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Bicalutamide as anti-androgenic therapy in gender-affirming care for adolescents and young adults: a retrospective chart review

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Bicalutamide as anti-androgenic therapy in gender-affirming care for adolescents and young adults: a retrospective chart review

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Content Copyright 2024 Jonathan Daniel Warus, MD
BICALUTAMIDE AS ANTI-ANDROGENIC THERAPY IN GENDER-AFFIRMING CARE FOR
ADOLESCENTS AND YOUNG ADULTS:
A RETROSPECTIVE CHART REVIEW
by
Jonathan Daniel Warus, MD
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL, BIOMEDICAL AND TRANSLATIONAL INVESTIGATIONS)
December 2024

ii
ACKNOWLEDGEMENTS
This project was conducted in part with support from the Southern California Clinical
and Translational Science Institute (SC CTSI) through grant KL2TR001854.
This research and manuscript preparation would not have been possible without the
contributions from all team members and thesis committee members including Marianela
Jordan, Bianca Salvetti, Amy Mora, Johanna Olson-Kennedy, Marvin Belzer, and Cecilia
Patino-Sutton. I would also like to acknowledge our patients in the Center for Transyouth
Health and Development within the Division of Adolescent and Young Adult Medicine at
Children’s Hospital Los Angeles for bravely living their truth and teaching us more about this
care every day. Lastly, I would like to express my heartfelt appreciation to my parents,
siblings, nephews, niece, and partner. Thank you all for your unwavering love,
encouragement, and support.

iii
TABLE OF CONTENTS
Acknowledgements ...................................................................................................... ii
List of Tables ............................................................................................................... iv
List of Figures ............................................................................................................... v
Abstract ...................................................................................................................... vi
Chapter One: Introduction.............................................................................................1
Gonadotropin-Releasing Hormone Agonists.............................................................1
Spironolactone.......................................................................................................2
Bicalutamide..........................................................................................................3
Chapter Two: Methods ..................................................................................................6
Study Design..........................................................................................................6
Measures...............................................................................................................6
Statistical Analysis .................................................................................................8
Chapter Three: Results................................................................................................ 10
Participant Characteristics ................................................................................... 10
Reasons for Bicalutamide Use and Dosing ............................................................. 11
Bicalutamide Side Effects, Adverse Effects, and Reasons for Discontinuation .......... 12
Reported Side Effects of Bicalutamide ............................................................... 12
Bicalutamide Dose and Concern for Continued Masculine Changes .................... 12
Reasons for Bicalutamide Discontinuation......................................................... 13
Liver Testing Results ......................................................................................... 14
Participants with Moderately Elevated ALT or Liver Concerns .............................. 14
Switching from Spironolactone to Bicalutamide ..................................................... 15
Chapter Four: Discussion............................................................................................ 17
Reasons for Bicalutamide Use, Medication Dosing, and Efficacy ............................. 17
Bicalutamide Side Effects, Adverse Effects, and Reasons for Discontinuation .......... 18
ALT Elevations on Bicalutamide............................................................................. 18
Potential Benefits of Bicalutamide......................................................................... 19
Summary, Strengths, and Limitations .................................................................... 20
Conclusions and Recommendations ..................................................................... 21
References................................................................................................................. 23
Appendix .................................................................................................................... 27

iv
LIST OF TABLES
Table 1: Participant Characteristics.............................................................................. 25
Table 2: Reasons for Bicalutamide Use & Medication Doses .......................................... 26
Table 3: Reported Side Effects and Concerns on Bicalutamide....................................... 26
Table 4: Reasons for Bicalutamide Discontinuation....................................................... 27
Table 5: Reasons for Switching from Spironolactone to Bicalutamide and Documented
Improvement.............................................................................................................. 27

v
LIST OF FIGURES
Figure 1: Flowchart of Participant Selection and ALT Measurement Availability ............... 28
Figure 2: Age at First Bicalutamide Prescription............................................................. 28
Figure 3: Maximum ALT While on Bicalutamide ............................................................. 29

vi
ABSTRACT
Gender-affirming medical intervention for adolescents and young adults (AYAs) with
functioning testes and a transfeminine gender identity often involves the use of a
testosterone-blocking medication and feminizing hormone. The most commonly used
testosterone-blocking medications in the United States are gonadotropin releasing
hormone (GnRH) agonists and spironolactone, but their use can be limited by cost, side
effects, and adverse events. Bicalutamide is an androgen receptor blocker FDA-approved
for the treatment of prostate cancer. Increases in liver enzymes with bicalutamide are
uncommon, transient, and often asymptomatic. Two small retrospective chart review
studies involving transgender youth have shown clinical efficacy of bicalutamide with no
side effects. However, practitioners have been hesitant to use this medication given case
reports of bicalutamide-associated fulminant hepatitis in cisgender men 59-88 years of age
for prostate cancer treatment and the lack of larger studies providing safety data in
transgender and gender diverse populations.
The goal of this study was to describe demographic characteristics of AYAs who
were prescribed bicalutamide for the treatment of gender dysphoria and to assess
hepatotoxicity and other reported side effects or adverse events. A retrospective chart
review was conducted in the Center for Trans Youth Health and Development at Children’s
Hospital Los Angeles for all patients who were prescribed bicalutamide for this purpose
between August 2018 and February 2023.
Results: In this study, 393 AYAs 10-24 years of age were prescribed bicalutamide for
the treatment of gender dysphoria. The mean time on bicalutamide was 1.99 years, with a

vii
total follow-up time of 782 person-years. Most patients (91.3%) reported no side effects
and three patients had moderately elevated ALT levels. All three patients were
asymptomatic, required no treatment, and ALT elevation resolved without stopping
bicalutamide. Providers should consider bicalutamide as another option for anti-androgen
therapy and remember to center patients and families in shared decision-making regarding
treatment.

