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management of estradiol therapy. Because of this potential interaction, the gender-
afrming care provider should discuss with the transplant team prior to starting
estradiol. For some patients, due to excess tacrolimus accumulation at therapeutic
levels of estradiol, estrogen dosing may be reduced and treatment supplemented by
the use of a GnRH agonist such as leuprolide (see Sect. 17.3.4). This combination
supports greater suppression of endogenous testosterone, enhancing the effective-
ness of low-dose estrogen treatment.
While some drug interaction databases note a potential interaction between
cyclosporine and estrogen (based on a case report of hepatotoxicity in a patient tak-
ing oral contraceptives, and a study showing decreased clearance of cyclosporine
associated with conjugated estrogens) [10, 11], the amount of data is limited, and
not all databases list this interaction as signicant. A conservative recommendation
is to monitor cyclosporine levels and discuss with the transplant team if initiating
estradiol therapy in a patient who is treated with cyclosporine.
Mycophenolate is not known to have signicant interactions with estrogen-based
therapies used in gender-afrming care, although conclusive studies are lacking.
Most interaction concerns with mycophenolate and hormonal therapy pertain to its
use in patients taking combined oral contraception because of mycophenolate’s
teratogenicity as well as its potential drug interaction with progestins such as levo-
norgestrel that may reduce contraceptive efcacy (see Chap. 13).
Azathioprine and sirolimus do not have known interactions with estradiol or
spironolactone.
17.3.1.3 Adverse Effects andMonitoring
Estrogen therapy increases the risk of venous thromboembolism. For this reason, a
patient’s individual risk for venous thromboembolism must be assessed prior to
initiating estrogen therapy. For those at increased risk, transdermal and injectable
formulations are recommended as they have the lowest risk of venous thromboem-
bolism [1, 12]. If there is uncertainty as to the overall risk/benet assessment for a
patient at increased risk (e.g., a patient who has a known hypercoagulable state),
then hematology consultation is advised.
Estradiol therapy adjustment would need to be considered for elective surgeries,
including gender-afrming surgery, post-transplant. Balancing the risk of venous
thromboembolism with the risk of loss of feminizing effects needs to be weighed
with the patient and their surgical teams.
There remains debate as to how much estrogen increases cardiovascular risk in
transgender women. While estrogen therapy is known to increase triglycerides,
there is mixed evidence regarding clinical outcomes such as heart attack and stroke,
largely due to variations in adjusting for pre-existing cardiovascular disease, the
type and amount of hormone therapy exposure, and the appropriate comparison
sample [1]. Because solid organ transplant recipients are already at increased risk
for metabolic conditions such as diabetes, hypertension, and dyslipidemia (see
Chap. 11), the addition of hormone therapy must be assessed in the context of a
patient’s overall metabolic risks.
J. Becke et al.
471
Estrogen therapy has been associated with an increased risk of breast cancer.
However, whether this risk is also conferred to transgender women receiving estro-
gen therapy is uncertain. Although solid organ transplant recipients are at markedly
increased risk for multiple types of cancers, breast cancer has not been consistently
shown to be at higher risk in this population (see Chap. 10).
Transgender patients do need cancer screening of organs they retain after treat-
ment. For example, transwomen continue to require discussion of whether to receive
prostate cancer screening.
The Endocrine Society recommends monitoring of serum prolactin levels at
baseline, then every year during initial transition and every 2 years during mainte-
nance therapy. High dose estrogen therapy has been reported to induce prolacti-
noma after long-term use due to its induction of growth of lactotroph cells in the
pituitary gland. Reports have identied up to 20% of transgender women may have
elevated prolactin levels and enlargement of the pituitary gland. These studies were
in patients also receiving cyproheptadine, a component of gender-afrming care
commonly used in Europe. The risk of prolactinoma in patients using estradiol
alone appears to be very low. Reducing the estradiol dose will often result in nor-
malization of the prolactin level. Radiologic assessment would be indicated in those
whose levels did not normalize or continued to increase despite medication adjust-
ment [1].
