- Email: [email protected]
Prostate Cancer in Transgender Women: Incidence, Etiopathogenesis, and Management Challenges
Oncology Prostate Cancer in Transgender Women: Incidence, Etiopathogenesis, and Management Challenges Nicholas A. Deebel, Jacqueline P. Morin, Riccardo Autorino, Randy Vince, Baruch Grob, and Lance J. Hampton OBJECTIVE
MATERIALS AND METHODS
RESULTS
CONCLUSION
To critically analyze the available evidence regarding the incidence, etiopathogenesis, and management of prostate cancer (CaP) in transgender women. In addition, this article aims to present a recent case report of a transgender woman with a unique presentation at the author’s institution. An electronic nonsystematic literature search was performed to identify pertinent studies. PubMed search engine was queried by using the following search terms: “prostate cancer,” “male to female transsexual,” “transgender patient,” “androgen + prostate cancer,” “estrogen therapy + prostate cancer,” and “health care barrier.” In addition, a clinical case managed at our institution was reviewed and critically discussed. Including our case, there have been only 10 documented cases of CaP in transgender women. Additionally, an emerging body of literature has questioned the role of androgens in the development of CaP and suggested that estrogen therapy may not be as protective as initially thought. Therefore, the current evidence suggests that the transgender woman should be screened for CaP the same as a nontransgender men. Barriers to care in the transgender female population include accessing resources, medical knowledge deficits, ethics of transition-related medical care, diagnosing vs pathologizing transgender patients, financial restrictions of the patient, and health system determinants. Although rare, CaP in transgender women has been documented. Both the mechanism and the impact of receiving a bilateral orchiectomy on disease development are unclear. Future study is needed to examine these factors, and to further shape the treatment and screening regimen for these patients. UROLOGY 110: 166–171, 2017. Published by Elsevier Inc.
G
ender identity describes how one views his or her own gender. When a person’s gender identity and expression do not match his or her physical phenotype, the person is classified as being “transgender.” Furthermore, the urge and execution of living as the phenotypically opposite sex somatically, psychosocially, and legally is termed “transsexualism.”1 This set of conditions was previously medicalized as gender identity disorder. However, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, now labels this constellation of findings as gender dysphoria (Fig. 1).2 A variety of studies have shown the upward trend in the prevalence of transgender individuals. In 2011 it was estimated that there are roughly 700,000 transgender individuals in the United States.3 A subsequent study by Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Urology, Virginia Commonwealth University, Richmond, VA Address correspondence to: Riccardo Autorino M.D., Ph.D, F.E.B.U., Division of Urology/Department of Surgery, Virginia Commonwealth University School of Medicine, PO BOX 980118, Richmond, VA 23298. E-mail: [email protected] Submitted: July 1, 2017, accepted (with revisions): August 21, 2017
166
Published by Elsevier Inc.
Flores et al estimated that there are 1.4 million transgender adults in the United States.4 This population’s increased prevalence and acceptance by society have been echoed in the business world. Schuster et al highlighted that in 2015, 375 Fortune 500 companies prohibited discrimination related to an individual’s gender identity.3 This number was a steady increase from only 15 companies in 2002. Although only 16% of people in the United States know a transgender individual, the total population of these individuals is rapidly increasing.1 Therefore, it is important that physicians increase their literacy on this subject to adequately care for transgender individuals. Although most of the controversy surrounding these individuals is psychosocial in nature, there can be medical implications associated with the process of gender reassignment. One is the development of prostate cancer (CaP) in transgender women. To achieve a successful male to female transition, there are various medical or surgical interventions that an individual must go through. The main goal is to deprive the phenotypically male body of androgen through GnRH agonist, testosterone (T) antagonist, or bilateral orchiectomy https://doi.org/10.1016/j.urology.2017.08.032 0090-4295
Figure 1. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for gender dysphoria diagnosis.
while simultaneously supplementing the body with estrogen therapy to obtain the female phenotype. Although the prostate is biologically a male organ, it is not customary to perform a prostatectomy during the “transition” as this operation is associated with complications such as urinary incontinence.5 Despite the lack of androgens and high level of estrogens in these patients, rare cases of CaP have been reported in transgender women.6-14 The development of CaP in these patients has puzzled many as it opposes the tenants of the androgen hypothesis that CaP is dependent on serum androgen levels.15 In addition to these scattered case reports, there have been numerous basic science projects demonstrating the multifactorial nature of CaP development. Some studies have identified a potential role of estrogen in the development of cancer.16-18 The purpose of this article is to highlight the literature on existing cases of CaP in transgender women, the hypotheses as to why CaP occurs in this unique setting, and the psychosocial barriers and implications of caring for these individuals. We will also present our own recent case report of a transgender woman with a unique presentation. To the best of our knowledge, this is the first article that comprehensively integrates all these categories.
MATERIALS AND METHODS An electronic nonsystematic literature search was performed to identify pertinent studies. PubMed search engine was queried by using the following search terms: “prostate cancer,” “male to female transsexual,” “transgender patient,” “androgen + prostate cancer,” UROLOGY 110, 2017
“estrogen therapy + prostate cancer,” and “health care barrier.” In addition, a clinical case managed at our institution was reviewed and critically discussed.