1
CHAPTER ONE: INTRODUCTION
Gender incongruence refers to the condition of an individual whose gender identity
does not align with their sex assigned at birth (Coleman et al., 2022). While gender
incongruence is not a pathological state, it is often accompanied by gender dysphoria or
the experience of distress related to this discordance that often results in impairments in
psychosocial functioning (Rafferty et al., 2018). Gender-affirming medical interventions,
when indicated, have been shown to have positive effects on mental health, quality of life,
and overall well-being, and are considered medically necessary treatments for patients
with gender dysphoria (Becker-Hebley, et al. 2021; Tordoff, et al. 2022).
Gonadotropin-Releasing Hormone Agonists
Medical interventions for individuals with functioning testes and a feminine gender
identity may involve the use of both a testosterone-blocking medication and feminizing
hormones. The most commonly used testosterone-blocking medications in the United
States are gonadotropin-releasing hormone (GnRH) agonists and spironolactone. The
effects of GnRH agonists are reversible, and their mechanism of action involves
interrupting the pulsatile GnRH signal from the hypothalamus to the pituitary gland,
thereby turning off pituitary production of luteinizing hormone (LH) and follicle stimulating
hormone (FSH), which turns off gonadal tissue production of testosterone and estradiol.
While GnRH agonists are frequently preferred in youth, they are not widely available in oral
preparations and use is often limited by variable insurance coverage and high out-ofpocket costs. Further, there is some concern about the possibility of low bone mineral

2
density with prolonged use in the absence of both estradiol and testosterone (Neyman et
al., 2019; Salas-Humara et al., 2019).
Spironolactone
Spironolactone is a mineralocorticoid receptor blocker originally developed for the
treatment of heart failure and is often dosed twice daily due to its short elimination half-life
of 1.4 hours (Maron & Leopold, 2008). As spironolactone also binds to and blocks androgen
receptors, it has been used in the treatment of polycystic ovarian syndrome, acne, and
gender dysphoria (Lainscak et al., 2015; Salas-Humara et al., 2019; Searle et al., 2020).
Due to its effects on the kidney as a potassium-sparing diuretic, there have been concerns
for increased rates of hyperkalemia associated with spironolactone use in heart failure
treatment with studies showing mixed results (Desai et al., 2022; Pitt et al., 2014). In one
study of gender-affirming care, spironolactone use in transgender adults showed a
significantly increased risk of hyperkalemia in transgender patients over the age of 45 years
when compared to those 45 years or younger (Hayes et al., 2022). Other studies in
transgender adults and adolescents have not shown an increase in hyperkalemia with
spironolactone use for androgen blockade, with two studies showing that infrequent
hyperkalemia was often transient and asymptomatic (Gupta et al., 2022; Millington et al.,
2019; Millington et al., 2024). While spironolactone is a low-cost alternative that is
available to be taken by mouth twice daily, side effects (particularly polyuria, polydipsia,
lightheadedness, and hypotension) can be bothersome or unacceptable for some patients
(Salas-Humara et al., 2019).

3
Bicalutamide
Bicalutamide is a potent nonsteroidal peripheral androgen receptor blocker that is
FDA-approved for the treatment of metastatic prostate cancer and is available for daily oral
administration given its long elimination half-life of 7 days. Based on its mechanism of
action, bicalutamide often leads to an increase in LH and FSH due to a lack of negative
feedback at the level of the hypothalamus and pituitary gland with subsequent increase in
production of testosterone and estradiol (Goa & Spencer, 1998). In prostate cancer studies,
testosterone is effectively blocked at the receptor level and the presence of estradiol has
been shown to preserve bone mineral density in contrast to GnRH analogs (Wellington &
Keam, 2007). The most commonly reported side effects of bicalutamide include breast
tenderness, gynecomastia, diarrhea, nausea, and hot flashes (Goa & Spencer, 1998).
In population studies, bicalutamide has been associated with mild, transient, and
asymptomatic liver enzyme elevations in around 6% of patients (LiverTox, 2023). In clinical
trials, clinically meaningful elevations in liver enzymes necessitating discontinuation of
bicalutamide occurred in 1% of patients, and the FDA indicates that cases of
hepatotoxicity generally occur within 3-4 months of starting the medication (AstraZeneca
Pharmaceuticals LP, 2017). Since 1997, in seven cases involving older adult cisgender
males with prostate cancer, bicalutamide was taken prior to the onset of possible druginduced liver injury (DILI). In one of these cases, DILI was instead attributed to
enzalutamide use (Liu et al., 2019). Of the four cases in those 60-81 years of age that
resulted in resolution after discontinuation and supportive care, three had questionable
timelines that are not consistent with typical presentations of DILI and two used a higher

4
dose of bicalutamide at 100-150 mg daily (Dawson et al., 1997; Hussain et al., 2014; Saito,
2020; Yun et al., 2016). Of the two cases in those 59-61 years of age that resulted in death,
one also had a questionable timeline for DILI attributable to bicalutamide and did not
specify the dose used (Castro Beza et al., 2008; O’Bryant et al., 2008). In all of these cases,
proving the causality of bicalutamide in DILI can be very difficult due to many comorbidities
associated with patient age and diagnoses as well as concomitant treatments.
As bicalutamide works by blocking the effects of testosterone, it has also been used
off-label in younger patients for the treatment of some forms of precocious puberty in
cisgender males at a recommended dose of 2 mg/kg per day and for hirsutism in cisgender
females with polycystic ovarian syndrome at a dose of 50 mg per day (Lenz et al., 2010;
Moretti et al., 2018). Due to concerns about possible DILI associated with bicalutamide,
this medication has not been used as widely in gender-affirming care. In 2019, a pilot study
was conducted using bicalutamide for androgen blockade in those designated male at
birth due to the cost-prohibitive nature of accessing GnRH analog medications and
concerns about side effects of spironolactone in younger patients. This study of 23 patients
12 to 18 years of age showed that bicalutamide was effective at preventing masculine
changes, resulted in varying amounts of breast development, and no liver side effects were
observed (Neyman et al., 2019). Three subsequent studies of bicalutamide in genderaffirming care showed similar results with no concerns for DILI among 317 patients
(Burgener et al., 2023; Ozturan et al., 2023; Vierregger et al., 2023). There has recently been
one case report of possible bicalutamide-associated DILI in a 17-year-old transgender
female which resulted in complete resolution (Wilde et al., 2024).

