An estimated 1.4 million U.S. adults (0.6% of all adults) self-report as transgender; yet, to date, little research has been conducted to understand cancer prevalence or the hematologic complications of hormone replacement therapies among this population.1 These gaps in knowledge are preventing hematologists and oncologists from offering the best possible care to this patient population, according to Joseph Shatzel, MD, Assistant Professor of Hematology and Biomedical Engineering at Oregon Health & Science University.
"We are missing a lot of information about the care and health of transgender individuals that we as a hematology community could provide," he told ASH Clinical News.
Many clinicians also may not be well-versed in the unique treatment considerations for this patient population, such as balancing the emotional benefits of hormone therapy with potential hematologic risks for transgender individuals taking these drugs or incorporating culturally sensitive practices into care settings.
Some research has suggested that transgender women (those assigned male sex at birth who identify as female) have an increased thrombotic risk compared to cisgender women, a term used for those whose gender identity matches the female sex they were assigned at birth. Other research has found that transgender men – those who were assigned female sex at birth but identify as male – may have a greater prevalence of certain types of cancer than cisgender men.
But, without clear protocols or standards of care, questions remain about optimal management of transgender patients. For example, if a transgender woman taking estrogen as part of her feminizing hormone therapy experiences a blood clot, how should anticoagulation be managed? If a transgender male develops erythrocytosis while taking testosterone, is that a risk factor for future health problems?
The abundance of unanswered questions regarding the treatment of transgender individuals prompted the 2020 American Society of Hematology (ASH) Annual Meeting organizers to select the topic for an Education Session at this year's meeting. Here, ASH Clinical News speaks with experts in hematology and transgender medicine about what we do and do not know about special care considerations in this population, and how to create an inclusive and welcoming environment for all patients, regardless of gender identity.
A Review of Transition-Related Interventions
Transgender people may pursue any of a number of gender-affirming interventions that have been deemed medically necessary by the World Professional Association for Transgender Health. The most common gender-affirming medical treatments include cross-sex hormone therapies (CSHTs) and surgery.1
Transgender men often take exogenous testosterone to induce virilization and suppress feminizing characteristics.2 In the U.S., formulations of testosterone, including testosterone enanthate or cypionate, are usually administered through intramuscular or subcutaneous routes, often at weekly intervals.
Physicians often prescribe exogenous estrogen for transgender women, which feminizes a patient's characteristics. While injectable formulations of ethinyl estradiol were once a mainstay of estrogen-directed therapies, most recommendations now suggest using oral estrogens or transdermal patches.
Transgender women often also use antiandrogens to inhibit production of testosterone and other male sex hormones, helping to suppress masculinizing features. Those who retain their testes may use a combination of both antiandrogens and estrogens to reduce testosterone levels, usually to a level below 100 ng/dL (typical levels in cisgender men are 300-1,000 ng/dL), while making sure not to reach an excessive level of estradiol.3
Some patients also may choose to undergo gender-affirming surgeries. For transgender women, these interventions could include breast augmentation, orchiectomy, vaginoplasty, laryngeal surgery, or facial feminization. For transgender men, these could include mastectomy, facial masculinization, or genital reconstruction through metoidioplasty (i.e., creation of a phallus from a hormonally-enlarged clitoris) or phalloplasty (i.e., multistep construction of a neophallus, often with a free flap of tissue taken from the forearm.) Transgender men who choose to undergo these procedures may opt to remove or to retain their uterus or ovaries.
Hormones and Thrombosis
The most significant hematologic concern for transgender women is the risk of thrombosis while taking exogenous estrogen. Specific data on transgender women are currently limited, which is why most of what researchers know about thrombotic risk for transgender women is implied from much larger studies assessing the impact of hormone replacement therapy in cisgender women, Dr. Shatzel explained.
While research focusing on transgender women may be sparse, he called the data on cisgender women "gigantic," following large populations over decades. "We just don't have that kind of science for transgender women," he said.
Researchers believe thrombosis risk in the two groups – transgender and cisgender women – are likely comparable because of some commonalities.
"A reasonable biologic correlate to the hormone supplementation transgender women receive is menopausal hormone replacement therapy," Dr. Shatzel and colleagues wrote in a 2016 review.3 This generally consists of combined estrogen and progesterone in women who retain their uterus (due to the protective effects of progesterone against uterine malignancy) and estrogen monotherapy in women who have undergone hysterectomy, they added.