17.3.1.4 Timing
Preoperative assessment for solid organ transplantation in the context of gender-
afrming hormone therapy is beyond the scope of this book and is managed by the
transplant team in coordination with the patient’s gender-afrming care provider. In
general, for patients who are receiving gender-afrming hormone therapy with
estrogen prior to transplant surgery, their medications will typically be modied for
a period of time pre-surgery as well as post-operatively. This is primarily related to
the thrombotic risk associated with estrogen treatment in the post-operative state. A
small case series of renal transplant recipients reported that patients stopped estra-
diol therapy for an average of 12 weeks prior to transplant, then resumed at an aver-
age of 9 weeks after transplant [13]. Another institution has reported substantially
reducing but not totally stopping estradiol therapy in the peri-operative state for a
heart-kidney transplant recipient due to high risk of reversal of feminizing effects
and the associated psychologic stress impacting surgical recovery [14]. One prac-
tice is to hold estradiol therapy for 3–12 months peri-operatively. However, a sys-
tematic review of the risks of hormone therapy in the peri-operative transgender
patient suggests the practice of pausing estradiol peri-operatively warrants further
study, as the available data focuses on oral estrogen regimens used in cis-gender
women, not the typical regimens used in transgender women [15]. Some patients
may experience increased gender dysphoria off of their hormone treatment, which
could negatively impact their ability to participate in transplant care. Lee etal
reported a case of maintaining low-dose transdermal estradiol in a patient preparing
17 Gender-Afrming Care oftheAdult Solid Organ Transplant Recipient
472
for heart transplant [13]. In light of these variations in practice, the transplant team
and patient would need to carefully weigh the potential risks and benets of peri-
operative hormone therapy.
For solid organ transplant recipients not already receiving gender-afrming hor-
monal therapy, it is generally not recommended to initiate estrogen-containing gen-
der-afrming care treatment in the immediate post-operative period after
transplantation because of the increased risk of venous thromboembolism. The opti-
mal time period to delay estrogen-containing therapy is uncertain due to lack of con-
trolled studies. Similar to the re-initiation of hormone therapy discussed above, many
transplant centers recommend a delay of at least 3 months, preferably 12 months,
post-transplantation, with decision-making factoring in stability of graft function, the
current medication regimen, and whether other complications have occurred.
17.3.2 Spironolactone andFinasteride
Spironolactone is often used to augment the effects of estradiol because of its antag-
onistic activity at testosterone receptors and ability to cause gynecomastia.
Finasteride may also be used, particularly if there is pre-existing male pattern
alopecia.
17.3.2.1 Dosing andTherapeutic Monitoring
Spironolactone dosing in the general population is between 25 and 100mg daily
and occasionally up to 300mg daily in the transgender population. It is titrated to
desired effect and to support the goal of adequate testosterone suppression to
achieve a measured total testosterone less than 50 ng/dL.However, if used in a solid
organ transplant recipient, lower doses should be considered due to lack of studies
in this population, as well as concern for side effects.
Finasteride is dosed at 1–5mg daily and does not require therapeutic monitoring.
17.3.2.2 Drug Interactions (Table17.2)
There is low likelihood of direct spironolactone interaction with tacrolimus but
there is an increased risk of hyperkalemia and increased creatinine when the two
medications are taken together. Spironolactone may be considered in select solid
organ transplant recipients if potassium and estimated glomerular ltration rate
(eGFR) are monitored carefully.
Hyperkalemia: In a study of kidney transplant recipients who received spirono-
lactone (25–50 mg) or placebo, all of whom were treated with calcineurin inhibitors,
those in the spironolactone group had an increase in potassium of 0.3–0.4 mEq/L,
with a few patients requiring dose reduction because of the hyperkalemia [16].
Renal function: In the same study of renal transplant recipients taking calcineu-
rin inhibitors, those who received spironolactone developed an initial decrease in
J. Becke et al.
473
eGFR of −7.6 ml/min that stabilized thereafter [13]. The study authors suggest that
this is a known effect of spironolactone even in the general population, rather than
specic to transplant recipients, and that it does not cause progressive renal
dysfunction.
Nevertheless, because of these potential risks, it is recommended to discuss with
the transplant team prior to prescribing spironolactone. Patients with normal renal
function and normal or low-normal potassium levels at baseline may be better can-
didates for spironolactone therapy.
Azathioprine and sirolimus do not have known interactions with
spironolactone.
Finasteride does not have drug interactions with common immunosuppressive
medications used in solid organ transplantation.