5
Given the cost and concern of potential bone density loss with GnRH agonist
medications and side effects with spironolactone, bicalutamide could represent an
alternative option for androgen blockade in gender-affirming care; however, providers have
been hesitant to prescribe bicalutamide in gender-affirming care due to a possible link to
DILI in prostate cancer research and the lack of data in transgender and gender diverse
adolescents and adults. Therefore, this descriptive study aims to provide comprehensive
data among AYAs who have been prescribed bicalutamide for androgen blockade in the
treatment of gender dysphoria, including demographics, reasons for use, side effects and
adverse effects of medication, including liver concerns, and patient experiences in
switching from spironolactone to bicalutamide.

6
CHAPTER TWO: METHODS
Study Design
This study consisted of a retrospective chart review within one large urban
academic center in Los Angeles providing gender-affirming care to adolescents and young
adults (AYAs) up to 24 years of age. Participants included patients designated male at birth
with a diagnosis of gender dysphoria and an initial prescription written for bicalutamide
between August 2018 and February 2023. Patients were initially identified through the
electronic medical record using diagnosis and prescription information. Any duplicate
patients were removed, and charts were further assessed to ensure that participants
started the medication and had at least one follow-up data point after their first
prescription in order to be included in the study. Charts were then reviewed by four
investigators using agreed upon standardized instructions for consistency and each chart
was reviewed twice for accuracy. There were no discrepancies between reviewers.
Measures
Demographic measures included age at first prescription for bicalutamide
(calculated using date of birth and date of first prescription), gender identity (as
documented in the chart with multiple selections allowed as needed), health insurance
type (as registered in the medical record at the time of chart review), race/ethnicity (as
documented at registration with the clinic), and concomitant use of estradiol and/or
progesterone. Data points collected related to bicalutamide included reasons for
bicalutamide use (early puberty with no GnRH agonist, late/post puberty with no GnRH
agonist, bridge to GnRH agonist only, after GnRH agonist only, or both bridge to and after

7
GnRH agonist), minimum and maximum dose of bicalutamide during the study period,
reasons for not using GnRH agonists (for those using bicalutamide in early puberty with no
GnRH agonist, with multiple selections allowed), side effects reported on bicalutamide,
and reasons for discontinuing bicalutamide (in those who stopped the medication during
the study period). For patients who were previously taking spironolactone and switched to
bicalutamide, additional data points extracted included reasons for switching from
spironolactone and whether there was documented improvement in spironolactonerelated side effects or concerns after switching to bicalutamide.
In assessing DILI, the laboratory value that is most specific to liver injury is alanine
aminotransferase (ALT), whereas aspartate aminotransferase (AST) is also present in red
blood cells as well as heart, brain, skeletal muscle, and kidney tissue (Giannini et al.,
2005). For setting the upper limit of normal (ULN) for ALT laboratory values, the most
conservative (lowest) value of 22 U/L was selected from all normal ranges for those in the
study’s age demographic (Anderson, 2023). The ranges of ALT elevation categories were
then calculated based on the most recent cutoffs set by the American College of
Gastroenterology (mild = 2-5x ULN = 44-110 U/L, moderate = 5-15x ULN = 111-330 U/L,
severe = >15x ULN = >330 U/L) (Kwo et al., 2017). Of note, according to one source, the
most sensitive and specific level to identify acute toxic liver injury for ALT is at a level of 300
U/L with sensitivity of 96% and specificity of 94%. This is due to the fact that lower ALT
elevations are more often seen associated with idiopathic causes, metabolic dysfunctionassociated steatotic liver disease, chronic hepatitis, liver cirrhosis, alcoholic liver disease,
and autoimmune hepatitis (Giannini et al., 2005).

8
Statistical Analysis
Descriptive statistics were used to characterize all patient demographic data as well
as bicalutamide and spironolactone data. Frequencies were reported for all categorical
variables (i.e., demographics, reasons for medication use and discontinuation, and side
effects and concerns) while means and standard deviations were reported for all
continuous variables (i.e., medication dose, time on medication, and maximum ALT). Time
on bicalutamide was calculated separately for each of three sub-cohorts based on
treatment status at the time of chart review. For those still on bicalutamide at the time of
chart review, time on bicalutamide was calculated using the date of the chart review and
the date of the first bicalutamide prescription. For those with documented discontinuation
of bicalutamide during the interval covered by the chart review, time on bicalutamide was
calculated using the documented date of stopping bicalutamide and the date of the first
bicalutamide prescription. For those with no documented discontinuation of bicalutamide
and unknown status of anti-androgenic medication at the time of chart review, time on
bicalutamide was calculated using the date of their last visit documenting bicalutamide
use and the date of the first bicalutamide prescription. Time on bicalutamide was then
added for all three sub-cohorts to obtain a total time on bicalutamide for the entire cohort.
Mantel-Haenszel’s Chi-Square test was used to assess the association between maximum
bicalutamide dose (dichotomous: 25 mg vs 50 mg) and concern for continued masculine
changes while on bicalutamide (dichotomous: yes vs no) while controlling for pubertal
status (those in early vs late endogenous puberty) with the Breslow-Day being used to

9
determine homogeneity of the common odds ratio. Statistical significance level was set at
0.05 and all statistical analyses were conducted using SPSS version 29.0.1.0 (IBM).