RESULTS Literature Search Nine cases of CaP in transgender women have been reported in the literature between 1975 and 2017 (Table 1).6-14 Clinical Case We present the case of a 65-year-old transgender woman who presented to our urology clinic for evaluation of an elevated prostate-specific antigen (PSA). She reported having identified as a female since an early age and began feminization in her 20s with oral and injectable estrogen for roughly 20 years. She achieved feminization including increased breast volume but did not undergo further gender transition interventions such as orchiectomy because of financial restrictions. She ceased supplemental estrogen at the age of 55, leaving a 10-year gap after receiving estrogen therapy. Her referral to our urology clinic was ultimately a byproduct of her complicated medical history including diagnoses of human immunodeficiency virus, stage IV chronic kidney disease, prior cerebral ischemic event, diabetes mellitus type 2, and hypertension. In June 2015 her worsening chronic kidney disease led to an evaluation for renal transplantation, which included a PSA value of 7.5 ng/ mL in February 2011. Her family history was negative for CaP. At the time of presentation, her PSA had increased 167
Table 1. Review of CaP in transgender women. Adapted from Gooren et al5
Age, y
Age at Start of Cross-sex Hormones, y
Markland (1975)6 Thurston (1994)7 van Haarst et al. (1998)8 Miksad et al. (2006)9
54 64 63
48 52 53
60
19
Unknown LUTS Weight loss, bone pain Hematuria
Dorff et al (2007)10
78
52
Hematuria
Molokwu et al. (2008)11 Turo et al. (2013)12 Ellent et al (2016)13 Sharif et al (2017)14
60
19
LUTS
75 65 56
45 30 36
LUTS LUTS Unknown
Reference
Presenting Symptom
PSA at Diagnosis (ng/mL)
Metastases Present?
Gleason Score
Unknown 27 >100
Unknown + +
Unknown Unknown Unknown
240
+
8
177
+
9
Unknown
Unknown
+ + -
7 9 7
Increased, no specific value 13.5 19 5
Mortality Unknown + Clinically stable Clinically stable Clinically stable Unknown + Unknown Clinically stable
LUTS, lower urinary tract symptoms; PSA, prostate-specific antigen.
to 8.5 ng/mL and physical examination demonstrated a prostate size of approximately 70 grams. The patient denied any lower urinary tract symptoms. Transrectal ultrasound with biopsy was performed. Pathology demonstrated a Gleason 7 (3 + 4) adenocarcinoma in 6 of 12 cores. The patient underwent a robotically assisted laparoscopic radical prostatectomy in June 2016. Surgical pathology confirmed a Gleason 7 (3 + 4) prostate adenocarcinoma with 15% grade 4 content. The operative margins were cancerfree, and pelvic lymph nodes were negative for regional metastasis. The 1-month postoperative PSA value was 0.1 ng/ mL. This has increased to 0.2 ng/mL at 9 months and 1 year follow-up. The patient continues to have stress urinary incontinence and erectile dysfunction for which she receives pelvic floor physical therapy. She follows up in our clinic with regular PSA checks and has been referred to a radiation oncologist for restaging imaging to evaluate for initiation of radiotherapy. She is otherwise asymptomatic.
COMMENTS Incidence and Etiopathogenesis Studies looking at the prevalence of CaP in this patient population remain limited. Gooren and Morgentaler reported a 0.04% prevalence in their cohort of 2306 transgender women. Although it is a very low percentage, it is important to note that patients in this cohort did not undergo regular screening, and therefore it is possible that subclinical cases were overlooked.5 There are numerous theories explaining the development of CaP in the previously mentioned cases (Table 1). One theory is that the CaP was already present prior to the initiation of estrogen therapy. This is supported by the fact that several patients did not initiate hormonal treatment until after the age of 45.5 Additionally, most patients demonstrated an extremely high initial PSA value at diagnosis, which supports the fact that CaP is detected late in this patient population. This is further supported by the presence of metastases in 6 of 9 existing cases 168
(66.7%). Consequently, treatment in this population has largely been centered on the utilization of chemotherapy. Therefore, the ultimate challenge in this cohort is detecting CaP early enough so that radiation or surgical intervention can be utilized. The patient we presented is unique in that her cancer was an incidental finding during pretransplant screening. In addition, our patient did not receive a bilateral orchiectomy and relied solely on estrogen therapy to achieve feminization. This has previously been documented in only 2 of 9 cases (22.2%).13,14 The lack of bilateral orchiectomy may be of minimal consequence in our patient’s likelihood of developing CaP. The transgender patient population provides a unique in vivo opposition to the androgen hypothesis of CaP development. It was originally hypothesized by Huggins and Hodges that “prostatic cancer is influenced by androgenic activity.”15 Additionally, they concluded “disseminated carcinoma of the prostate is inhibited by eliminating androgens or neutralization of their activity by estrogen injection.” This has been a widely accepted idea within urology for the past 70 years. Recently, a large body of literature has called these previously accepted notions into question. This would make the occurrence of CaP in transgender women less surprising. A study by Rhoden et al showed that hypogonadal men with prostatic intraepithelial neoplasia who received testosterone replacement therapy (TRT) for 1 year did not have a significantly elevated PSA level compared with hypogonadal individuals without prostatic intraepithelial neoplasia.19 These findings were further bolstered by a paper by Marks et al that looked at a hypogonadal population undergoing 6 months of TRT.20 They used prostate biopsy at baseline and after treatment to show that TRT normalizes serum androgen level but has little effect on prostate tissue androgen level or cellular function. In subsequent years, a new theory termed “the saturation model” was established.21 This model demonstrated that prostate growth is sensitive to changes in androgen level when the baseline level is low (castrated individuals). However, the prostate appears to lose its sensitivity UROLOGY 110, 2017
