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

By Aly W. | First published July 1, 2020 | Last modified September 21, 2021

Abstract / TL;DR

Bicalutamide is an antiandrogen which was introduced for 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. 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. But 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 (Aly W., 2019) 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; Aly W., 2019). 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 seemingly 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; Aly W., 2019). 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; Lenz et al., 2010; Reiter et al., 2010; Lewis et al., 2009; Mitre & Lteif, 2009; Stenger et al., 2009; 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 use or discussion of bicalutamide in transfeminine people prior to 2015, this started to change in mid-2015. The Wikipedia content for bicalutamide progressively expanded from a barebones page to the present state, and information about bicalutamide became more accessible. In addition, certain transfeminine people, such as myself—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 at 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) is helping 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 (Aly W., 2019). 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 W., 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 a few very credible people in the field of transgender medicine, 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.

In any case, the transfeminine case has not been published and 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 in a 4,000-patient phase 3 randomized controlled trial—a 1.5% higher incidence attributable to bicalutamide (Anderson, 2003; Iversen et al., 2004). Moreover, there were no cases of serious liver toxicity or liver failure with bicalutamide in over 8,000 treated men in rigorous clinical trials of bicalutamide for prostate cancer (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004). However, 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 1.4% of men taking 50 to 150 mg/day bicalutamide in clinical trials developed liver changes that required discontinuation (Blackledge, 1996; See et al., 2002). Hence, regular liver monitoring is essential in people using bicalutamide to ensure that the possibility of severe liver toxicity is avoided.

Bicalutamide has a far 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 women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020). The latter studies have observed low though significant rates of liver changes with bicalutamide.

Certain transgender medical researchers are showing interest in bicalutamide as well (Aly W., 2019). 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 W., 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 e.g. inadequately effective, poorly tolerated, contraindicated, unavailable, etc.). The transgender medical community isn’t there yet 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.

Update

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 W., 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.

More excerpts on bicalutamide for transfeminine people from the Fenway Health guidelines, including recommendations on safety monitoring, are provided elsewhere (Aly W., 2019).

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