why the incidence of gallstones increases in pregnancy when oestrogen levels are elevated (Zu et al., 2021). While there has been a case report of pancreatitis caused by gallstones in a trans women (Freier et al., 2021), the prevalence of gallstones in trans women has not been specifically investigated. Current clinical practice indicates that the degree of risk of gallstones with feminising hormone treatment is very small (Deutsch, 2020).

Oral oestrogen and transdermal oestrogen

There are differences in the ways oral oestrogen (tablets) and transdermal oestrogen (gel) are metabolised in the body. Oral oestrogen is initially absorbed in the gastrointestinal tract and transported to the liver. It then undergoes metabolism by the liver before it enters the systemic bloodstream. By contrast, transdermal oestrogen is absorbed through the skin and enters the systemic bloodstream. Therefore, it bypasses the initial metabolism by the liver.

This does not mean that oral oestrogen is harmful to the liver. There is currently no evidence that oral oestrogen as part of feminising hormone treatment causes clinically significant liver injury. However, the above differences between oral oestrogen and transdermal oestrogen do have some health implications.

First, due to the way it is metabolised, oral oestrogen may be associated with a greater risk of thromboembolic disease (blood clots, stroke, heart disease) than transdermal oestrogen (Milionis et al., 2023; von Schoultz, 2009).

Second, while oral oestrogen is unlikely to cause liver injury, the presence of liver impairment may make it more difficult to metabolise oral oestrogen. Hence, transdermal oestrogen may be more preferable for a person who has liver impairment. Of course, it may sometimes be unfeasible to avoid oral oestrogen. For example, if transdermal oestrogen has been ineffective or if treatment is suboptimal despite the the maximum dose of transdermal oestrogen being reached, then it may be recommended to try oral oestrogen. In this scenario, where a person with liver impairment is taking oral oestrogen in addition to the maximum dose of transdermal oestrogen, it may be prudent to offer monitoring of liver enzymes.

Other medications

While oestrogen itself does not cause liver injury, there other medications used in feminising hormone treatment that can affect the liver. Specifically, the antiandrogens cyproterone acetate and biculutamide (no longer widely used) are associated with liver injury, which can range from mild elevations of liver enzymes to severe liver damage. Therefore, regular monitoring of liver enzymes is recommended for people who are taking cyproterone acetate or bicalutamide.

Conclusion

The current available evidence indicates that oestrogen use in feminising hormone treatment does not cause clinically significant liver injury. While oestrogen may be associated with mild elevations in liver enzymes, these are generally temporary and are not associated with clinically significant problems.

In general, there is no clinical need for regular monitoring of liver enzymes as part of feminising hormone treatment with oestrogen. Two exceptions are (1) if the person is also taking cyproterone acetate or bicalutamide as an antiandrogen and (2) if the person has a history of liver impairment and is taking oral oestrogen in addition to the maximum dose of transdermal oestrogen.

References

Deutsch, M. (2020). “Information on Estrogen Hormone Therapy”. UCSF Transgender Care. https://transcare.ucsf.edu/article/information-estrogen-hormone-therapy

Freier, E., Kassel, L., Rand, J., and Chinnakotla, B. (2021). “Estrogen-induced gallstone pancreatitis in a transgender female”. American Journal of Health System Pharmacy, 78(18): 1674-1680.

Hashemi, L., Zhang, Q., Getahun, D., Jasuja, G. K., McCracken, C., Pisegna, J., Roblin, D., Silverberg, M. J., Tangpricha, V., Vupputuri, S., and Goodman, M. (2021). “Longitudinal Changes in Liver Enzyme Levels Among Transgender People Receiving Gender Affirming Hormone Therapy”. Journal of Sexual Medicine, 18(9): 1662–1675.

Milionis, C., Ilias, I., and Koukkou, E. (2023). “Liver function in transgender persons: Challenges in the COVID-19 era”. World Journal of Clinical Cases, 11(2): 299–307.

von Schoultz, B. (2009). “Oestrogen therapy: oral versus non-oral administration”. Gynecology and Endocrinology, 25(9): 551-553.

Zu, Y., Yang, J., Zhang, C., and Liu, D. (2021). “The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives”. Frontiers in Pharmacology, 12: 761255.

Updated on April 2, 2024

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