to androgens when androgen receptors are saturated. Saturation appears to occur at a testosterone (T) concentration far below physiologic range. This is why changes in prostate growth are observed when T is given to castrated men but not to noncastrated men. The ability for the prostate to lose sensitivity to T after reaching saturation would make the androgen hypothesis of CaP development less likely. The saturation model was further validated by the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial.22 In the placebo arm (no dutasteride), 4073 men with PSA greater than 2.5 or 3.0 (depending on age) and a negative transrectal ultrasound biopsy <6 months prior to the study received transrectal ultrasound-guided biopsies at 2 and 4 years into the study. The primary findings showed that baseline T and dihydrotestosterone (DHT) levels were unrelated to CaP risk. Secondary analysis of men with low T showed that men with the lowest baseline T level had the lowest CaP risk. Patients with increased baseline T level up to a level of 10 nmol/L had an increased CaP risk. T levels over 10 nmol/L conferred no additional CaP risk, therefore implying the presence of androgen receptor (AR) saturation. Additional studies by Morgantaler et al provide evidence against the link between androgen level and CaP development. This group observed that 11 of 77 prostate biopsies in men with low T showed CaP.23 This prompted a follow-up study in 345 men with low T and normal PSA, which showed a cancer rate of 15%.23 As evidenced by several other studies, low T hardly seems to confer a protective effect from CaP and may instead impart a harmful risk for developing CaP. 24 Morgantaler et al further downplayed the role of T in CaP progression by administering T therapy in 13 men during active surveillance of their CaP. There was no progression of any of the patient’s CaP at the 2-year mark.25 Another theory focuses on estrogen’s role in the development of CaP. In all 10 of the reported cases of CaP in transgender women, patients had received extended estrogen therapy as part of their transition.6-14 There has been recent speculation that estrogen could be playing a role in the development of CaP. A study by King et al showed that both prostate stromal cells and a malignant cell line called LNCaP showed increased growth (compared with the control group) with estrogen treatment.16 King et al further examined the ratio of estrogen to DHT (E2:DHT) and showed that in stromal cells an increased E2:DHT had the highest effect on stromal cell growth. The ratio was found to be insignificant in the growth of the malignant cell line. The authors also discuss the ability of estrogen to upregulate AR. The results of this paper are especially interesting when the results are applied to transgender women, a population with elevated E2:DHT levels. Additional studies in rat and human prostates have shown that the combination of estrogen and T may lead to the development of CaP.17,18 Finally, a case report by Sharif et al highlighted the case of CaP in a transgender woman.14 The prostate was analyzed through immunohistochemistry and was found to be UROLOGY 110, 2017
positive for increased levels of ERα, which has been positively implicated in CaP induction. Although more research is necessary, it is possible that estrogen therapy used in transitions could be fueling prostatic changes. As this relatively new cohort of patients ages, it will be paramount to examine the nature of their estrogen therapy and the incidence of CaP development. Future directions for studying CaP in the transgender woman include prospective studies to more accurately determine incidence, analysis of E2:T ratios and its correlation to CaP development, and immunohistochemistry studies to further establish the estrogen receptor and AR status of the transgender prostate received from biopsy or prostatectomy. Furthermore, analysis of CaP in transgender women undergoing voluntary androgen suppression might suggest whether cancer in these individuals is more or less aggressive than cisgendered men. Finally, noncastrated, transgender women with CaP requiring additional hormonal manipulation should be followed to determine the cancer’s response. This may identify whether CaP is phenotypically different from CaP in the cisgendered male. Barriers to Health Care for Transsexual Individuals There is currently a deficit in the standard of care provided for transgender women. A qualitative analysis by Snelgrove et al highlighted barriers to care from the physician point of view.26 After 13 physicians were interviewed, barriers were categorized into the following groups: accessing resources, medical knowledge deficits, ethics of transition-related medical care, diagnosing vs pathologizing (treating aspects of the human condition as a psychiatric illness) transgender patients, and health system determinants. Many practitioners added that knowing who to refer these patients to is confusing and can sometimes result in negative experiences for the patient. There are conflicting opinions regarding how to resolve the lack of medical knowledge. Several participants felt that education regarding transgender patients should be included in the medical school curriculum, whereas others endorsed robust guideline dispersal among the medical community.26 Finally, the study noted that some participants felt gender dysphoria is overemphasized as a subspecialty of psychiatry and that care needs to be transitioned to primary care and associated specialists. An additional review on the barriers to health care for transgender patients by Safer et al highlighted a series of tasks that should be completed to improve overall health and well-being for this population.27 Safer et al argue that a formal study on the medical knowledge of health care providers is necessary. Based on the results of this review, ideas on how to address the knowledge gap can be formulated. In addition to knowledge gap assessment, future study should also examine the nonmedical biases of providers such as attitudes toward transgender patients and the fear of the stigma associated with caring for these individuals. Finally, the authors address that insurance companies have often been cited as a barrier to care. There is, however, little quantitative data regarding the degree to which third-party payer 169