17.3.2.3 Adverse Effects andMonitoring
Spironolactone: As noted above, serum creatinine and potassium levels are impor-
tant to monitor with long-term spironolactone use.
Finasteride: There is no special medication monitoring needed in the setting of
solid organ transplant.
17.3.3 Progestins
Progesterone is occasionally used to support breast growth for feminizing gender-
afrming care. Although there are no currently published studies to support the
efcacy of progesterone for breast development in transwomen [1], expert opinion
suggests progesterone can be used after an informed discussion with interested
patients.
17.3.3.1 Dosing andTherapeutic Monitoring
Micronized progesterone is the preferred formulation when patient goals support
the use of this supplemental therapy. A typical starting dose is 100mg daily, then
increased to 200mg daily after shared decision-making regarding anticipated and
hoped- for effects. Treatment duration may be limited to 1–2 years, once breast
development has optimized. Levels are not monitored.
17.3.3.2 Drug Interactions
There are no interactions between progesterone and common immunosuppressive
medications used in solid organ transplantation (Table17.2). Although there is a
potential interaction between mycophenolate and progestins such as levonorgestrel
17 Gender-Afrming Care oftheAdult Solid Organ Transplant Recipient
474
used in combined oral contraceptive pills, there is not a known interaction between
mycophenolate and progestins used in gender-afrming care (typically micronized
progesterone or medroxyprogesterone) (See Chap. 13).
17.3.3.3 Adverse Effects andMonitoring
Data is lacking regarding adverse effects of progesterone in solid organ transplant
recipients. The data regarding potential increased risk of heart disease and breast
cancer are specic to cis-gendered women using post-menopausal hormone therapy
in the general population. To what extent these risks apply to solid organ transplant
recipients is uncertain, and should prompt a careful shared decision-making
discussion.
17.3.4 Gonadotropin-Releasing Hormone (GnRH) Agonists
Leuprolide is a GnRH agonist and is sometimes used to augment testosterone sup-
pression in combination with estrogen therapy in transwomen. While common in
adolescents, GnRH agonists are less commonly employed in adults as part of a
gender-afrming medication regimen, but may have a role in patients with a solid
organ transplant in order to reduce estrogen dosing.
17.3.4.1 Dosing andTherapeutic Monitoring
Leuprolide can be administered via IM injection in clinic every 3–6 months depend-
ing on formulation. Monitoring of effect is through measurement of estradiol and
testosterone levels.
17.3.4.2 Drug Interactions
There are no known medication interactions between leuprolide and common
immunosuppressive medications used in solid organ transplant (Table 17.2).
However, it is important to be aware that leuprolide can prolong the QTc as can
tacrolimus and cyclosporine. Clinicians may decide to monitor the QTc when these
medications are used together, although there is not clear guidance in the data for
this practice (it remains uncertain whether QTc prolongation risk is additive among
drugs that independently have a risk of prolonged QTc but do not directly increase
the other drug’s levels).
J. Becke et al.
475
17.3.4.3 Adverse Effects andMonitoring
GnRH agonists may increase the risk of osteopenia and osteoporosis, a signicant
concern in solid organ transplant recipients because of their already increased risk
of metabolic bone disease (see Chap. 11). The impact on bone loss is highest in
people for whom all sex hormones are suppressed; this effect would presumably be
less in transwomen who are receiving gender-afrming hormone therapy, as estro-
gen will typically be in a normal adult range for their desired gender. The potential
adverse effect on bone health may be worsened in solid organ transplant recipients
who are treated with prednisone. It is recommended to consider a DEXA scan at the
start of treatment with a GnRH agonist, then every 2–3 years through the course of
treatment.
17.3.5 Testosterone
In transgender men, gender-afrming hormone treatment with testosterone supports
the development of male sexual characteristics.
17.3.5.1 Dosing andTherapeutic Monitoring
Testosterone may be administered via multiple formulations, with topical gels or
intramuscular/subcutaneous injections used most commonly. Expected effects
include voice deepening, facial hair growth, and increased muscle mass, among
other masculinizing changes. The testosterone dose is typically started at a low to
moderate dose, then titrated over several months to both a target of 200–1000 ng/dL
for the testosterone level as well as to the patient’s gender-afrming goals.
17.3.5.2 Drug Interactions
Neither tacrolimus nor prednisone has concerning interactions with testosterone.
