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Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy

By Aly | First published July 1, 2020 | Last modified April 6, 2024

Abstract / TL;DR

Bicalutamide is an antiandrogen which was introduced for the treatment of prostate cancer many years ago. Cost precluded its widespread use for other indications for many years. However, its cost has since come down and bicalutamide is now seeing significant adoption for use in transfeminine hormone therapy as well as for treatment of androgen-dependent conditions in other populations like cisgender women. Bicalutamide has risks of certain rare adverse effects like liver toxicity which have generated concerns about its safety and have limited its use in transfeminine people. However, while still significant, these risks are low with appropriate monitoring and clinical management. Prominent researchers in transgender medicine have recently shown openness to bicalutamide for potential use in transfeminine people and have written positively about it. Bicalutamide could eventually come to be regarded as acceptably safe for use in transfeminine hormone therapy, similarly to other antiandrogens with rare risks like spironolactone and cyproterone acetate. However, more studies and characterization of bicalutamide in transfeminine people will likely be needed before it could see wider adoption in transgender medicine.

History of Bicalutamide for Transfeminine People

Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selective antagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in cisgender men in 1995. Prostate cancer is an androgen-dependent disease, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of antiandrogenic potency, clinical effectiveness, pharmacological selectivity, and tolerability. It also has improved potency, pharmacokinetic properties, and tolerability, as well as far better safety, compared to the older nonsteroidal antiandrogens flutamide (Eulexin) and nilutamide (Anandron, Nilandron). However, use of bicalutamide as an antiandrogen in transfeminine hormone therapy is very recent. The employment of bicalutamide for transfeminine people was largely precluded for many years by the fact that bicalutamide had pharmaceutical patent protection and was very expensive. However, this changed with the availability of generic versions of bicalutamide starting in 2007 to 2009. In addition, newer and more effective antiandrogens like abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care antiandrogen for the treatment of prostate cancer. These developments have greatly reduced the cost of bicalutamide and it has gradually become much more affordable in the last decade.

Before 2015, there were only a few mentions in the literature of bicalutamide for transfeminine people and a handful of anecdotal reports online of transfeminine people using it. The earliest clear mention of bicalutamide in the literature in the context of transfeminine hormone therapy was by Louis Gooren in 2011 (Gooren, 2011). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). He and his colleagues at the Center of Expertise on Gender Dysphoria of the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (de Voogt et al., 1987a; de Voogt et al., 1987b; Gooren et al., 1987; Johannes et al., 1987; Rao et al., 1988; Asscheman, Gooren, & Peereboom-Wynia, 1989; van Kemenade et al., 1989; Wiki). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other off-target side effects. Nonetheless, Gooren began including nonsteroidal antiandrogens like flutamide and nilutamide in his publications as potential treatment options for transfeminine hormone therapy starting in the 1990s (Asscheman & Gooren, 1992; Gooren, 1999). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., Israel & Tarver, 1997; Levy, Crown, & Reid, 2003; Dahl et al., 2006a; Dahl et al., 2006b; Hembree et al., 2009; Moreno-Pérez et al., 2012). As a researcher interested in nonsteroidal antiandrogens for transfeminine people, bicalutamide—with its far better safety profile than flutamide and nilutamide—may have been appealing to Gooren. However, Gooren and his colleagues didn’t conduct clinical studies on bicalutamide for transfeminine people and never went beyond brief mention of it for such uses in their publications. Nor did any other academics.

Besides transfeminine people and men with prostate cancer, bicalutamide has been studied for use in the treatment of androgen-dependent conditions in other populations. For example, it has been used in the treatment of hirsutism (excessive facial/body hair growth) in cisgender women with and without polycystic ovary syndrome (PCOS) (Müderris, Bayram, & Güven, 1999; Müderris et al., 2002; Bahceci et al., 2004; Müderris & Öner, 2009; Moretti et al., 2016; Moretti et al., 2018; Wiki). Bicalutamide has also been studied in combination with anastrozole (Arimidex), an aromatase inhibitor, for the treatment of gonadotropin-independent precocious puberty in cisgender boys (Kreher et al., 2006; Lewis et al., 2009; Mitre & Lteif, 2009; Stenger et al., 2009; Lenz et al., 2010; Reiter et al., 2010; Tessaris et al., 2012; Özcabı et al., 2015; Kor, 2018; Arya & Davies, 2019; Nabhan & Eugster, 2019; Finkle et al., 2020; Gurnurkar, DiLillo, & Carakushansky, 2021; Wiki). This is a rare form of precocious puberty in which gonadotropin-releasing hormone modulators are not effective. A phase 2 clinical trial was completed and a New Drug Application (NDA) was submitted in the United States for treatment of the condition with bicalutamide and anastrozole, but the application was not approved due to inadequate evidence of effectiveness on the primary efficacy endpoint of limiting height (AstraZeneca, 2008). However, bicalutamide is still used off-label for this indication, and information on bicalutamide for this use is provided in the the Casodex Food and Drug Administration (FDA) label (FDA, 2017).

