Introduction
Transgenders are the ones who have a gender individuality that is different from the
sex at the time of birth.[1] It is estimated that from 8 to 25 million individuals worldwide now identify as
transgenders.[2] The census of 2011 in India revealed the total population of transgenders to be
around 4.88 lakh.[3] These people experience unique disparities in terms of social, hormonal, or surgical
transition and are the subject of limited focused health research.[4]
[5] As a consequence, little is known regarding the medical and mental health of transgender
individuals.[6] Transgender people face psychological stress due to the uncomfortable feeling of
living in a discordant gender role.[4] To reduce this distress, these people opt for various measures such as cross-sex
hormone therapy (CSH) or gender-affirming hormone therapy (GAHT) apart from surgical
transitions, which are reported to be associated with serious conditions such as breast
and prostate cancers.[7]
[8]
Breast cancer (BC) is the second most common cancer overall and the most common cancer
in females with a lifetime risk of 12% and 0.1% in males.[2]
[9]
[10] The molecular pathogenesis of BC differs between sexes.[2] The proportion of transgender affected with BC is not known accurately although
one study reported the overall prevalence of BC in transgenders to be 200 per 1,00,000
patients after years of CSH treatment in a cohort study.[10] In transgenders, the first two cases were reported in 1968 in two male to female
(MtF) patients.[11] Among transgenders, transwomen (male to female) are at a higher risk of BC, as reported
by de Block et al in a retrospective study.[10] In this report, we try to gain more insights into types of transgenders, GAHT, the
risk associated with GAHT, patient presentation, and the dilemmas faced by this population
in our society. We would also discuss the paucity of standard international guidelines
on the screening and management of transgender individuals and possible solutions.
Relevant clinical articles (published in the English language) included in this narrative
review are selected from PubMed, Google Scholar, and appropriate websites (keywords:
transgender, breast cancer, transwomen, transmen, female to male, male to female,
hormone therapy). Also, transgender is a heterogeneous entity and consists of transmen
and transwomen with different clinical characteristics and hormonal profiles. Below
is a brief description of the types of transgenders and [Table 1] shows the differences between them.
Table 1
Difference between MtF and FtM transgenders
|
Male to Female (MtF)
|
Female to Male (FtM)
|
|
|
|
|
Transwoman
|
Transman
|
|
Assigned male sex at birth
|
Assigned female sex at birth
|
|
They require predominant hormone manipulation with estrogen and progesterone
|
They require predominant hormone manipulation with testosterone
|
|
To develop female characteristics, they usually undergo orchiectomy, vaginoplasty,
breast augmentation
|
Surgical intervention required is hysterectomy, oophorectomy, and phalloplasty, and
subcutaneous mastectomy
|
|
Estrogens given exogenous increase the risk of prolactinoma and breast cancer
|
Exogenous testosterone increases the risk of breast and endometrial cancer
|
Types of Transgenders
Male To Female Patients
Male to female (MtF) or transwomen are persons assigned male sex at birth but have
a longing to live as a female.[5]
[10]
[12] The important physical features of a female body are breast growth, wider hips,
less fat in the abdominal region, decreased hair growth on the body, and softer skin.[7]
[8] To develop these characteristics, transwomen require surgical transitions including
breast augmentation and orchiectomy or vaginoplasty[10]
[13] and exogenous hormones or GAHT including estrogens and anti-androgens.[5]
[6]
[7] Also, therapy should be able to reduce the number of spontaneous erections and sperm
production, which are characteristics of a male body.[7]
[8] The surgical interventions such as breast augmentation and placements of implants
may give rise to rare type of lymphomas of the breast such as implant-associated anaplastic
large cell lymphoma.