systems impede access to comprehensive care for transgender women. Although ameliorating physician-related barriers to care is important, financial restrictions may be one of the most profound impediments to health care for these individuals.28 Gender reassignment-based care is often regarded as elective and thus rarely covered by insurance in the United States. This often leads to patients with an “intermediate sexed state.” The medical and psychological consequences of this are unclear but warrant future study. There are numerous roles that urologists can play in the alleviation of barriers to care. Firstly, urologists should continue to educate themselves and their colleagues on the following topics: pathogenesis of CaP, current screening recommendations for transgender women, and the psychosocial implications of gender reassignment. A competency in these 3 areas will adequately allow the urologist to provide optimal care. Secondly, just like any medically complex patient, team-based care for the transgender woman is essential to optimize outcomes. Urologists are encouraged to work closely with primary care specialists, endocrinologists, and mental health professionals to fully understand the care of the transgender woman. Finally, transgender women are frequently deterred from office visits by societal stigma and lack of acceptance among office staff. Urologists should serve as leaders in their workplace by encouraging professional behavior and downplaying the associated stigma to build rapport with transgender women. Prostate Cancer Screening One of the challenges to caring for transgender women is keeping both generalists and specialists informed on the standards of care. The World Professional Association or Transgender Health and the Endocrine Society provide an expansive set of guidelines regarding CaP screening protocol.29,30 Because of a lack of data, these institutions recommend individuals be screened with the same standards (as stated by the American Urological Association) as cisgendered men: nontransgender individuals.1 Of note, Gooren and Morgentaler recommend that given a low T environment, the upper limit of normal for PSA should be 1 ng/mL.5 This recommendation was established using evidence that a CaP-positive biopsy despite a low PSA value is more common in the setting of T deficiency, which is commonly seen in the transgender woman. Further studies are needed to determine the incidence and prevalence of CaP in transgender women. A more complete understanding of the epidemiology would allow for robust recommendations regarding screening protocols. Future recommendations may include annual screening with PSA with or without digital rectal examination and maintaining an elevated level of suspicion for PSA values of 1-4 ng/mL. In light of an inadequately defined incidence and prevalence of CaP in transgender women, we recommend that urologists should counsel their patients on the seemingly low but evident risk of CaP development at the time of initial presentation. This will allow the urologist to engage their patient in shared decision making and ini170
tiate screening in those who desire regular screening or are at an increased risk for CaP.
CONCLUSION To the best of our knowledge, this represents the first comprehensive review on CaP in transgender women. More research is necessary to determine whether incomplete sexual reassignment leads to an increased risk of CaP. An additional concern that has been raised is the role of estrogen in the development of CaP. Although the literature is still growing, there has been some suggestion that testosterone does not fuel CaP as once hypothesized. Furthermore, estrogen may play a role in tumorigenesis, which would be of concern in the current population of transgender women. More research and consideration of estrogen’s role in therapy is needed. Finally, to adequately screen this population, barriers to health care such as physician education regarding this population and financial burdens must be overcome. With adequate screening, CaP may be detected at a less aggressive grade, therefore resulting in better outcomes. As this population grows older and increases in number, it will be imperative to monitor the incidence of CaP development in order to alter our standards of care as our society evolves. Acknowledgment. The authors wish to thank James Tomkinson for his valuable contributions to the inception of this project.
References 1. GLAAD. 2017. GLAAD Media Reference Guide. Available at: http://www.glaad.org/reference/transgender. Accessed January 15, 2017. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, DC: American Psychiatric Association; 2013. 3. Schuster MA, Reisner SL, Onorato SE. Beyond bathrooms— meeting the health needs of transgender people. N Engl J Med. 2016;375:101-103. 4. Flores AR, Herman JL, Gates GJ, et al. How many adults identify as transgender in the United States? Los Angeles, CA: The Williams Institute; 2016: 1-13. 5. Gooren LJ, Morgentaler A. Prostate cancer incidence in orchidectomised male-to-female transsexual persons treated with oestrogens. Andrologia. 2014;46:1156-1160. 6. Markland C. Transexual surgery. Obstet Gynecol Annu. 1975;4:309330. 7. Thurston AV. Carcinoma of the prostate in a transsexual. Br J Urol. 1994;73:217. 8. van Haarst EP, Newling DW, Gooren LJ, et al. Metastatic prostatic carcinoma in a male-to-female transsexual. Br J Urol. 1998;81:776. 9. Miksad RA, Bubley G, Church P, et al. Prostate cancer in a transgender woman 41 years after initiation of feminization. JAMA. 2006;296:2316-2317. 10. Dorff TB, Shazer RL, Nepomuceno EM, et al. Successful treatment of metastatic androgen- independent prostate carcinoma in a transsexual patient. Clin Genitourin Cancer. 2007;5:344-346. 11. Molokwu CN, Appelbaum JS, Miksad RA. Detection of prostate cancer following gender reassignment. BJU Int. 2008;101:259. 12. Turo R, Jallad S, Prescott S, et al. Metastatic prostate cancer in transsexual diagnosed after three decades of estrogen therapy. Can Urol Assoc J. 2013;7:E544-E546.