Research has consistently shown that cisgender women on hormone replacement therapy have an increased risk of venous thromboembolism (VTE). In nested case-control studies of more than 80,000 women, exposure to hormone replacement therapy in the previous 90 days was associated with a 43% increase in the risk of VTE, compared with women who had not used hormone replacement therapy in the previous year.4
While the research on thrombotic risk in transgender women is less comprehensive, some smaller cohort and retrospective studies seem to confirm a similar risk. For example, a 2018 cohort study that looked at data from more than 2,800 transgender women using CHST identified a higher incidence of VTE.5 Relative to cisgender men, the 2- and 8-year risk differences were 4.1 and 16.7 per 1,000 persons, respectively, in transgender women. Incidence was also higher compared with cisgender women, with 2- and 8-year risk differences of 3.4 and 13.7.
Understanding this potential risk could help clinicians select estrogen products with the lowest perceived risk profiles. For instance, the 2019 nested case-control study demonstrated a slightly lower overall thrombotic risk with transdermal estrogens compared with oral estrogens.
"We know that patches don't increase the risk of thrombosis as much as oral estrogens," said Ash B. Alpert, MD, MFA, a fellow in hematology and oncology at the Wilmot Cancer Institute at the University of Rochester Medical School, whose preferred pronoun is they. "That is likely because the thrombotic risk is related to estrogen's effects on the liver, which happen when people take oral pills," they said. "But, when people are using patches or other transdermal applications, there are no effects on the liver."
In addition to the hormone therapy application route, patient history can complicate treatment decisions, Dr. Shatzel said. If a cisgender woman on estrogen-based birth control develops a blood clot, such as a deep vein thrombosis (DVT), he would stop the birth control and typically treat her for 3 months with anticoagulant. Once her risk levels return to normal, he would typically feel comfortable stopping the blood thinner.
With transgender women, however, there are other factors to consider.
"Transgender women value the ability to stay on estrogen as part of their gender transition," he said. "We need to look for alternative means to continue estrogen but also keep them safe."
For example, by extrapolating data from cisgender women on hormonal therapy, one could assume that, if the patient does not want to discontinue hormonal therapy, concomitant anticoagulation can be used as a protective measure against thrombosis, Dr. Shatzel explained.
"Anything we can do individually as clinicians or as part of larger institutions to make [health care] settings more gender-inclusive can be helpful to our patients."
—Ash Alpert, MD, MFA
"So, for transgender women who want to stay on estrogen but who have had a blood clot, we will often continue the estrogen along with an indefinite blood thinner, as long as the patient is at a low bleeding risk and seems to be tolerating the blood thinner without issues."
If a transgender woman plans to undergo gender-affirming surgery, Dr. Shatzel said he usually recommends that she stops the estrogen products for 14 days prior to the procedure to reduce the chance of blood clots as a result of surgery. Routine DVT prophylaxis after surgery is also recommended.
Transgender Men and Erythrocytosis
After taking testosterone, transgender men will often see increases in their hemoglobin or hematocrit levels beyond the laboratory's normal range for cisgender men and women, but the implications of this erythrocytosis are unclear.
"In certain hematologic settings, particularly with patients who have mutations that lead to polycythemia vera, increase in red blood cells is a risk factor for stroke or other blood clots," Dr. Shatzel said. "So, in that case, we do try to lower the red blood cell count. However, it is very unclear if you need to do that in transgender men."
Dr. Alpert added that the higher risk of stroke in cisgender men with elevated hemoglobin levels was observed in the Framingham Heart Study. However, after controlling for elevated blood pressure and smoking history, there was no statistically significant effect of higher hemoglobin.6 "I don't think we have any evidence that erythrocytosis increases stroke risk outside of the setting of polycythemia vera or other risk factors," they said.
The Social Stigma of Transgender Identity and SCD
Transgender patients who are also living with sickle cell disease (SCD) may benefit from hematologic consultation to discuss whether hormone therapy is safe.
"Sickle cell disease confers a higher risk of thrombosis," Dr. Alpert noted. "In fact, 12% of patients with SCD have a thrombotic event before the age of 40.7 So, in that setting, if someone wanted to go on estrogen, I think it would make a lot of sense to have a hematology consult."
The challenges of such a consult are outlined in a 2018 report from clinicians at Johns Hopkins Medicine. The authors described the management of a 22-year-old transgender woman with hemoglobin SS, mild protein S deficiency and Moyamoya disease complicated by bilateral ischemic strokes at age 12.8
At age 20, the patient told her pediatric hematologist that she planned to transition from male to female and wanted to begin estrogen treatment. After a team of specialists evaluated her case, the team developed a plan for CSHT including endogenous testosterone suppression with spironolactone, leuprolide, and transdermal 17-beta estradiol. She only reached a maximum estradiol dose of 50 mcg, as nonadherence to chronic partial exchange transfusions was felt to preclude prescribing higher estrogen doses. Clinicians suspected she was taking nonprescribed estrogen as well, but overall, she had never experienced VTE or stroke since beginning transdermal estradiol 16 months earlier.
