By Aly W. | First published July 1, 2020 | Last modified November 20, 2020
Bicalutamide is an antiandrogen which was introduced for prostate cancer many years ago. Cost precluded its 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, these risks are low—though still significant—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 spoken positively about it. Bicalutamide may ultimately come to be regarded as acceptably safe for use in transfeminine hormone therapy, similarly to spironolactone and cyproterone acetate. But more studies and characterization of bicalutamide in transfeminine people will be needed before it will see widespread adoption in transgender medicine.
Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selective antagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in 1995. It has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of effectiveness, selectivity, and tolerability. However, use of bicalutamide as an antiandrogen in transfeminine hormone therapy is very new. 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effective antiandrogens like abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care antiandrogen for the treatment of prostate cancer.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 brought the cost of bicalutamide way down and it has gradually become much more affordable in the last decade. Bicalutamide still remains somewhat more expensive than conventional antiandrogens like spironolactone and cyproterone acetate however.
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 mention of bicalutamide for transfeminine people in the literature was by Louis Gooren (Gooren, 2011), a major longtime researcher in the field of transgender medicine and one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). Gooren and his colleagues at the VUMC in Amsterdam had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (Wiki). However, they seemingly abandoned it—probably due to its high incidence of lung toxicity. As a researcher interested in the idea of nonsteroidal antiandrogens for transfeminine people, bicalutamide—with its far better safety profile than nilutamide—surely appealed 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.
Although there was little use or discussion of bicalutamide in transfeminine people prior to 2015, this began to change rapidly in mid-2015. The Wikipedia article for bicalutamide progressively expanded from this to its present state and information about bicalutamide became more accessible. In addition, certain transfeminine people, such as myself and Juno Krahn of the TransHRT Facebook group, started advocating for use of bicalutamide in transfeminine hormone therapy online. A number of adventurous clinicians began adopting bicalutamide in transfeminine people at this time and thereafter as well. The first clinical study of bicalutamide in transfeminine people was published as an abstract in 2017 and as a full paper in 2019 (Neyman, Fuqua, & Eugster, 2017 (PDF); Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a puberty blocker in adolescent transgender girls and remains the only published clinical data on bicalutamide in transfeminine people at present. It’s not exactly great data by any means, but it’s a study at least. Moreover, it’s generating significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.
In any case, due to the recentness of bicalutamide for 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. Transgender hormone therapy guidelines largely don’t even mention it still. The use of bicalutamide in transfeminine people is mostly limited at present to a small number of more open-minded clinicians and to the transgender DIY/self-medication community.
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). That’s an acceptable risk in men with prostate cancer because the benefit–risk ratio is very high—the benefit of treating prostate cancer vastly outweighs the harm of the rare instances of liver toxicity. But transfeminine people are typically young and healthy and bicalutamide isn’t treating a terminal illness when used in us. If a transfeminine person develops liver failure and dies because of bicalutamide then that’s unnecessary harm and a life needlessly lost. Accordingly, the UCSF guidelines by Maddie Deutsch currently warn against use of bicalutamide in transfeminine people due to potential liver risks (Deutsch, 2016). There is also a lack of data to guide appropriate dosing of bicalutamide in transfeminine people (Aly W., 2019). A typical bicalutamide dosage of 50 mg/day is being used and recommended, but this is arbitrary with little basis to support it.
To date there are only 8 published case reports of serious liver toxicity in association with bicalutamide, all in men with prostate cancer (Wiki-Table). But quantity of published case reports tends to vastly underestimate the true incidence of rare adverse reactions like these. As an example, there are about 50 published case reports of meningioma with cyproterone acetate (Wiki-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, there are 40 reports of liver failure, including 25 consequent deaths, in association with bicalutamide in the U.S. FDA’s MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Wiki-Table.) These instances are merely co-occurrences, and causality in terms of bicalutamide and liver toxicity has not been established, but they are concerning nonetheless. In addition, there is an unpublished case anecdote of death in a young transfeminine person caused by bicalutamide that’s been making its rounds through the transgender medical community. Per a few important 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 case remains to be 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 taking bicalutamide to ensure that the possibility of severe liver toxicity is avoided.
Although bicalutamide has a much lower risk of liver toxicity than its analogue flutamide, it retains a small risk of liver toxicity of its own—one with potentially serious consequences.
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 recently been published (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 colleague of Gooren at the VUMC as well as 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). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).
The risks of bicalutamide with appropriate safety monitoring may ultimately prove to be acceptable to the transgender medical community. This would be analogous to the rare incidences of serious adverse effects with say spironolactone (e.g., hyperkalemia; Wiki) or cyproterone acetate (e.g., liver toxicity, brain tumors, blood clots, breast cancer, etc.; Wiki). The medical community isn’t there yet though. More developments—namely clinical studies and characterization of bicalutamide in actual transfeminine people—will likely be needed before bicalutamide could become widely accepted for use in transfeminine people or recommended in transgender hormone therapy guidelines.