Although there was little discussion or use of bicalutamide in transfeminine people prior to 2015, this started to change in mid-2015. At that time, the Wikipedia content for bicalutamide was greatly expanded, which made information about bicalutamide more accessible. In addition, certain transfeminine people, noting its advantages over existing options and its excellent potential for use in transfeminine hormone therapy, began advocating for use of bicalutamide in transfeminine people in online circles. A number of open-minded clinicians started adopting bicalutamide in transfeminine people around this time and thereafter as well. The first clinical study of bicalutamide in transfeminine people, which began in 2013, was published as an abstract in 2017 and as a full paper in 2019 (Neyman, Fuqua, & Eugster, 2017; Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a second-line puberty blocker in adolescent transgender girls for whom gonadotropin-releasing hormone analogues were denied by insurance. As of present, it remains the only published clinical data on bicalutamide in transfeminine people. It’s not exactly great data by any means, but it’s a study at least. The researchers who conducted the study had previously published on bicalutamide as a puberty blocker in boys with gonadotropin-independent precocious puberty (e.g., Lenz et al., 2010; Haddad & Eugster, 2012). While limited in its findings, Neyman, Fuqua, and Eugster (2019) helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.

In any case, due to the recent nature of bicalutamide as an option for use in transfeminine hormone therapy, as well as the lack of studies and characterization of bicalutamide in transfeminine people and concerns about its safety (see next section), bicalutamide isn’t widely used in transfeminine people at this time. In fact, transgender hormone therapy guidelines largely don’t even mention it still. At present, the use of bicalutamide in transfeminine people is mostly limited to a number of more flexible clinicians and to people in the transgender do-it-yourself (DIY) hormone therapy community.

Concerns About Bicalutamide Limiting its Use

The transgender medical community has been reluctant to endorse the use of bicalutamide in transfeminine people to date. This is because of the lack of clinical studies and characterization of bicalutamide in transfeminine people, most importantly in terms of safety. There have been concerns about rare instances of liver failure that have occurred with bicalutamide in men with prostate cancer (Wiki). The reported cases of liver toxicity with bicalutamide have generally been sudden-onset and severe. Rare liver toxicity is an acceptable risk in men with prostate cancer because the risk–benefit ratio of bicalutamide therapy is very favorable, with the benefit of treating prostate cancer vastly outweighing the harm of the very rare instances of liver problems. But transfeminine people are typically young and healthy, and bicalutamide isn’t treating a terminal illness when it’s used in us. If a transfeminine person develops liver failure and dies because of bicalutamide, that’s unnecessary harm and a life needlessly lost. Accordingly, the University of California San Francisco (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (Deutsch, 2016). Aside from risks, there is also a lack of data to guide appropriate dosing of bicalutamide in transfeminine people at this time. A typical bicalutamide dosage of 50 mg/day is being used and recommended, but this has been arbitrarily chosen with little basis to support it.

To date, there are 10 published case reports of serious liver toxicity in association with bicalutamide (Table). All of these cases were in men with prostate cancer and all occurred within 6 months of initiation of bicalutamide therapy, with two of the cases resulting in death. While this is not a lot of cases and may seem reassuring, it must be noted that quantity of published case reports tends to vastly underestimate the true incidence of rare adverse reactions. As an example, there are around 50 published case reports of meningioma with cyproterone acetate (Table), but a recent large study by the French government found that there were more than 500 operated instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (Aly, 2020). Accordingly, as of writing there are 40 reports of liver failure, including 25 consequent deaths, in association with bicalutamide in the U.S. FDA’s international MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Table.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (Graham, Ahmad, & Piazza-Hepp, 2002). Hence, the true numbers may be much greater. These instances are merely co-occurrences, and causality in terms of bicalutamide and liver toxicity has not been established. But they are concerning nonetheless. There is additionally an unpublished case anecdote of death in a young transfeminine person associated with bicalutamide that’s been making its rounds through the transgender medical community. Per certain very credible people in the field of transgender medicine (e.g., Asa Radix and Zil Goldstein), she is said to have been a 20-year-old transgender girl in Texas taking bicalutamide with rapid-onset liver failure and no warning signs. This case has given clinicians and researchers who are aware of it reservations about the use of bicalutamide in hormone therapy for transfeminine people. Another case of liver failure and death in a transgender person over 60 years of age who was treated with bicalutamide has also been informally reported (QueerDoc).