"No studies specifically guide CSHT for transgender patients with SCD," the authors wrote. "Given the risks of CSHT for this population, we utilized management principles based upon known evidence-based strategies to reduce SCD morbidities."
The authors also highlighted the importance of a multidisciplinary approach that addresses complex medical and psychosocial concerns in treatment recommendations. "Both transgender identity and SCD are associated with stigma and increased morbidity and mortality," they wrote. "Nonadherence [to recommended treatment] is common and may compromise care teams' confidence that CSHT can be safely prescribed. Yet patients with gender dysphoria may pursue nonprescribed therapy, so a collaborative, harm-reduction approach to managing CSHT must be considered."
Concerns About Cancer
A major question in transgender medicine is why transgender men appear to have an increased risk of developing cancer. Earlier this year, Ulrike Boehmer, PhD, and colleagues examined cancer survivorship among more than 3,000 transgender or gender-nonconforming adults and found that, compared with cisgender men, transgender men had a more than a 2-fold increase in the number of cancer diagnoses.9 However, cancer prevalence among gender-nonconforming individuals and transgender women was not significantly different from that of cisgender men and cisgender women.
"The results we found are in line with the belief that transgender individuals have more cancers possibly due to some increased cancer risk behaviors," Dr. Boehmer, Associate Professor of Community Health Sciences at Boston University School of Public Health, told ASH Clinical News. Previous data from a 2017 report have suggested that transgender individuals are more likely to avoid health care, have higher levels of smoking, and are less likely to get screened for cancer than their cisgender counterparts.10 Higher rates of HIV infection in the transgender population also may predispose these patients to a higher risk of cancer.
"One could hypothesize that these factors have implications such as later cancer diagnoses, but we don't really have the data to examine this issue," she added. But, while Dr. Boehmer's study provides some valuable insight into this patient subgroup, overall, there are "very, very few data" about cancer prevalence in this population.
One notable finding is that transgender individuals who were diagnosed with cancer also had high levels of comorbidities, including what Dr. Boehmer called "staggering numbers" of patients with diabetes and cardiovascular disease.
Commenting on the study, Dr. Alpert noted that the confidence intervals in the analyses were "incredibly wide," suggesting that much larger sample sizes are needed to truly assess the discrepancies in cancer prevalence among transgender individuals.
They pointed to the 2017 study that found transgender patients have an overrepresentation of malignancies linked to HIV and HPV infections, including Kaposi sarcoma and anal carcinoma. "Again, it was a small sample with retrospective data, so we need much higher-quality data to be able to answer these questions," they said.
How Hematologists Can Help
Due to the unique considerations for treating transgender individuals, some experts who spoke with ASH Clinical News recommended that hematologic consults or screenings be conducted before a patient begins gender-affirming therapies.
"I personally believe that good transgender care is multidisciplinary and involves several specialists, including endocrinologists, hematologists, and surgeons with experience in transgender procedures," Dr. Shatzel said.
Jean M. Connors, MD, Medical Director of the Anticoagulation Management Service at Brigham and Women's Hospital and Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School, said she is often asked to weigh in on the use of hormone therapy in patients who are transitioning gender, particularly for those patients with risk factors for thrombosis, including thrombophilia, obesity, smoking, a past history of thrombosis, or family history.
"How do you balance the risk and benefits in an individual patient? I think that is a question best addressed by someone who knows [the field of] thrombosis," said Dr. Connors. Of course, she added, "you also need to know the risks for transgender women using estrogen, the specific risks associated with different estrogen preparations, and how to best manage all of those factors."
Balancing the Benefits of Gender-Affirming Therapies
As Dr. Shatzel noted that when managing estrogen-based birth control in a cisgender woman who experiences a blood clot, the decision to stop the hormonal therapy is typically clear cut. In transgender patients, however, the mental health benefits provided by gender-affirming CHST complicate that decision. When developing a care plan for transgender patients, psychosocial factors and patients' goals need to be considered.
"Many patients have said that they feel like their need for hormone therapy is not considered as significant and that they are often advised to just stop their hormone therapy, which conflicts with who they are and their sense of wellbeing," Dr. Connors said. "So, clinicians need to realize that they have to work within the framework of the patient's specific needs, which are unique when it comes to transgender hormone use."
In a 2018 study looking at the emotional benefits of transition-related medical interventions in transgender U.S. veterans, the authors established that patients who have access to these interventions have lower levels of depression and suicidal ideation, compared with people without access.11
Another study published in the International Journal of Transgenderism found that transgender individuals reported statistically significant improvement in body image after hormone therapy, as well as a general improvement in quality of life.12
"We know that hormone therapies improve mental health for transgender patients," Dr. Alpert said. "In that context, it is essential to talk about the risks [associated with CSHT] and ensure that we have quality data to share."