Female to Male Patients
Female to male (FtM) or transmen are persons born as female at the time of birth but
associate themselves to male sex.[2]
[6]
[12] Transmen require testosterone preparations in their GAHT regimens to stimulate virilization,
to emulate male-like body hair growth and contours, along with surcease of menstruation,
diminished glandular tissue, and increased fibrous connective tissue.[2]
[13] Progestational agents are administered when transdermal or oral testosterone is
used as they are unable to cease menstruation and to prevent endometrial hyperplasia.[2]
[14] Surgical transition in transmen includes subcutaneous mastectomy, which is primarily
done to achieve aesthetic masculine thorax and uterus extirpation and/or oophorectomy,
and phalloplasty.[10]
[18]
Dilemmas Faced by Transgenders in the Healthcare System and Transgender Care
Apart from society, transgenders have to face a lot of discrimination in the healthcare
system.[5] Although the standard treatments for transgenders are available, they still face
many barriers.[15] According to the Virginia Transgender Health Initiative Study, the social stigma
of being transgender is the basis of poor health status, resulting in alienation that
accumulates throughout their life.[15] Various studies reported that transgenders were either denied medical care or have
faced some form of harassment in the healthcare system.[15]
[16]
[18] The doctors refuse to provide treatment to them either because they feel insufficient
to care for them[5] or due to their low financial status.[7]
[14]
[17]
[18] As a consequence, to avoid harassment, these people either hide their gender identity
from doctors, which is important for getting correct advice regarding their breast
health or avoid seeking medical attention.[5]
[15] These difficulties and a serious urge of confirming their physical attributes to
the gender felt by them incite them to use alternatives to the standard treatments
such as non-prescribed hormones (NPH).[5]
[18]
Transgender Care
Prevalent inequity and neglect threaten the health and well-being of the transgender
population, making them one of the most marginalized populations in medicine.[18] Therefore, as per the Endocrine Society's updated clinical practice guidelines 2017,
the medical team dealing with transgenders should involve a psychiatrist having the
knowledge to diagnose gender dysphoria, and GAHT should be trained and experienced
in assessing psychopathology and should be willing to participate in ongoing care.[19] The involvement of a psychiatrist helps by supporting access to care to the transgender
population that may benefit from treatment.[18] For optimum care, pretreatment education and assessment, customized dosing, continuous
monitoring, and standard screening for BC and prostate cancer are important.[20]
For children and adolescents who qualify for gender dysphoria, standards of care have
been developed that involve puberty suppression, appropriate mental health support,
and hormonal interventions, which may make future affirmation easier and safer.[20]
[21] The development of undesired secondary sexual characteristics in transgender adolescents
can be prevented by drugs that either suppress the sex hormone production or block
its action.[21] Drugs such as GnRH agonists for pubertal suppression, progestins for the reduction
in biologic hormone production, and androgen receptor antagonists are useful.[21] The best treatment regimen for adolescents is the use of a GnRH agonist for complete
suppression of puberty starting at tanner stage 2, followed by the introduction of
cross-sex hormones in later adolescence.[21]
Gender Affirming Hormone Therapy
Gender affirming hormone therapy is the standard treatment used along with surgical
transitions in transgenders to develop secondary sexual characteristics that align
with their felt gender.[8] Transgenders have been receiving GAHT since the early 1960s.[6] GAHT is a key feature of transition-related care, rehabbing mental health, and the
quality of life of transgenders.[5] The treatment regimens of GAHT are different for MtF patients and FtM patients.[2]
[6]
[10]
[13]
GAHT for Transwomen
The GAHT regimen for transwomen includes estrogen and anti-androgen drugs such as
spironolactone.[5]
[6]
[7] Cyproterone is given as adjunctive therapy for lowering testosterone concentrations
in the body and adds to curb testosterone production or to deter the androgen receptor.[7] This therapy helps in developing female secondary sex characteristics (breast development,
redistribution of fat, reduction in body hair) and minimizing male characteristics
(reduced number of spontaneous erections, reduced sperm production, slowing of scalp