In any case, the reported cases of serious liver toxicity with bicalutamide in transgender people have not been published nor properly confirmed. In addition, the absolute incidence of liver toxicity with bicalutamide is likely to be very low. For instance, the incidence of abnormal liver function tests (i.e., elevated liver enzymes on blood work) was only 3.4% with high-dose (150 mg/day) bicalutamide monotherapy relative to 1.9% for placebo (a 1.5% difference attributable to bicalutamide) at 3.0 years of follow-up in the Early Prostate Cancer (EPC) clinical programme, a series of three phase 3 randomized controlled trials consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (Anderson, 2003; Iversen et al., 2004; Wiki; Wiki). Moreover, there were no cases of serious liver toxicity or liver failure with bicalutamide in the initial clinical development programme of bicalutamide for advanced prostate cancer, in which almost 4,000 men were treated with bicalutamide (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004; Wiki). However, it should be noted that this was with careful monitoring of liver function in patients and with prompt discontinuation of bicalutamide upon detection of clinically concerning hepatic abnormalities. About 0.5 to 1.5% of men taking 50 to 150 mg/day bicalutamide in the major clinical programmes of bicalutamide for prostate cancer developed liver changes sufficiently marked that they required discontinuation (Blackledge, 1996; See et al., 2002; Wiki). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.

Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (Kolvenbag & Blackledge, 1996; Schellhammer et al., 1997; Thole et al., 2004; Manso et al., 2006; Table). However, it retains a small risk of liver toxicity of its own—one with the potential for serious consequences. Hence, caution is warranted with its use, and careful liver monitoring is a necessity for anyone taking it.

Recent Developments and the Future

Bicalutamide is currently being adopted and characterized for use in the treatment androgen-dependent skin and hair conditions in cisgender women. For instance, a rigorous Italian phase 3 randomized controlled trial of bicalutamide for hirsutism was recently published (Moretti et al., 2018). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020; Moussa et al., 2021). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.

Certain transgender medical researchers are showing interest in bicalutamide as well. Perhaps most notably, Wylie Hembree—the lead author of the Endocrine Society’s 2009 and 2017 transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017)—wrote positively about bicalutamide for transfeminine people in a recent review (Fishman, Paliou, Poretsky, & Hembree, 2019). He and his colleagues cited the recent phase 3 trial of bicalutamide for hirsutism in cisgender women and the study of bicalutamide as a puberty blocker in transgender girls in support of potential use of bicalutamide for transfeminine people. Guy T’Sjoen—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (Hembree et al., 2017; Mitchell, 2020)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (Iwamoto et al., 2019). Researchers outside of the United States in particular may be more open to bicalutamide, owing to accumulating health concerns with cyproterone acetate—the most commonly used antiandrogen outside of the United States (Aly, 2020). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (Randolph, 2018), though he may have since changed his mind on it (Michigan Medicine, 2020). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).

The small risks of bicalutamide with appropriate monitoring may prove to be acceptable to the transgender medical community. This would perhaps be analogous to the rare incidences of serious adverse effects with say spironolactone (e.g., hyperkalemia) or cyproterone acetate (e.g., benign brain tumors, blood clots, breast cancer, liver toxicity). It’s possible that bicalutamide may not ultimately be recommended as a first-line therapy due to its risks. However, it could still be allowed as a second-line option when other antiandrogens are less feasible or not possible due to being for instance inadequately effective, poorly tolerated, contraindicated, or unavailable. The transgender medical community isn’t there at this time though. More developments—namely studies and characterization of bicalutamide in actual transfeminine people—are likely to be needed before bicalutamide could become more accepted for use in transfeminine people or recommended in transgender hormone therapy guidelines.