10
CHAPTER THREE: RESULTS
Participant Characteristics
A total of 425 charts were identified using diagnosis and prescription data from the
electronic medical record. Four were removed as duplicates; nine were removed due to
never starting bicalutamide; and 19 were removed due to lack of any follow-up data points
after their first bicalutamide prescription, resulting in a final total of 393 patients (see
Figure 1). Participant age at first bicalutamide prescription ranged from 10 to 24 years with
a mean of 16.6 ± SD 3.1 years (see Figure 2). The majority of participants (90.1%) identified
as female or transgender female with 7.9% identifying as transfeminine and 7.4%
identifying as non-binary. Most (66.9%) had commercial insurance and 32.3% were insured
by Medicaid. The most commonly self-reported race was White (47.3%) followed by
Multiracial (10.7%), and Asian (7.1%), with only 3.3% identifying as Black. Of the
participants included in the chart review, 27.2% identified as Hispanic or Latiné.
Most participants (92.1%) were taking bicalutamide in combination with estradiol
with 82.4% taking oral estradiol, 26.7% taking injectable estradiol, and 8.4% using estradiol
patches during the course of the review period. Progesterone was also commonly taken
during the review period with 72.3% of participants being prescribed this medication in
conjunction with bicalutamide. The mean maximum dose of bicalutamide during the
review period was 45.8 ± 9.4 mg/day. The total time on bicalutamide for the entire cohort
was 781.97 person-years and for each individual ranged from 0.06-5.16 years with a mean
of 1.99 ± 1.20 years (see Table 1). Of all participants, 89.3% were on bicalutamide for at
least 6 months.

11
Reasons for Bicalutamide Use and Dosing
The majority of participants (69%) were taking bicalutamide after progression into
late endogenous puberty with no history of GnRH analog medication use. Additionally,
2.5% of participants previously started a GnRH analog medication in late puberty and then
transitioned to bicalutamide. Forty-four participants (11.2%) used bicalutamide in early
puberty with no GnRH analog medication use. Thirty-seven participants (9.4%) previously
started a GnRH analog medication in early puberty and then transitioned to bicalutamide.
The remaining 8.9% of participants used bicalutamide on a short-term basis in early
puberty as a “bridge” medication to block testosterone while awaiting the approval and
administration of a GnRH analog medication. Note that four participants used
bicalutamide both as a bridge to early puberty GnRH analog medication and after use of
early puberty GnRH analog (see Table 2).
Of the 44 participants who did not use a GnRH analog medication, 15 (34.1%)
experienced cost or insurance issues, 11 (25.0%) expressed concern about the necessary
procedures involved (i.e., implantation or injection), 4 (9.1%) wanted the breast
development effects of bicalutamide, 2 (4.5%) expressed concerns around the potential
bone density side effects of GnRH analogs, and 1 (2.3%) had desire for potential additional
genital growth for future gender-affirming surgery.
For the 318 participants using bicalutamide in late puberty (no GnRH analog) or
after GnRH analog medication use, 264 (83%) used a minimum dose of 50 mg daily and
287 (90%) used a maximum dose of 50 mg daily during the study period. For the 79
participants using bicalutamide in early puberty (no GnRH analog) or as a bridge to GnRH

12
analog medication use, 56 (70.9%) used a minimum dose of 25 mg daily and 42 (53.2%)
used a maximum dose of 50 mg daily during the study period. In general, for those
participants at younger ages (generally within 1-2 years of the onset of their endogenous
puberty), bicalutamide was most often dosed at 25 mg (one-half of a 50 mg tablet) by
mouth daily. For most participants who were further out from the onset of their
endogenous puberty (regardless of how much endogenous puberty they went through),
bicalutamide was most often dosed at 50 mg by mouth daily (see Table 2).
Bicalutamide Side Effects, Adverse Effects, and Reasons for Discontinuation
Reported Side Effects of Bicalutamide
Most participants (91.3%) had specific documentation of no side effects while
taking bicalutamide during the study period with an additional 2.3% having no comments
regarding the presence or absence of side effects documented in the chart. Twelve
participants (3.1%) reported concern for bicalutamide inefficacy manifesting as concern
for continued masculine changes such as facial hair growth, body hair growth, voice
deepening, or laryngeal tissue growth. Eight participants (2%) expressed mood concerns,
five (1.3%) endorsed hot flashes, three (0.8%) reported nausea, three (0.8%) reported hair
loss on the scalp, and two (0.5%) reported asymptomatic concerns for liver safety (see
Table 3).
Bicalutamide Dose and Concern for Continued Masculine Changes
For those in early endogenous puberty, 2 (4.4%) of the 45 participants taking 25 mg
of bicalutamide daily reported concern for continued masculine changes compared to 4
(6.0%) of the 67 participants taking 50 mg. For those in late endogenous puberty, 3 (14.3%)

13
of the 21 participants taking 25 mg of bicalutamide daily reported concern for continued
masculine changes compared to 4 (1.2%) of the 260 participants taking 50 mg. The MantelHaenszel’s Chi-Square test yielded a significant Breslow-Day test [χ
2
(1) = 12.59, p < 0.001]
indicating heterogeneity of the odds ratio. Each strata (early vs late endogenous puberty)
was then analyzed separately using Fisher’s Exact test due to the presence of cells with
expected count less than 5. For those in early endogenous puberty, there was no significant
association between bicalutamide dose (25 mg vs 50 mg) and concern for continued
masculine changes (p = 0.223). For those in late endogenous puberty, there was a
significant association between bicalutamide dose and concern for continued masculine
changes with the concern for inefficacy occurring more often in those on 25 mg (p = 0.006).
Reasons for Bicalutamide Discontinuation
During the study period, 92 of the 393 participants (23.4%) discontinued
bicalutamide. Of those who discontinued bicalutamide, 59 (64.1%) stopped bicalutamide
as the medication was no longer medically indicated (i.e., after the planned bridge use of
bicalutamide was completed, after orchiectomy, or because testosterone was suppressed
on blood work). Only nine individuals (2.2% of all participants) discontinued bicalutamide
due to concern for inefficacy. Other less common reasons for discontinuation included
high testosterone level on blood work, concerns about liver safety, change in goals for
gender expression, excessive breast growth, scalp hair loss, low libido, mood concerns,
nausea, desire to limit linear growth (i.e., height), and inability to check routine liver
surveillance labs due to needle phobia (see Table 4).