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13. Ellent E, Matrana MR. Metastatic prostate cancer 35 years after sex reassignment surgery. Clin Genitourin Cancer. 2016;14:e207-e209. 14. Sharif A, Malhotra NR, Acosta AM, et al. The development of prostate adenocarcinoma in a transgender male to female patient: could estrogen therapy have played a role? Prostate. 2017;77:824-828. 15. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;68:9-12. 16. King KJ, Nicholson HD, Assinder SJ. Effect of increasing ratio of estrogen: androgen on proliferation of normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP. Prostate. 2006;66:105-114. 17. Bosland MC. A perspective on the role of estrogen in hormoneinduced prostate carcinogenesis. Cancer Lett. 2013;334:28-33. 18. Hu WY, Shi GB, Lam HM, et al. Estrogen-initiated transformation of prostate epithelium derived from normal human prostate stemprogenitor cells. Endocrinology. 2011;152:2150-2163. 19. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol. 2003;170(6 Pt 1):2348-2351. 20. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296:2351-2361. 21. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgendependent growth. Eur Urol. 2009;55:310-320.
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22. Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial. Eur Urol. 2012;62:757-764. 23. Morgentaler A. Goodbye androgen hypothesis, hello saturation model. Eur Urol. 2012;62:765-767. 24. Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol. 2000; 163:824-827. 25. Morgentaler A. Controversies and advances with testosterone therapy: a 40-year perspective. Urology. 2016;89:27-32. 26. Snelgrove JW, Jasudavisius AM, Rowe BW, et al. “ompletely outat-sea” with “two-gender medicine”: a qualitative analysis of physicianside barriers to providing healthcare for transgender patients. BMC Health Serv Res. 2012;12:1-13. 27. Safer JD, Coleman E, Feldman J, et al. Barriers to healthcare for transgender individuals. Curr Opin Endocrinol Diabetes Obes. 2016;23:168-171. 28. Trum HW, Hoebeke P, Gooren LJ. Sex reassignment of transsexual people from a gynecologist’s and urologist’s perspective. Acta Obstet Gynecol Scand. 2015;94:563-567. 29. Coleman E, Adler R, Bockting W, et al. Standards of care for the health of transsexual, transgender, and gender nonconforming people. Int J Transgend. 2012;13:165-232. 30. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. Endocrine treatment of transsexual persons: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2009;94:31323154.
171
MATERIALS AND METHODS
RESULTS
CONCLUSION
To critically analyze the available evidence regarding the incidence, etiopathogenesis, and management of prostate cancer (CaP) in transgender women. In addition, this article aims to present a recent case report of a transgender woman with a unique presentation at the author’s institution. An electronic nonsystematic literature search was performed to identify pertinent studies. PubMed search engine was queried by using the following search terms: “prostate cancer,” “male to female transsexual,” “transgender patient,” “androgen + prostate cancer,” “estrogen therapy + prostate cancer,” and “health care barrier.” In addition, a clinical case managed at our institution was reviewed and critically discussed. Including our case, there have been only 10 documented cases of CaP in transgender women. Additionally, an emerging body of literature has questioned the role of androgens in the development of CaP and suggested that estrogen therapy may not be as protective as initially thought. Therefore, the current evidence suggests that the transgender woman should be screened for CaP the same as a nontransgender men. Barriers to care in the transgender female population include accessing resources, medical knowledge deficits, ethics of transition-related medical care, diagnosing vs pathologizing transgender patients, financial restrictions of the patient, and health system determinants. Although rare, CaP in transgender women has been documented. Both the mechanism and the impact of receiving a bilateral orchiectomy on disease development are unclear. Future study is needed to examine these factors, and to further shape the treatment and screening regimen for these patients. UROLOGY 110: 166–171, 2017. Published by Elsevier Inc.
G
ender identity describes how one views his or her own gender. When a person’s gender identity and expression do not match his or her physical phenotype, the person is classified as being “transgender.” Furthermore, the urge and execution of living as the phenotypically opposite sex somatically, psychosocially, and legally is termed “transsexualism.”1 This set of conditions was previously medicalized as gender identity disorder. However, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, now labels this constellation of findings as gender dysphoria (Fig. 1).2 A variety of studies have shown the upward trend in the prevalence of transgender individuals. In 2011 it was estimated that there are roughly 700,000 transgender individuals in the United States.3 A subsequent study by Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Urology, Virginia Commonwealth University, Richmond, VA Address correspondence to: Riccardo Autorino M.D., Ph.D, F.E.B.U., Division of Urology/Department of Surgery, Virginia Commonwealth University School of Medicine, PO BOX 980118, Richmond, VA 23298. E-mail: [email protected] Submitted: July 1, 2017, accepted (with revisions): August 21, 2017
166
Published by Elsevier Inc.