Updates

Update 1: Thompson et al. (2021) [Fenway Health Guidelines]

In March 2021, the Fenway Health transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (Aly, 2020):

  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]

This update is notable as these guidelines included bicalutamide as an antiandrogen option for transfeminine people. While they did not recommend bicalutamide as a first-line agent due to its limited characterization in transfeminine people and its known small risk of liver toxicity, they were cautiously permissive of its use in transfeminine hormone therapy:

Bicalutamide can be used for [gender-affirming hormone therapy], but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.

These are the first transgender care guidelines to allow the use of bicalutamide, and only the second guidelines to include bicalutamide. Previously, only the UCSF guidelines mentioned bicalutamide, but they were not permissive of its use in transfeminine people.

Update 2: Tomson et al. (2021) [SAHCS Guidelines]

In September 2021, the Southern African HIV Clinicians Society (SAHCS) published clinical guidelines for transgender care for the first time:

  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]

Surprisingly, these guidelines not only included bicalutamide but recommended it as the preferred antiandrogen over spironolactone and cyproterone acetate. The reason stated for this was “less risk of neurosteroid depletion (does not cross blood-brain-barrier readily).” However, this supposed effect isn’t a known concern with antiandrogens besides 5α-reductase inhibitors, and bicalutamide actually does appear to be centrally permeable in humans (Wiki). Also surprisingly, no mention of liver toxicity or liver enzyme monitoring with bicalutamide was made in these guidelines. Considering these apparent oversights and others, these guidelines’s recommendations should probably be interpreted with caution.

Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]

In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published (Coleman et al., 2022). The WPATH SOC8 are among the most important if not the most important transgender care guidelines that exist and that are consulted by health care professionals. These guidelines briefly discussed bicalutamide including in the following two instances:

Bicalutamide is an antiandrogen that has been used in the treatment of prostate cancer. It competitively binds to the androgen receptor to block the binding of androgens. Data on the use of bicalutamide in trans feminine populations is very sparse and safety data is lacking. One small study looked at the use of bicalutamide 50 mg daily as a puberty blocker in 23 trans feminine adolescents who could not obtain treatment with a GnRH analogue (Neyman et al., 2019). All adolescents experienced breast development which is also commonly seen in men with prostate cancer who are treated with bicalutamide. Although rare, fulminant hepatotoxicity resulting in death has been described with bicalutamide (O’Bryant et al., 2008). Given that bicalutamide has not been adequately studied in trans feminine populations, we do not recommend its routine use.

When selecting a medication, we advise using those which have been studied in multiple transgender populations (i.e., estrogen, cyproterone acetate, GnRH agonists) rather than medications with little to no peer-reviewed scientific studies (i.e., bicalutamide, rectal progesterone, etc.) (Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019).

As can be seen, the WPATH SOC8 did not recommend the routine use of bicalutamide in transfeminine people owing to the lack of studies of it in this population and its potential risks. As touched on in the present article, it is likely that more studies of bicalutamide in transfeminine people will be needed before bicalutamide could become endorsed by major transgender care guidelines.

Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case

In February 2023, Jamie Reed, a former case manager at the The Washington University Transgender Center at St. Louis Children’s Hospital in St. Louis, Missouri, published the op-ed “I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.” in a conservative online news outlet called The Free Press. In this article, Reed expressed that she had become disillusioned with the medical care of transgender youth and layed out her grievances. In addition however, she briefly described an additional case of liver toxicity with bicalutamide in a transfeminine person that had allegedly occurred at her center. This individual was said to be 15 years of age and was given bicalutamide as a puberty blocker by Dr. Christopher Lewis, one of the co-founders of the center. She was said to have subsequently developed liver toxicity and was taken off of bicalutamide. In an electronic message to the center, her mother said that they were “lucky her family was not the type to sue”. This instance, and Reed’s op-ed in general, were subsequently widely reported on in conservative news media, for instance on Fox News and in the Daily Mail (Google). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general Andrew Bailey, who proceeded to launch an investigation of the clinic (Missouri Government, 2023a). The following further information was released in the affidavit:

One doctor at the Center, Dr. Chris Lewis, is giving patients a drug called Bicalutamide. The drug has a legitimate use for treating pancreatic cancer [sic], but it has a side effect of causing breasts to grow, and it can poison the liver. There are no clinical studies for using this drug for gender transitions, and there are no established standards of care for using this drug.