14
Liver Testing Results
Baseline ALT results obtained prior to starting bicalutamide were available in 81.2%
of all participants. Of the 320 patients with follow-up ALT data, the mean maximum ALT
during bicalutamide treatment for all participants was 22.6 ± 21.7 U/L. Maximum ALT was
below two times the ULN for 296 participants (92.5%). Twenty-one participants (6.6%) had
mild ALT elevation between two and five times the ULN while on bicalutamide, fifteen of
which decreased to below two times the ULN on subsequent recheck without stopping
medication, and six of which did not have a subsequent value available. Three participants
(0.9%) had moderate ALT elevation greater than five times the ULN (see Figure 3). No
participants had severe ALT elevation (>330 U/L) and no participants had ALT elevation
above the most sensitive and specific level to identify acute toxic liver injury (>300 U/L).
Participants with Moderately Elevated ALT or Liver Concerns
Three participants with moderate ALT elevation had a mean age at first bicalutamide
prescription of 15.7 ± 1.2 years, all identified as female or transgender female, with two
identifying as Hispanic Latiné on Medicaid insurance and 1 identifying as non-Hispanic
White on commercial insurance. All three participants were taking bicalutamide 50 mg
daily in late puberty with no history of GnRH analog use and all were on estradiol with two
participants also taking progesterone. The total mean time on bicalutamide for these three
participants was 3.1 ± 1.5 years with a mean maximum ALT during bicalutamide treatment
of 191 ± 87.3 U/L and all were asymptomatic (see Table 1).
One of these cases occurred 15 months after starting bicalutamide during
admission for acute malnutrition secondary to disordered eating with ALT decreasing from

15
126 U/L to 51 U/L at six months after hospital discharge while still taking bicalutamide. The
second case had a history of seizures and substance use and was also taking other
potentially hepatotoxic medications (valproic acid, topiramate, mirtazapine, and
quetiapine) and had ALT elevation three months after starting bicalutamide. This
participant had a decrease of their ALT from 156 U/L to 79 U/L after three months and
subsequent decrease to 26 after an additional 14 months while still taking bicalutamide.
The last case had no known risk factors for hepatotoxicity and ALT elevation of 290 U/L
occurred 3.5 months after starting bicalutamide with normalization to 11 U/L at six months
without discontinuing bicalutamide.
In addition, two participants discontinued bicalutamide due to liver concerns. One
participant was 14 years of age and had ALT elevation to 85 U/L seven months after starting
bicalutamide. This patient switched to spironolactone and ALT normalized to 14 U/L four
months after discontinuing bicalutamide. The second participant was 14 years of age and
had ALT elevation to 40 U/L six months after starting bicalutamide. This patient also
switched to spironolactone and ALT normalized to 12 U/L ten months after discontinuing
bicalutamide.
Switching from Spironolactone to Bicalutamide
During the study period, 93 participants switched from spironolactone to
bicalutamide for androgen blockade. The most common spironolactone-related concerns
cited as the reason for switching included frequent urination (31.2%),
dizziness/hypotension (12.9%), concern for spironolactone inefficacy (12.9%), and brain
fog (8.6%). Some participants only had a patient preference for switching documented

16
(26.9%), 5.4% switched due to less frequent dosing with bicalutamide, and 22.6% of
participants did not have any reason for switching documented. Of note, no patients who
switched from spironolactone had clinician concern for hyperkalemia.
Of the 29 participants who switched to bicalutamide due to concerns for frequent
urination with spironolactone, 26 (89.7%) had documented improvement. In addition, of
those who switched to bicalutamide due to concerns for dizziness/hypotension with
spironolactone, 91.7% documented improvement after switching. Out of the participants
who switched due to brain fog and frequency of medication dosing, 75% and 80% reported
improvements in these concerns, respectively. Lastly, 66.7% of participants who felt
spironolactone was not effective in decreasing masculine features reported that this
concern declined with switching to bicalutamide (see Table 5).

17
CHAPTER FOUR: DISCUSSION
This retrospective chart review aimed to describe the demographic characteristics
of AYAs who were prescribed bicalutamide for the treatment of gender dysphoria, and to
assess for side effects and adverse events including hepatotoxicity.
Reasons for Bicalutamide Use, Medication Dosing, and Efficacy
Most participants in this study (71.5%) used bicalutamide for androgen blockade
after progression into late endogenous puberty or after the completion of endogenous
puberty with the most common minimum and maximum dose for this indication being 50
mg PO daily. For those in early endogenous puberty using bicalutamide short-term while
awaiting GnRH analog medication, the most common minimum and maximum doses were
both 25 mg PO daily. For those who started a blocking medication early in their endogenous
puberty and continued bicalutamide for longer-term androgen blockade, 25 mg PO daily
was typically used in the first 1-2 years after the onset of endogenous puberty and then
increased to 50 mg PO daily thereafter. Those who remained on a dose of bicalutamide 25
mg PO daily past this point were significantly more likely to report concern for continued
masculine changes (inefficacy) when compared to those on 50 mg PO daily (p = 0.006).
These findings indicate that bicalutamide 25 mg PO daily may be effective for androgen
blockade for those within 1-2 years of endogenous pubertal onset, whereas bicalutamide
50 mg PO daily may be required for effective androgen blockade for those more than 2
years out from endogenous pubertal onset (regardless of how much endogenous puberty
occurred).

18
Bicalutamide Side Effects, Adverse Effects, and Reasons for Discontinuation
The majority of participants in this study did not have any documented side effects
while taking bicalutamide. The most common side effects reported were mood concerns,
hot flashes, nausea, and scalp hair loss (each affecting ≤2% of participants). Only 2.2% of
participants discontinued bicalutamide due to concern for inefficacy. Less common
reasons for discontinuation included testosterone already being suppressed, mood
concerns, nausea, low libido, scalp hair loss, and asymptomatic concerns for liver safety.
ALT Elevations on Bicalutamide
In this study, 393 participants took bicalutamide with a total cumulative time on
medication of 782 person-years and 351 participants (89%) took bicalutamide individually
for at least 6 months (DILI related to bicalutamide typically has onset within 3-4 months of
starting medication). Only 6.6% of participants had mild elevation of ALT and all those with
subsequent ALT available showed resolution while still taking bicalutamide. Less than 1%
of participants (n = 3) had moderate ALT elevation with only one participant (0.3%) who had
no other potential cause of ALT elevation. In this one case, ALT was normal at baseline,
increased to 290 U/L after 3.5 months of starting bicalutamide, and then subsequently
decreased to the normal range within 6 months while continuing medication. In DILI, one of
the key aspects to linking medication as the cause of ALT elevation, is that the liver injury
improves after discontinuation of the medication. All three cases of moderate ALT elevation
in this study were asymptomatic, transient, and resolved without discontinuation of
medication.