The hepatotoxic effects of cyclosporine can be potentially increased by androgen
therapy; close monitoring of liver functions tests with testosterone should be con-
sidered (Table17.2).
17.3.5.3 Adverse Effects andMonitoring
Testosterone therapy in gender-afrming care may increase triglycerides and low
density lipoprotein (LDL) [17]. Because of the limited number of long-term studies,
conclusive data regarding clinical outcomes is lacking [1], with studies suggesting
17 Gender-Afrming Care oftheAdult Solid Organ Transplant Recipient
476
an increased cardiovascular risk either similar to cisgender males, or between that
of cisgender females and cisgender males [18].
Testosterone therapy is associated with weight gain and acne, which can be
potentiated by concomitant prednisone therapy. Because solid organ transplant
recipients at baseline are at increased risk for metabolic conditions (see Chap. 11),
those receiving testosterone therapy should be monitored for diabetes, hyperten-
sion, and hyperlipidemia.
Alopecia may be problematic with both testosterone and tacrolimus.
Erythrocytosis due to testosterone therapy is a common side effect and requires
laboratory monitoring.
With testosterone treatment, there may be a rise in serum creatinine. As dis-
cussed further below, a shift to the reference range for cis-gendered men in trans-
men on testosterone therapy may be appropriate. This warrants close monitoring
and discussion with the transplant and gender care teams.
Some studies have identied a rise in transaminases as well as alkaline phospha-
tase in people using testosterone treatment. While there had previously been con-
cern for hepatotoxicity related to testosterone therapy, the Endocrine Society
Guidelines suggest more recent studies have alleviated that as an issue [1]. As
described below, it may be reasonable to adjust expected transaminase and alkaline
phosphatase measurements into the cis-male range for transmale patients after 1
year of testosterone therapy.
17.4 Gender-Afrming Surgery
Gender-afrming surgeries are part of the therapeutic plan for some people seeking
gender-afrming care. Not all transgender people desire gender-afrming surgery
or may have only certain procedures they wish to pursue. Surgical interventions for
gender-afrming care include facial feminization or masculinization procedures,
chest surgeries, and genitourinary reconstructions. Multiple surgical specialties
may be involved, including plastic surgery, otolaryngology, gynecology and urol-
ogy. Interprofessional consultation is crucial for the solid organ transplant recipient
seeking gender-afrming surgery, as the graft location and time from transplant can
impact surgical timing, approach, and feasibility.
In renal transplant recipients, both graft placement and time from transplant will
inuence gender-afrming surgical planning when considering genitourinary pro-
cedures. As with any elective procedure, patients are recommended to wait at least
6–12 months after kidney transplant to move forward with gender-afrming surger-
ies. In transfeminine patients, the location of the renal graft precludes the full depth
vaginoplasty approach. As peritoneum overlying the graft location is used for the
full depth approach, penile inversion vaginoplasty offers a safe alternative. This
decision would be made in extensive consultation with the operating urologist and
transplant team.
J. Becke et al.
477
In transmasculine patients, genitourinary surgeries such as metoidioplasty, which
involves urethral lengthening, may increase risk of voiding abnormalities immedi-
ately post-renal SOT.Stenosis or altered course of the surgical urethra can contrib-
ute to urinary retention or difculty with urinary catheter placement. One case
report documented difculty with catheter placement peri-operatively in a transman
with metoidioplasty requiring stula creation to facilitate urinary output monitor-
ing [19].
For patients with a lung transplant, chest surgery warrants close consultation
between the plastic surgeon, transplant surgical team and primary care provider.
Some transplant surgeons request that patients with breast implants have their
implants removed at the time of lung transplant due to potential complications.
Surgeons may have concern for infection risk associated with the clamshell lung
transplant incision and its proximity to the implants. Breast implants may be rein-
serted 6–12 months after lung transplant, depending on clinical status.
Transmasculine heart or lung transplant recipients who are considering chest
surgery such as mastectomy should have shared decision-making involving the
patient and their surgical teams.
For patients with heart or liver transplant, overall data is very limited. As with
kidney and lung transplant recipients, waiting 6–12 months post-transplantation is
crucial to allow for surgical recovery and stability of graft function. Choices about
gender-afrming surgery should then involve all members of the patient’s health
care team.