Because of these risks and the lack of scientific studies, other centers that do gender transitions will not use Bicalutamide. The adult center affiliated with Washington University will not use this medication for this reason. But the Center treating children does.

I know of at least one patient at the Center who was advised by the renal department to stop taking Bicalutamide because the child was experiencing liver damage. The child’s parent reported this to the Center through the patient’s online self-reporting medical chart (MyChart). The parent said they were not the type to sue, but “this could be a huge PR problem for you.”

While unpublished and unverified like the earlier reports of liver toxicity with bicalutamide in transfeminine people, this case represents yet another report, and is notably by far the best-documented one. No other clinical details on the case were provided, and it is unclear whether it involved serious liver toxicity, merely asymptomatic liver function test abnormalities, or a clinical situation somewhere in-between these extremes. In any case, it does seem clear that this instance is not likely to have a positive influence on the further adoption of bicalutamide in transfeminine hormone therapy.

Subsequent to the investigation of the clinic being launched, in April 2023, Missouri greatly restricted gender-affirming care for transgender youth and adults, with some of the most severe limits that have been enacted in the United States (Associated Press, 2023a; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments. The new state law restricting gender-affirming care took effect August 28, 2023, and Washington University announced that it would stop prescribing puberty blockers and hormone therapy to transgender youth shortly thereafter (Associated Press, 2023b).

A New York Times article with additional information on the case was also subsequently published (Ghorayshi, 2023 [Excerpts]). It was noted that the adolescent had been on bicalutamide for 1 year and definitely experienced hepatotoxicity. However, she also had a complicated medical history, including being immunocompromised, having recently had COVID-19, and having taken another drug known to be associated with hepatotoxicity. As such, the hepatotoxicity cannot be definitively attributed to bicalutamide, but it simultaneously cannot be ruled out that bicalutamide was involved or causative.

Subsequent Burgener et al. (2023, 2024) Findings

Following the preceding case, Lewis and colleagues went on to publish a conference abstract and preprint of a study of bicalutamide in transfeminine youth and young adults in which they stated that it does not increase liver enzymes in this population (Burgener et al., 2023; Burgener et al., 2024). However, a closer look at their data show that bicalutamide did statistically significantly elevate certain liver parameters relative to other antiandrogens, namely rates of elevated aspartate aminotransferase (AST) (upper limit of normal 10.7% vs. 1.5%, P = 0.02) (Burgener et al., 2024). Likewise, rates of elevated alanine aminotransferase (ALT) appeared to trend in the direction of being increased, though this was not statistically significant (upper limit of normal 16.7% vs. 11.6%, P = 0.37) (Burgener et al., 2024). In any case, rates of clinically significant elevations in liver enzymes with bicalutamide, defined as greater than three times the upper limit of normal, were not significantly increased in the study.

On the basis of the relevant research in men with prostate cancer (Wiki), Lewis and colleagues’ study, with a bicalutamide-group sample size of only 84 transfeminine individuals, was clearly greatly underpowered for evaluating liver function changes. Per the Early Prostate Cancer trial of high-dose bicalutamide monotherapy in men with prostate cancer, elevated liver enzymes appear to occur with bicalutamide at a rate of only about 1.5% more than placebo, or roughly an additional 1 in every 66 people (Wiki). Based on power analysis, this would require a far larger sample size to have adequate statistical power and actually have a chance of achieving statistical significance.

As such, it seems to the present author premature to conclude that bicalutamide does not elevate liver enzymes in transfeminine people.

Lewis and colleagues didn’t mention in their study paper the transfeminine adolescent liver toxicity case reported by Jamie Reed that was said to have occurred at their clinic nor have they published a case report about this instance. Instead, only the following is stated:

One case report published in 2024 described a transgender female adolescent prescribed bicalutamide 50 mg daily who presented to a hospital with liver toxicity that resolved after stopping bicalutamide (Wilde et al., 2024). This appears to be the first documented case of bicalutamide-induced hepatoxicity in a transgender female.

While this case was, coincidentally, also a 17-year-old transfeminine adolescent (Wilde et al., 2024), this instance, per the medical histories and reporting authors/institutions, appears to be distinct from Dr. Lewis’s that was reported by Jamie Reed.