Dr. Alpert, who also serves on a community advisory board for transgender people who have cancer, added that, "at the same time, it's important to decrease any barriers that may exist for patients to access hormone therapy." For example, clinicians might consider adding prophylactic anticoagulation to the treatment plan for a transgender woman who is at high risk for thrombosis so she can continue estrogen therapy.
A More Inclusive Future
Researchers have been gathering more data on the health outcomes of transgender individuals, but, as everyone who ASH Clinical News spoke with on this topic said, what we know about the hematologic considerations for transgender patients is eclipsed by what we do not know.
"We need some prospective studies about the impact of CSHT on coagulation profiles, cardiovascular risk profile, and bone health," Dr. Connors said. She also believes further research should be conducted to determine the optimal doses of hormone therapy.
There also are substantial gaps in research in cancer prevalence and outcomes seen in these patients. "Any information we can get in terms of the types of cancers that might be prevalent in the transgender population will be very important," Dr. Boehmer said.
Ideally, Dr. Alpert said, researchers would have long-term prospective data from large sample sizes of transgender individuals followed over decades. "Those data could inform decisions about prophylaxis or other interventions we could provide in specific contexts, and would also allow us to have real, informed consent decisions with our patients," they said.
That type of data will take time to accumulate, but hematologists and oncologists can start taking steps to improve the patient experience for transgender and gender-nonconforming people. Culturally sensitive care can include asking patients for their preferred pronouns, ensuring that gender neutral restrooms are available, and offering dressing gowns in colors or patterns that aren't typically associated with either gender. Doctors can also avoid language that makes assumptions about a person's gender or sexual preferences, such as asking a patient to bring a "loved one" rather than their husband or wife.
The health care provider's goal should be ensuring that each person who interacts with the patient along the way – from the hospital staff cleaning the rooms to the physician making treatment decisions – establishes a welcoming, inclusive environment for all patients, Dr. Connors added.
That also means building a working knowledge of the types of medications that transgender patients may be taking, even those that can be acquired without a prescription. Dr. Connors recalled being unaware that there was a once-monthly injectable formulation of combination contraceptives available in Europe, but not the U.S., until it came up in a patient visit.
"You have to be willing to engage in a dialogue and be open about it, but you can't have a conversation if you aren't knowledgeable," she said. "These topics can be difficult because talking about sexuality is not easy in many cultures and religions. If a transgender patient feels they are not in a welcoming situation, they may not share all of their concerns or open up about everything they are doing."
"Our health care settings are so inherently gendered both in the ways that we talk to patients and in the structure of our health care system," Dr. Alpert said. "So, anything we can do individually as clinicians or as part of larger institutions to make those settings more gender-inclusive can be helpful to our patients." —By Jill Sederstrom
References
- World Professional Association for Transgender Health. Position Statement on Medical Necessity of Treatment, Sex Reassignment, and Insurance Coverage in the U.S.A. Accessed October 30, 2020, from https://www.wpath.org/newsroom/medical-necessity-statement.
- Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016;5(6):877-884.
- Shatzel J, Connelly K, DeLoughery T. Thrombotic issues in transgender medicine: A review. Am J Hematol. 2017;92(2): 204-208.
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019; 364:k4810.
- Getahun D, Nash R, Flanders WD, et al. Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study. Ann Intern Med. 2018;169(4):205-213.
- Kannel WB, Gordon T, Wolf PA, McNamara P. Hemoglobin and the risk of cerebral infarction: the Framingham Study. Stroke. 1972;3(4):409-420.
- Brunson A, Lei A, Rosenberg AS, et al. Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. Br J Haematol. 2017;178(2):319-326.
- Ronda J, Nord A, Arrington-Sanders R, et al. Challenges in the management of the transgender patient with sickle cell disease. Am J Hematol. 2018;93(11):E360-E362.
- Boehmer U, Gereige J, Winter M. Transgender individuals' cancer survivorship: Results of a cross-sectional study. Cancer. 2020; 126(12):2829-2836.
- Braun H, Nash R, Tangpricha V, Brockman J, Ward K, Goodman M. Cancer in Transgender People: Evidence and Methodological Considerations. Epidemiol Rev. 2017;39(1):93-107.
- Tucker R, Testa R, Simpson T, et al. Hormone therapy, gender affirmation surgery, and their association with recent suicidal ideation and depression symptoms in transgender veterans. Psychol Med. 2018;48(14):2329-2336.
- Manieri C, Castellano E, Crespi C, et al. Medical treatment of subjects with gender identity disorder: the experience in an Italian public health center. Intl J Transgenderism. 2014;15(2):53-65.