Flores et al estimated that there are 1.4 million transgender adults in the United States.4 This population’s increased prevalence and acceptance by society have been echoed in the business world. Schuster et al highlighted that in 2015, 375 Fortune 500 companies prohibited discrimination related to an individual’s gender identity.3 This number was a steady increase from only 15 companies in 2002. Although only 16% of people in the United States know a transgender individual, the total population of these individuals is rapidly increasing.1 Therefore, it is important that physicians increase their literacy on this subject to adequately care for transgender individuals. Although most of the controversy surrounding these individuals is psychosocial in nature, there can be medical implications associated with the process of gender reassignment. One is the development of prostate cancer (CaP) in transgender women. To achieve a successful male to female transition, there are various medical or surgical interventions that an individual must go through. The main goal is to deprive the phenotypically male body of androgen through GnRH agonist, testosterone (T) antagonist, or bilateral orchiectomy https://doi.org/10.1016/j.urology.2017.08.032 0090-4295
Figure 1. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for gender dysphoria diagnosis.
while simultaneously supplementing the body with estrogen therapy to obtain the female phenotype. Although the prostate is biologically a male organ, it is not customary to perform a prostatectomy during the “transition” as this operation is associated with complications such as urinary incontinence.5 Despite the lack of androgens and high level of estrogens in these patients, rare cases of CaP have been reported in transgender women.6-14 The development of CaP in these patients has puzzled many as it opposes the tenants of the androgen hypothesis that CaP is dependent on serum androgen levels.15 In addition to these scattered case reports, there have been numerous basic science projects demonstrating the multifactorial nature of CaP development. Some studies have identified a potential role of estrogen in the development of cancer.16-18 The purpose of this article is to highlight the literature on existing cases of CaP in transgender women, the hypotheses as to why CaP occurs in this unique setting, and the psychosocial barriers and implications of caring for these individuals. We will also present our own recent case report of a transgender woman with a unique presentation. To the best of our knowledge, this is the first article that comprehensively integrates all these categories.
MATERIALS AND METHODS An electronic nonsystematic literature search was performed to identify pertinent studies. PubMed search engine was queried by using the following search terms: “prostate cancer,” “male to female transsexual,” “transgender patient,” “androgen + prostate cancer,” UROLOGY 110, 2017
“estrogen therapy + prostate cancer,” and “health care barrier.” In addition, a clinical case managed at our institution was reviewed and critically discussed.
RESULTS Literature Search Nine cases of CaP in transgender women have been reported in the literature between 1975 and 2017 (Table 1).6-14 Clinical Case We present the case of a 65-year-old transgender woman who presented to our urology clinic for evaluation of an elevated prostate-specific antigen (PSA). She reported having identified as a female since an early age and began feminization in her 20s with oral and injectable estrogen for roughly 20 years. She achieved feminization including increased breast volume but did not undergo further gender transition interventions such as orchiectomy because of financial restrictions. She ceased supplemental estrogen at the age of 55, leaving a 10-year gap after receiving estrogen therapy. Her referral to our urology clinic was ultimately a byproduct of her complicated medical history including diagnoses of human immunodeficiency virus, stage IV chronic kidney disease, prior cerebral ischemic event, diabetes mellitus type 2, and hypertension. In June 2015 her worsening chronic kidney disease led to an evaluation for renal transplantation, which included a PSA value of 7.5 ng/ mL in February 2011. Her family history was negative for CaP. At the time of presentation, her PSA had increased 167
Table 1. Review of CaP in transgender women. Adapted from Gooren et al5
Age, y
Age at Start of Cross-sex Hormones, y
Markland (1975)6 Thurston (1994)7 van Haarst et al. (1998)8 Miksad et al. (2006)9
54 64 63
48 52 53
60
19
Unknown LUTS Weight loss, bone pain Hematuria
Dorff et al (2007)10
78
52
Hematuria
Molokwu et al. (2008)11 Turo et al. (2013)12 Ellent et al (2016)13 Sharif et al (2017)14
60
19
LUTS
75 65 56
45 30 36
LUTS LUTS Unknown
Reference
Presenting Symptom
PSA at Diagnosis (ng/mL)
Metastases Present?
Gleason Score
Unknown 27 >100
Unknown + +
Unknown Unknown Unknown
240
+
8
177
+
9
Unknown
Unknown
+ + -
7 9 7
Increased, no specific value 13.5 19 5
Mortality Unknown + Clinically stable Clinically stable Clinically stable Unknown + Unknown Clinically stable
LUTS, lower urinary tract symptoms; PSA, prostate-specific antigen.
to 8.5 ng/mL and physical examination demonstrated a prostate size of approximately 70 grams. The patient denied any lower urinary tract symptoms. Transrectal ultrasound with biopsy was performed. Pathology demonstrated a Gleason 7 (3 + 4) adenocarcinoma in 6 of 12 cores. The patient underwent a robotically assisted laparoscopic radical prostatectomy in June 2016. Surgical pathology confirmed a Gleason 7 (3 + 4) prostate adenocarcinoma with 15% grade 4 content. The operative margins were cancerfree, and pelvic lymph nodes were negative for regional metastasis. The 1-month postoperative PSA value was 0.1 ng/ mL. This has increased to 0.2 ng/mL at 9 months and 1 year follow-up. The patient continues to have stress urinary incontinence and erectile dysfunction for which she receives pelvic floor physical therapy. She follows up in our clinic with regular PSA checks and has been referred to a radiation oncologist for restaging imaging to evaluate for initiation of radiotherapy. She is otherwise asymptomatic.