However, Lewis and colleagues did note the following in their paper, which plausibly might have been the Jamie Reed case:

There was one individual in whom bicalutamide was stopped after the follow-up period designated for the study. This individual developed ALT and AST >2x ULN after an episode of COVID and had a thorough hepatology evaluation. As ALT and AST were never > 3x ULN, it was not recommended that bicalutamide be stopped; however, ultimately a clinical decision was made to stop the medication and ALT and AST normalized.

Another concern with Lewis and colleagues’ paper pertains to the following statements:

Whereas bicalutamide doses for prostate cancer reach 150 mg daily, doses used in the care of AMAB transfeminine individuals are much lower (25-50 mg daily).

Bicalutamide doses used in prostate cancer are up to 150 mg daily. Due to these concerns of liver toxicity, bicalutamide has not been routinely used as an anti-androgen in AMAB transfeminine individuals, despite the much lower doses needed in this population (∼25-50 mg daily).

In actuality, bicalutamide is most widely used in prostate cancer, in the form of combined androgen blockade with surgical or medical castration, at a dosage of 50 mg/day, whereas the 150 mg/day dosage is used less commonly, in the form of monotherapy (Wiki). Moreover, only the 50 mg/day dosage is used in the United States, where monotherapy is not approved. Among the published case reports of hepatotoxicity with bicalutamide in men with prostate cancer, half have been at a dose of 50 mg/day and the other half have been at a dose of 80 to 150 mg/day (Wiki). The two instances of death due to hepatotoxicity with bicalutamide were both at 50 mg/day. There is currently no evidence that the hepatotoxicity of bicalutamide is dose-dependent across its clinically used dosage range (Wiki), although employment of the lowest effective dose in transfeminine people nonetheless seems prudent just in case. Hence, in contrast to Lewis and colleague’s claims, a bicalutamide dosage of 50 mg/day is not less than that generally used in prostate cancer, and clearly retains substantial hepatotoxic potential.

Update 5: New Bicalutamide Publications in 2022 Through 2024

  • Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
  • Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
  • Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]), 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
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Update 6: Original Bicalutamide Liver and Lung Toxicity Analysis by Sam

A few years ago back in 2021, Transfeminine Science author Sam conducted an original analysis of the incidence of liver and lung toxicity with bicalutamide in the published clinical trial literature. This project was never finished or made publicly available. However, with bicalutamide being increasingly studied and adopted for use in transfeminine people, it seems quite valuable and relevant today. As such, we have opted to now publish Sam’s analysis in this section.

Sam’s analysis can be found in the provided document here. In terms of methodology, she searched PubMed for all clinical trials of bicalutamide, collated all of the relevant results into a table, and then calculated the incidences of serious liver toxicity and lung toxicity from those data. In clinical trials, adverse events are rated in terms of grades of severity, with a Grade 3 adverse event defined as “severe”, Grade 4 as “life-threatening”, and Grade 5 as “death” (Wiki).

Of 229 results, 33 trials were found to be relevant and were included. Most of the trials were in men with prostate cancer, but a few were in women with cancer and boys with precocious puberty. Sam found that of a total of 7,703 evaluable participants, there were 2 instances of serious liver toxicity and 2 instances of serious lung toxicity with bicalutamide. This resulted in the same incidence rate of 0.026% (95% CI: 0.003% to 0.094%) or approximately 1 in 3,846 individuals for both liver toxicity and lung toxicity. Combining these toxicities resulted in a total incidence of serious liver or serious lung toxicity with bicalutamide of 0.052% (95% CI: 0.014% to 0.133%) or approximately 1 in 1,923 individuals. All of the observed toxicity events were rated as Grade 3 or 4. It should be noted that clinical trials of bicalutamide typically employ careful laboratory monitoring and assessment of clinical adverse events as well as prompt medication discontinuation upon unfavorable laboratory changes.

While the confidence intervals (CIs) in Sam’s analysis were wide and hence the estimates are very rough, they provide an idea of the potential real-world risk of serious toxicity with bicalutamide in transfeminine people based on high-quality clinical data. Notably, they do not suffer from the problem of under-reporting of adverse events that occurs with published case reports, pharmacovigilance databases, and certain types of observational studies. However, limitations of Sam’s analysis include (1) toxicity incidence rates for non-bicalutamide-treated controls not being assessed and (2) most of the patients having cancer and being of older age, and hence the generalizability of the findings to healthy transfeminine people not being fully clear. In any case, I was surprised by how high the incidence rates were when I first saw her analysis, and I suspect that others may be as well.

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