alopecia).[7]
[8]
[18] The use of progestin along with these drugs is controversial. According to a study,
adding progestin to estrogen does not alter breast size,[2]
[22] rather it increases the risk of BC.[15]
In guidelines, estrogen also has caveats to its use as serum concentrations of conjugated
equine estrogens cannot be accurately measured, conferring dose adjustments difficult.[5] Additionally, two studies reported that estrogens use in MTF individuals might put
them at risk of BC due to high levels of circulating androgens and increased estrogen
exposure.[1]
[2] The length and dosage of estrogen treatment also play a role in the propagation
of neoplastic breast epithelium.[11] Oral ethinylestradiol, an estrogen preparation, is not advised owing to the associated
increased risks of blood clots and cardiovascular (CV) morbidity and mortality. However,
transdermal estradiol patches or gel are safer to use as the risk of blood clotting
is low. The use of transdermal estradiol has been suggested and employed predominantly
in older TW.[5]
After the administration of GAHT, breast development is modest in transwomen.[8] Mean breast-chest difference increase ranged from 3.7 cm (95% CI: 3.3–4.2) to 4.16 ± 2.9 cm
at baseline to 7.9 ± 3.1 cm after 1 year of CHT.[8] Additionally, anatomical differences in the thoracic bone structure compared with
ciswomen may result in breast size appearing smaller than the objectively measured
volume.[5]
GAHT for Transmen
Testosterone preparations are the standard treatment to stimulate virilization, emulate
male-like body hair growth and contours, along with surcease in menstruation, diminished
glandular tissue, and increased fibrous connective tissue.[2]
[13] Testosterone is administered in the form of injectable, gels, and transdermal patches.[14] Androgens are usually administered 6 months prior to reassignment surgery and continued
thereafter.[13] Progestational agents are administered when transdermal or oral testosterone is
used as they are unable to cease menstruation and prevent endometrial hyperplasia.[2]
[14] In transmen, serum testosterone levels are in the mid to normal range.[2] The removal of breasts in sex reassignment surgery (SRS) reduces the risk of BC
in transmen by around 90%.[15] However, a few studies have reported BC in transmen. One study reported BC in the
residual mammary cells of transmen after 10 years of mastectomy.[14] Another study reported a total of four cases of BC in transmen, three of which were
diagnosed several years after subcutaneous mastectomy and the other at the time of
mastectomy.[10] A large retrospective study conducted at the U.S. Veterans Affairs medical health
system identified seven cases of BC in transmen.[22] Various studies reported that the aromatization of the circulating testosterone
into estradiol by the aromatase enzyme was the reason for BC in transmen.[2]
[14]
[23]
Self-Use of Hormone Therapy
The widespread use of NPH has been documented in several studies.[17]
[18] In Washington, DC, 58% of transgenders reported the use of NPH once in their lives.[17] A report in Virginia suggested that around 60% of MTFs and 22% of FTMs patients
were using NPH.[5] Similar reports were obtained from Chicago, California (San Francisco),[26] and Europe.[27]
,
[5] The majority of patients taking NPH were transwomen.[17] The major sources to obtain NPH were friends and online purchasing.[18]
[27] In rare cases, people have performed surgeries on themselves as they were unable
to afford SRS.[17] Opting for such dangerous measures indicates pre-existing mental conditions such
as depression, psychiatric comorbidity, social distress, and body dissatisfaction.[17]
Risks associated with GAHT
Gender affirming hormone therapy certainly improves the QOL of transgenders, but at
the expense of their health. Various studies have reported that GAHT use is associated
with severe health conditions such as cancer in transgenders.[10]
[28]
[29]
[30] Many benign and malignant tumors are known to be associated with CSH therapy as
different organ-specific malignancies express sex hormone receptors.[31] It is seen that breast tumors develop rapidly in transgenders after short-term exposure
to hormone therapy (median duration: 18 years).[10]
International guidelines published by the World Professional Association for Transgender
Health in 2012 and the Endocrine Society in 2017 suggest estrogens presents a moderate
risk of prolactinoma and BC development[31] and testosterone therapy is associated with a moderate risk of breast and endometrial
cancer.[22] The proposed mechanism of BC development in transwomen is the binding of exogenous