COMMENTS Incidence and Etiopathogenesis Studies looking at the prevalence of CaP in this patient population remain limited. Gooren and Morgentaler reported a 0.04% prevalence in their cohort of 2306 transgender women. Although it is a very low percentage, it is important to note that patients in this cohort did not undergo regular screening, and therefore it is possible that subclinical cases were overlooked.5 There are numerous theories explaining the development of CaP in the previously mentioned cases (Table 1). One theory is that the CaP was already present prior to the initiation of estrogen therapy. This is supported by the fact that several patients did not initiate hormonal treatment until after the age of 45.5 Additionally, most patients demonstrated an extremely high initial PSA value at diagnosis, which supports the fact that CaP is detected late in this patient population. This is further supported by the presence of metastases in 6 of 9 existing cases 168
(66.7%). Consequently, treatment in this population has largely been centered on the utilization of chemotherapy. Therefore, the ultimate challenge in this cohort is detecting CaP early enough so that radiation or surgical intervention can be utilized. The patient we presented is unique in that her cancer was an incidental finding during pretransplant screening. In addition, our patient did not receive a bilateral orchiectomy and relied solely on estrogen therapy to achieve feminization. This has previously been documented in only 2 of 9 cases (22.2%).13,14 The lack of bilateral orchiectomy may be of minimal consequence in our patient’s likelihood of developing CaP. The transgender patient population provides a unique in vivo opposition to the androgen hypothesis of CaP development. It was originally hypothesized by Huggins and Hodges that “prostatic cancer is influenced by androgenic activity.”15 Additionally, they concluded “disseminated carcinoma of the prostate is inhibited by eliminating androgens or neutralization of their activity by estrogen injection.” This has been a widely accepted idea within urology for the past 70 years. Recently, a large body of literature has called these previously accepted notions into question. This would make the occurrence of CaP in transgender women less surprising. A study by Rhoden et al showed that hypogonadal men with prostatic intraepithelial neoplasia who received testosterone replacement therapy (TRT) for 1 year did not have a significantly elevated PSA level compared with hypogonadal individuals without prostatic intraepithelial neoplasia.19 These findings were further bolstered by a paper by Marks et al that looked at a hypogonadal population undergoing 6 months of TRT.20 They used prostate biopsy at baseline and after treatment to show that TRT normalizes serum androgen level but has little effect on prostate tissue androgen level or cellular function. In subsequent years, a new theory termed “the saturation model” was established.21 This model demonstrated that prostate growth is sensitive to changes in androgen level when the baseline level is low (castrated individuals). However, the prostate appears to lose its sensitivity UROLOGY 110, 2017
to androgens when androgen receptors are saturated. Saturation appears to occur at a testosterone (T) concentration far below physiologic range. This is why changes in prostate growth are observed when T is given to castrated men but not to noncastrated men. The ability for the prostate to lose sensitivity to T after reaching saturation would make the androgen hypothesis of CaP development less likely. The saturation model was further validated by the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial.22 In the placebo arm (no dutasteride), 4073 men with PSA greater than 2.5 or 3.0 (depending on age) and a negative transrectal ultrasound biopsy <6 months prior to the study received transrectal ultrasound-guided biopsies at 2 and 4 years into the study. The primary findings showed that baseline T and dihydrotestosterone (DHT) levels were unrelated to CaP risk. Secondary analysis of men with low T showed that men with the lowest baseline T level had the lowest CaP risk. Patients with increased baseline T level up to a level of 10 nmol/L had an increased CaP risk. T levels over 10 nmol/L conferred no additional CaP risk, therefore implying the presence of androgen receptor (AR) saturation. Additional studies by Morgantaler et al provide evidence against the link between androgen level and CaP development. This group observed that 11 of 77 prostate biopsies in men with low T showed CaP.23 This prompted a follow-up study in 345 men with low T and normal PSA, which showed a cancer rate of 15%.23 As evidenced by several other studies, low T hardly seems to confer a protective effect from CaP and may instead impart a harmful risk for developing CaP. 24 Morgantaler et al further downplayed the role of T in CaP progression by administering T therapy in 13 men during active surveillance of their CaP. There was no progression of any of the patient’s CaP at the 2-year mark.25 Another theory focuses on estrogen’s role in the development of CaP. In all 10 of the reported cases of CaP in transgender women, patients had received extended estrogen therapy as part of their transition.6-14 There has been recent speculation that estrogen could be playing a role in the development of CaP. A study by King et al showed that both prostate stromal cells and a malignant cell line called LNCaP showed increased growth (compared with the control group) with estrogen treatment.16 King et al further examined the ratio of estrogen to DHT (E2:DHT) and showed that in stromal cells an increased E2:DHT had the highest effect on stromal cell growth. The ratio was found to be insignificant in the growth of the malignant cell line. The authors also discuss the ability of estrogen to upregulate AR. The results of this paper are especially interesting when the results are applied to transgender women, a population with elevated E2:DHT levels. Additional studies in rat and human prostates have shown that the combination of estrogen and T may lead to the development of CaP.17,18 Finally, a case report by Sharif et al highlighted the case of CaP in a transgender woman.14 The prostate was analyzed through immunohistochemistry and was found to be UROLOGY 110, 2017