19
Potential Benefits of Bicalutamide
As seen in this study, side effects associated with bicalutamide were rare and most
patients who discontinued the medication during the study period did so as the medication
was no longer medically indicated. Bicalutamide is also an inexpensive medication, can be
given via daily oral pill, and can be obtained quickly through a retail pharmacy. While GnRH
analog medications have been used longer in gender-affirming care and allow for less
frequent dosing via implant or injections, the high associated cost and logistical concerns
with the medication can impact its utility in patient care. For individuals whose bodies
make testosterone and are pursuing GnRH analog medications in early endogenous
puberty, bicalutamide may also be used at a lower dose as a bridge medication while the
GnRH analog is being ordered and administered. It may also be useful to overlap
bicalutamide for 1 month after initiation of GnRH analog in order to lessen the short-term
mood swings associated with increasing and then decreasing testosterone levels when
starting a GnRH analog. Additionally, ninety-three patients in this study previously took
spironolactone and switched to bicalutamide due to side effects (most commonly frequent
urination and dizziness/hypotension) or concern for inefficacy. Around 90% of those with
these side effect concerns reported improvement with bicalutamide. Frequent urination is
not only bothersome for patients, but also increases the need to use public bathrooms
which are a common source of anxiety and threats to safety for many trans feminine
individuals.

20
Summary, Strengths, and Limitations
This retrospective chart review of 393 patients on bicalutamide represents
the largest study to date on the use of this medication for androgen blockade in
transgender and gender diverse adolescents and young adults. The medication was very
well tolerated with minimal side effects, rare adverse events, and low concerns for
inefficacy. For those within 1-2 years of the onset of endogenous puberty, 25 mg PO daily
was effective for androgen blockade. Those further out from the onset of endogenous
puberty likely require higher dosing at 50 mg PO daily as this was shown to be associated
with significantly lower reports of continued masculinization compared to 25 mg PO daily.
Only three patients had moderately elevated ALT while taking bicalutamide and these all
were asymptomatic, transient, and improved without medication discontinuation.
This study is currently one of the largest studies of bicalutamide use for androgen
blockade in transgender and gender diverse individuals and also included patients who
started medication between 10 and 24 years of age. It is also the study with the largest
cumulative time on bicalutamide. This study was designed as a retrospective chart review
and outcome data (e.g., lab results and side effect reports) and relies on information
entered into and readily available from the electronic medical record. As a result, the study
may underestimate the occurrence of side effects or adverse events that were not
disclosed to a medical provider and entered into the medical record. This study period also
overlapped with the COVID-19 pandemic when many clinic visits were conducted over
tele-health and required outside lab draws. This may have resulted in an increased number
of lab results that were not entered into the electronic medical record and may lead to an

21
underestimation of LFT abnormalities. Lastly, this study was conducted in one large urban
academic center with a predominantly White and Latiné patient population and may not be
generalizable to other populations.
Conclusions and Recommendations
While there were no concerns for drug-induced liver injury in this study, it is still
recommended to check baseline aminotransferase levels prior to starting bicalutamide
and use caution in those with elevated baseline ALT, preexisting liver disease, or
concomitant medication with possible hepatotoxicity. ALT should be rechecked at least at
3 and 6 months after starting bicalutamide and with any dosage increases. Further
aminotransferase monitoring should occur every 3-12 months depending on patient risk for
liver disease and with any report of signs or symptoms of liver dysfunction (e.g., jaundice,
right upper quadrant abdominal pain, persistent nausea/vomiting, or dark urine). If ALT
increases to two- to five-times the ULN (mild increase), the provider should have an
informed discussion with the patient and, if continuing medication, ALT should be
rechecked within 1-3 months. If ALT increases above five-times the ULN (moderate
increase), this may still resolve without medication discontinuation, but until more data is
available, it is recommended to pause bicalutamide and consider switching to a different
anti-androgen medication. Practitioners should consider bicalutamide as another option
for androgen blockade in gender-affirming care and have patient- and family-centered
conversations about the risks and benefits of all medication options. These
recommendations may likely change over time as more data becomes available and

22
practitioners should stay up to date with emerging research and share this with patients
and families.