estrogen to the estrogen receptor (ER) in the breast tissue and stimulating carcinogenesis
via increased cell proliferation, decreased apoptosis, and elevated production of
oxidative metabolites that result in DNA damage.[32] For transmen, the aromatization of testosterone to estrogens in peripheral tissues,
and the activation of androgen receptors leads to cellular growth and proliferation,
particularly in mammary tissues leads to BC development.[33] Other risks associated with estrogens use in transwomen are myocardial infarction,
thrombosis,[25] and ischemic stroke.[34] Conversely, transmen receiving testosterone did not suggest the increased probability
of cardiovascular or cerebrovascular disease.[34]
Patient Presentation
The most common clinical feature of BC is a lump in the breast, which may be painful
or painless.[33]
[35] Other symptoms of BC are bloody nipple discharge,[11] enlarged lymph nodes in one of the axilla,[6] dense breast tissues, or subareolar masses[11] on mammographic screening. In a systemic review by Fledderus et al, 7 out of 23
FtM transgenders were diagnosed to have breast cancer incidentally on routine histological
examination after they underwent a cosmetic mastectomy. Genetic testing in transgenders
has shown that the use of CSH therapy is also associated with the upregulation of
various oncogenes.[10]
[35] Studies have reported that these symptoms are noticed after long-term use of CSH
therapy.[6]
[37] The types of BC diagnosed in transgenders after CSH therapy were variable, including
invasive ductal carcinoma, neuroendocrine carcinoma, and tubular adenocarcinoma.[35] Most of these tumors are hormone receptor-positive. The development of BC affects
the GAHT regimen in transgenders. Most patients were put on low doses of exogenous
hormones or even their CSH therapy was discontinued.[35]
[38]
Screening Recommendations for Transgenders
Breast cancer in transgenders is diagnosed at an early age as compared with ciswomen.[39] The median age of diagnosis of BC in transwomen is 51 years and for transmen, it
is 47 years.[6]
[10] There are no guidelines defined especially for transgenders. However, BC screening
recommendations for the cis population have been extrapolated for them.[36] The annual mammography screening is advised in transwomen older than 50 years of
age and continuously undergoing GAHT, having greater than 5 years use of estrogen
and progestin, a body mass index >35, or a positive family history.[6]
[10]
[15] For transwomen with implants, ultrasound serves as the first-line imaging technique
because mammographic screening becomes less sensitive in the presence of implants.[5] Magnetic resonance imaging (MRI) should be performed, if there is concern about
intracapsular rupture not visible by ultrasound.[5]
[40] Because the SRS does not include removal of the prostate, prostate cancer screening
should also be performed annually in transwomen after the age of 40 years.[6]
The current guidelines suggest the regular monitoring of the hormone profile of transwomen
under estrogen therapy to minimize the risk of thromboembolism, hypertension, and
cholestasis.[6]
[22] For transmen, who have undergone chest reconstruction surgery, annual examinations
of the sub- and peri-areolar breast by MRI or ultrasound, together with chest wall
and axillary examination remain the key screening tool.[10]
[15] Transmen who retain their physical characteristics should opt for routine annual
screening using mammography starting at the age of 40 years.[10]
[15]
[41]
Treatment Recommendations: Differences?
There is a scarcity of data regarding the plan of management of BC in transgenders
and so is the lack of data regarding the survival of these patients. The review of
literature also suggests management from a case-to-case basis with the management
in line with breast cancer in women. The plan of management involves surgical resection,
hormone status, and further management as per the stage of the patient. Most of the
patients reported were hormone positive thus receiving hormone therapies as a part
of their BC treatment. Individual hormonal profiles of the patient including serum
estradiol, luteinizing hormone, follicle-stimulating hormone, and testosterone levels
should be tested before deciding about the choice of hormonal therapy and whether
LHRH analogs are required in addition to aromatase inhibitors.
The basic difference comes in the treatment outcome as there are a lot of social reasons
for the delay in reaching the healthcare systems and further bias after reaching hospitals.
Special clinics may be needed in the major cancer centers where their medical needs
may be met and these patients visit at the earliest after detecting a lump in the
breast.