17.5 Sex/Gender-Specic Laboratory Reference Intervals
andRisk Tools
Certain laboratory studies have reference intervals that differ by gender. These
include creatinine, alanine aminotransferase (ALT), creatinine kinase (CK), hemo-
globin, and hematocrit. The optimal reference interval to use for transgender
patients remains a topic of research. A study compared 55 transgender women who
had been treated with hormone therapy for at least 6 months to 20 men and 20
women who were not transgender, and found that the creatinine values resembled
non- transgender men, while hemoglobin and hematocrit resembled non-transgen-
der women. There were also differences in lipids, alkaline phosphatase, and potas-
sium, but not aminotransferases or sodium [20]. The authors advocate for further
research in determining the most appropriate reference intervals for transgender
patients. However, a larger study of over 2000 patients found that for transgender
women, hemoglobin, hematocrit, aminotransferases, and creatinine decreased after
hormone therapy, while for transgender men, these indices increased after hormone
therapy [21]. The authors suggest using the reference range of the afrmed gender,
but starting 1 year after treatment, with uncertainty as to interpretation in the
rst year.
17 Gender-Afrming Care oftheAdult Solid Organ Transplant Recipient
478
For patients who have received a solid organ transplant, an accurate measure of
the estimated glomerular ltration rate (eGFR) is essential, both for kidney trans-
plant recipients, as well as other organ transplant recipients given the prevalence of
chronic kidney disease due to medical risk factors and calcineurin inhibitors (see
Chap. 11, for further discussion of chronic kidney disease). Some authors have
advocated for the use of measures that are independent of muscle mass such as cys-
tatin C [22].
Pending further research, it is recommended to work with a transgender patient’s
transplant team and transgender care team (if available) regarding the most accurate
way to interpret laboratory testing, taking in account the method and duration of
gender-afrming treatment.
Pre-transplant eGFR measurement for people who are transgender is an ongoing
discussion in the transplant community and beyond the scope of this book, which is
focused on post-transplant primary care.
Osteopenia and osteoporosis are common metabolic bone complications in solid
organ transplant recipients (see Chap. 11). For patients who are transgender, it
remains uncertain which gender is optimal to base Z-scores on, although some
guidelines suggest using the female-based score for transwomen [23]. There are not
enough data to guide assessment and management in transgender solid organ trans-
plant recipients—it is recommended to involve an endocrinologist experienced in
gender-afrming care and transplant medicine, if available.
Cardiovascular disease is common in solid organ transplant recipients (see Chap.
11). However, risk estimation in most tools requires a binary gender input, and there
is limited data on interpretation of risk tools in people who are transgender, despite
an increased risk of cardiovascular disease in the general (non-transplant) transgen-
der population. For example, one study of patients who were assigned male at birth
and who are now female or have feminine gender identity found that their estimated
risk of cardiovascular disease was lower when using their current gender identity,
which would result in less prescribing of statins for primary prevention [24]. It
remains uncertain whether cardiovascular risk tools are accurate in solid organ
transplant recipients, including those who are transgender.
17.6 Mental Health
Mental health conditions have a high prevalence in solid organ transplant recipients.
Although patients have mental health assessment prior to transplantation, it is not
uncommon to have mental health conditions occur de novo or recur post-
transplantation. Depression has a wide range of reported prevalence, between 5 and
75%, depending on the study and the transplanted organ, leading to recommenda-
tions for screening [25]. Mental health in transplant recipients is discussed in
Chap. 12.
People who are transgender have been reported to have higher rates of depres-
sion, anxiety, and substance use compared to the general population. However, there
J. Becke et al.
479
have not been studies on the prevalence of mental health conditions in transgender
patients who have also had a solid organ transplant. Case reports describe optimiz-
ing gender-afrming treatment pre-transplant to reduce depression and anxiety
[11], and patients successfully treated for depression either pre-transplant or post-
transplant [10].
17.7 Conclusion
Gender-afrming care to support and afrm an individual’s gender identity can be
safely provided in solid organ transplant recipients. There is variability in benets
and risks depending on a patient’s health, type of organ transplanted, immunosup-
pressive medication regimen, and comorbidities. A multidisciplinary team can assist
the primary care provider in optimizing care of transgender and gender diverse solid
organ transplant recipients.
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17 Gender-Afrming Care oftheAdult Solid Organ Transplant Recipient