23
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27
APPENDIX
Tables
Table 1: Participant Characteristics
Variable
All
Participants
(n = 393)
Participants
without
Follow-Up
ALT Elevation‡
(n = 317)
Participants
with Moderate
Follow-up
ALT Elevation‡
(n = 3)
Participants
without
Follow-up ALT
Measurement
(n = 73)
Age at first bicalutamide prescription, mean (SD),
y
16.6 (3.1) 16.6 (3.0) 15.7 (1.2) 16.4 (3.5)
Gender identity*, n (%)
Female/Transgender female 354 (90.1) 286 (90.2) 3 (100) 65 (89.0)
Transfeminine 31 (7.9) 25 (7.9) 0 (0) 6 (8.2)
Non-binary 29 (7.4) 22 (6.9) 0 (0) 7 (9.6)
Gender fluid 6 (1.5) 6 (1.9) 0 (0) 0 (0)
Gender queer 1 (0.3) 0 (0) 0 (0) 1 (1.4)
Demi-girl 1 (0.3) 1 (0.3) 0 (0) 0 (0)
Health insurance type, n (%)
Commercial (PPO/HMO) 263 (66.9) 215 (67.8) 1 (33.3) 47 (64.4)
Medicaid 127 (32.3) 99 (31.2) 2 (66.7) 26 (35.6)
Self-pay 2 (0.5) 2 (0.6) 0 (0) 0 (0)
Unknown 1 (0.3) 1 (0.3) 0 (0) 0 (0)
Race, n (%)
Asian 28 (7.1) 25 (7.9) 0 (0) 3 (4.1)
Black 13 (3.3) 11 (3.5) 0 (0) 2 (2.7)
Multiracial 42 (10.7) 33 (10.4) 0 (0) 9 (12.3)
Native American/Alaska Native 2 (0.5) 1 (0.3) 0 (0) 1 (1.4)
Native Hawaiian/Pacific Islander 3 (0.8) 2 (0.6) 0 (0) 1 (1.4)
Unknown 22 (5.6) 17 (5.4) 0 (0) 5 (6.8)
White 186 (47.3) 152 (47.9) 1 (33.3) 33 (45.2)
Ethnicity, n (%)
Hispanic or Latiné 107 (27.2) 81 (25.6) 2 (66.7) 24 (32.9)
Non-Hispanic or Latiné 286 (72.8) 236 (74.4) 1 (33.3) 49 (67.1)
Forms of estradiol taken with bicalutamide*, n (%)
Any estradiol 362 (92.1) 300 (94.6) 3 (100) 59 (80.8)
Estradiol injections 105 (26.7) 84 (26.5) 1 (33.3) 20 (27.4)
Estradiol patches 33 (8.4) 27 (8.5) 0 (0) 6 (8.2)
Estradiol pills 324 (82.4) 273 (86.1) 3 (100) 48 (65.8)
Progesterone taken with bicalutamide, n (%) 284 (72.3) 246 (77.6) 2 (66.7) 36 (49.3)
Maximum bicalutamide dose, mean (SD), mg/d 45.8 (9.4) 46.1 (9.1) 50 (0.0) 44.2 (10.6)
Time on bicalutamide, mean (SD), y 1.99 (1.2) 2.1 (1.2) 3.1 (1.5) 1.3 (1.1)
Baseline ALT available, n (%) 319 (81.2) 265 (83.6) 2 (66.7) 52 (71.2)
Maximum serum ALT†, mean (SD), U/L 22.6 (21.7) 21.0 (12.6) 191 (87.3) n/a
*Multiple selections allowed. †For ‘All Participants’ column: n = 320 due to missing values. ‡ALT elevation defined as an
ALT level greater than five times the upper limit of normal indicating potential mild liver injury (>115 U/L).

28
Table 2: Reasons for Bicalutamide Use & Medication Doses
Reasons for Bicalutamide Use, n (%)
All
Participants
(n = 393)
Dose (Min), n (%) Dose (Max), n (%)
12.5 mg 25 mg 50 mg 25 mg 50 mg
Late puberty (No GnRHa) 271 (69.0) 10 (3.7) 27 (10.0) 234 (86.3) 20 (8.0) 251 (92.0)
Late puberty (After GnRHa) 10 (2.5) 0 (0) 1 (10.0) 9 (90.0) 1 (10.0) 9 (90.0)
Early puberty (No GnRHa) 44 (11.2) 0 (0) 27 (61.4) 17 (38.6) 12 (30.4) 32 (69.6)
Early puberty (After GnRHa) 37 (9.4)* 3 (8.1) 13 (35.1) 21 (56.8) 10 (27.0) 27 (73.0)
Early puberty (Bridge to GnRHa) 35 (8.9)* 0 (0) 29 (82.9) 6 (17.1) 25 (71.4) 10 (28.6)
*Four patients used bicalutamide both as a bridge to GnRH agonist (GnRHa) and after early puberty GnRHa use.
Table 3: Reported Side Effects and Concerns on Bicalutamide
Side Effect Reported*
All Participants
(n = 393)
Participants in Early†
Endogenous Puberty
(n = 112)
Participants in Late‡
Endogenous Puberty
(n = 281)
No side effects (specifically noted), n (%) 359 (91.3) 98 (87.5) 261 (92.9)
Unknown (No mention of side effects), n (%) 9 (2.3) 2 (1.8) 7 (2.5)
Concern for inefficacy*, n (%)
Any continued masculine changes 12 (3.1) 6 (5.4) 6 (2.1)
Continued facial hair growth 7 (1.8) 1 (0.9) 6 (2.1)
Continued body hair growth 7 (1.8) 3 (2.7) 4 (1.4)
Voice deepening 5 (1.3) 5 (4.5) 0 (0)
Laryngeal growth 2 (0.5) 2 (1.8) 0 (0)
Facial structure changes 0 (0) 0 (0) 0 (0)
Body structure changes 0 (0) 0 (0) 0 (0)
Mood concerns, n (%) 8 (2.0) 4 (3.6) 4 (1.4)
Hot flashes, n (%) 5 (1.3) 3 (2.7) 2 (0.7)
Nausea, n (%) 3 (0.8) 2 (1.8) 1 (0.4)
Hair loss, n (%) 3 (0.8) 0 (0) 3 (1.1)
Liver concerns, n (%) 2 (0.5) 2 (1.8) 0 (0)
Sun sensitivity, n (%) 0 (0) 0 (0) 0 (0)
*Multiple selections allowed. †Early endogenous puberty included those participants using bicalutamide as a bridge to
GnRHa, in early puberty (no GnRHa), and after early puberty GnRHa. ‡Late endogenous puberty included those
participants using bicalutamide after late puberty GnRHa and in late/post-puberty (no GnRHa).