positive for increased levels of ERα, which has been positively implicated in CaP induction. Although more research is necessary, it is possible that estrogen therapy used in transitions could be fueling prostatic changes. As this relatively new cohort of patients ages, it will be paramount to examine the nature of their estrogen therapy and the incidence of CaP development. Future directions for studying CaP in the transgender woman include prospective studies to more accurately determine incidence, analysis of E2:T ratios and its correlation to CaP development, and immunohistochemistry studies to further establish the estrogen receptor and AR status of the transgender prostate received from biopsy or prostatectomy. Furthermore, analysis of CaP in transgender women undergoing voluntary androgen suppression might suggest whether cancer in these individuals is more or less aggressive than cisgendered men. Finally, noncastrated, transgender women with CaP requiring additional hormonal manipulation should be followed to determine the cancer’s response. This may identify whether CaP is phenotypically different from CaP in the cisgendered male. Barriers to Health Care for Transsexual Individuals There is currently a deficit in the standard of care provided for transgender women. A qualitative analysis by Snelgrove et al highlighted barriers to care from the physician point of view.26 After 13 physicians were interviewed, barriers were categorized into the following groups: accessing resources, medical knowledge deficits, ethics of transition-related medical care, diagnosing vs pathologizing (treating aspects of the human condition as a psychiatric illness) transgender patients, and health system determinants. Many practitioners added that knowing who to refer these patients to is confusing and can sometimes result in negative experiences for the patient. There are conflicting opinions regarding how to resolve the lack of medical knowledge. Several participants felt that education regarding transgender patients should be included in the medical school curriculum, whereas others endorsed robust guideline dispersal among the medical community.26 Finally, the study noted that some participants felt gender dysphoria is overemphasized as a subspecialty of psychiatry and that care needs to be transitioned to primary care and associated specialists. An additional review on the barriers to health care for transgender patients by Safer et al highlighted a series of tasks that should be completed to improve overall health and well-being for this population.27 Safer et al argue that a formal study on the medical knowledge of health care providers is necessary. Based on the results of this review, ideas on how to address the knowledge gap can be formulated. In addition to knowledge gap assessment, future study should also examine the nonmedical biases of providers such as attitudes toward transgender patients and the fear of the stigma associated with caring for these individuals. Finally, the authors address that insurance companies have often been cited as a barrier to care. There is, however, little quantitative data regarding the degree to which third-party payer 169
systems impede access to comprehensive care for transgender women. Although ameliorating physician-related barriers to care is important, financial restrictions may be one of the most profound impediments to health care for these individuals.28 Gender reassignment-based care is often regarded as elective and thus rarely covered by insurance in the United States. This often leads to patients with an “intermediate sexed state.” The medical and psychological consequences of this are unclear but warrant future study. There are numerous roles that urologists can play in the alleviation of barriers to care. Firstly, urologists should continue to educate themselves and their colleagues on the following topics: pathogenesis of CaP, current screening recommendations for transgender women, and the psychosocial implications of gender reassignment. A competency in these 3 areas will adequately allow the urologist to provide optimal care. Secondly, just like any medically complex patient, team-based care for the transgender woman is essential to optimize outcomes. Urologists are encouraged to work closely with primary care specialists, endocrinologists, and mental health professionals to fully understand the care of the transgender woman. Finally, transgender women are frequently deterred from office visits by societal stigma and lack of acceptance among office staff. Urologists should serve as leaders in their workplace by encouraging professional behavior and downplaying the associated stigma to build rapport with transgender women. Prostate Cancer Screening One of the challenges to caring for transgender women is keeping both generalists and specialists informed on the standards of care. The World Professional Association or Transgender Health and the Endocrine Society provide an expansive set of guidelines regarding CaP screening protocol.29,30 Because of a lack of data, these institutions recommend individuals be screened with the same standards (as stated by the American Urological Association) as cisgendered men: nontransgender individuals.1 Of note, Gooren and Morgentaler recommend that given a low T environment, the upper limit of normal for PSA should be 1 ng/mL.5 This recommendation was established using evidence that a CaP-positive biopsy despite a low PSA value is more common in the setting of T deficiency, which is commonly seen in the transgender woman. Further studies are needed to determine the incidence and prevalence of CaP in transgender women. A more complete understanding of the epidemiology would allow for robust recommendations regarding screening protocols. Future recommendations may include annual screening with PSA with or without digital rectal examination and maintaining an elevated level of suspicion for PSA values of 1-4 ng/mL. In light of an inadequately defined incidence and prevalence of CaP in transgender women, we recommend that urologists should counsel their patients on the seemingly low but evident risk of CaP development at the time of initial presentation. This will allow the urologist to engage their patient in shared decision making and ini170
tiate screening in those who desire regular screening or are at an increased risk for CaP.
CONCLUSION To the best of our knowledge, this represents the first comprehensive review on CaP in transgender women. More research is necessary to determine whether incomplete sexual reassignment leads to an increased risk of CaP. An additional concern that has been raised is the role of estrogen in the development of CaP. Although the literature is still growing, there has been some suggestion that testosterone does not fuel CaP as once hypothesized. Furthermore, estrogen may play a role in tumorigenesis, which would be of concern in the current population of transgender women. More research and consideration of estrogen’s role in therapy is needed. Finally, to adequately screen this population, barriers to health care such as physician education regarding this population and financial burdens must be overcome. With adequate screening, CaP may be detected at a less aggressive grade, therefore resulting in better outcomes. As this population grows older and increases in number, it will be imperative to monitor the incidence of CaP development in order to alter our standards of care as our society evolves. Acknowledgment. The authors wish to thank James Tomkinson for his valuable contributions to the inception of this project.
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