29
Table 4: Reasons for Bicalutamide Discontinuation
Reason for Discontinuation*
All
Participants
(n = 393)
Participants in Early†
Endogenous Puberty
(n = 112)
Participants in Late‡
Endogenous Puberty
(n = 281)
All discontinuation reasons combined 92 (23.4) 56 (50.0) 36 (12.8)
Started GnRHa (plan was bridge only)§ 31 (7.9) 31 (27.7) 0 (0)
Orchiectomy with or without vaginoplasty§ 23 (5.9) 8 (7.1) 15 (5.3)
Patient preference only 17 (4.3) 5 (4.5) 12 (4.3)
Concern for Inefficacy/Continued masculine
changes
9 (2.2) 4 (3.6) 5 (1.8)
Low testosterone level 5 (1.3) 2 (1.8) 3 (1.1)
High testosterone level 2 (0.5) 1 (0.9) 1 (0.4)
Liver concerns 2 (0.5) 2 (1.8) 0 (0)
Change in gender expression goals 2 (0.5) 0 (0) 2 (0.7)
Unknown/No reason specified 2 (0.5) 1 (0.9) 1 (0.4)
Excessive breast growth 2 (0.5) 1 (0.9) 1 (0.4)
Hair loss 1 (0.3) 0 (0) 1 (0.4)
Low libido 1 (0.3) 0 (0) 1 (0.4)
Mood concerns 1 (0.3) 0 (0) 1 (0.4)
Nausea 1 (0.3) 1 (0.9) 0 (0)
Needle phobia (declined liver testing) 1 (0.3) 1 (0.9) 0 (0)
To limit linear growth 1 (0.3) 1 (0.9) 0 (0)
Hot flashes 0 (0) 0 (0) 0 (0)
Sun sensitivity 0 (0) 0 (0) 0 (0)
*Multiple selections allowed. †Early endogenous puberty included those participants using bicalutamide as a bridge to
GnRHa, in early puberty (no GnRHa), and after early puberty GnRHa. ‡Late endogenous puberty included those
participants using bicalutamide after late puberty GnRHa and in late/post-puberty (no GnRHa). §These reasons for
discontinuation were that bicalutamide was no longer medically indicated.
Table 5: Reasons for Switching from Spironolactone to Bicalutamide and Documented
Improvement
Reasons for Switching*, n (%)
All Participants
(n = 93)
Documented Improvement in
Spironolactone Side Effect/Concern
Frequent urination 29 (31.2) 26 (89.7)
Patient preference only 25 (26.9) 7 (28.0)
Unknown/No reason specified 21 (22.6) n/a
Dizziness/Hypotension 12 (12.9) 11 (91.7)
Concern for Inefficacy/Continued masculine changes 12 (12.9) 8 (66.7)
Brain fog 8 (8.6) 6 (75.0)
Less frequent dosing of bicalutamide 5 (5.4) 4 (80.0)
Clinician concern for hyperkalemia 0 (0) n/a
*Multiple selections allowed.

30
Figures
Figure 1: Flowchart of Participant Selection and ALT Measurement Availability
Of participants included in the analysis, 319 (81%) had a baseline ALT measurement and 320 (81%) had at least one
follow-up ALT measurement.
Figure 2: Age at First Bicalutamide Prescription
N = 393, Mean = 16.6 years (SD 3.1 years).
0
10
20
30
40
50
60
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Number of Patients
Age (Years)

31
Figure 3: Maximum ALT While on Bicalutamide
N = 320, Median = 18 U/L (IQR 12 U/L). Mild ALT elevation (ALT 44-110 U/L), Moderate ALT elevation (ALT 111-330 U/L).
Severe ALT elevation (ALT > 330 U/L).

Abstract (if available)

Abstract Gender-affirming medical intervention for adolescents and young adults (AYAs) with functioning testes and a transfeminine gender identity often involves the use of a testosterone-blocking medication and feminizing hormone. The most commonly used testosterone-blocking medications in the United States are gonadotropin releasing hormone (GnRH) agonists and spironolactone, but their use can be limited by cost, side effects, and adverse events. Bicalutamide is an androgen receptor blocker FDA-approved for the treatment of prostate cancer. Increases in liver enzymes with bicalutamide are uncommon, transient, and often asymptomatic. Two small retrospective chart review studies involving transgender youth have shown clinical efficacy of bicalutamide with no side effects. However, practitioners have been hesitant to use this medication given case reports of bicalutamide-associated fulminant hepatitis in cisgender men 59-88 years of age for prostate cancer treatment and the lack of larger studies providing safety data in transgender and gender diverse populations.

The goal of this study was to describe demographic characteristics of AYAs who were prescribed bicalutamide for the treatment of gender dysphoria and to assess hepatotoxicity and other reported side effects or adverse events. A retrospective chart review was conducted in the Center for Trans Youth Health and Development at Children’s Hospital Los Angeles for all patients who were prescribed bicalutamide for this purpose between August 2018 and February 2023.

Results: In this study, 393 AYAs 10-24 years of age were prescribed bicalutamide for the treatment of gender dysphoria. The mean time on bicalutamide was 1.99 years, with a total follow-up time of 782 person-years. Most patients (91.3%) reported no side effects and three patients had moderately elevated ALT levels. All three patients were asymptomatic, required no treatment, and ALT elevation resolved without stopping bicalutamide. Providers should consider bicalutamide as another option for anti-androgen therapy and remember to center patients and families in shared decision-making regarding treatment.

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Asset Metadata

Creator Warus, Jonathan Daniel (author)

Core Title Bicalutamide as anti-androgenic therapy in gender-affirming care for adolescents and young adults: a retrospective chart review

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Degree Conferral Date 2024-12

Publication Date 12/23/2024

Defense Date 12/18/2024

Publisher Los Angeles, California (original), University of Southern California (original), University of Southern California. Libraries (digital)

Tag Adolescent,androgen antagonists,gender-affirming care,hormone replacement therapy,OAI-PMH Harvest,transgender persons

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Patino-Sutton, Cecilia (committee chair), Belzer, Marvin (committee member), Olson-Kennedy, Johanna (committee member)

Creator Email jdwarus@gmail.com,jwarus@chla.usc.edu

Unique identifier UC11399EZL6

Identifier etd-WarusJonat-13710.pdf (filename)

Legacy Identifier etd-WarusJonat-13710

Document Type Thesis

Format theses (aat)

Rights Warus, Jonathan Daniel

Internet Media Type application/pdf

Type texts

Source 20241223-usctheses-batch-1230 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA

Repository Email cisadmin@lib.usc.edu