ABSTRACT

Objective

To identify the available evidence on the risk of developing cancer in transgender people undergoing hormone therapy.

Methods

This was a rapid systematic review conducted in the PubMed, Embase, Virtual Health Library, Cochrane Library and Epistemonikos databases. Screening and data extraction were performed by independent reviewers using the Rayyan platform. Data extraction was carried out by 3 independent reviewers. We used the Joanna Briggs Institute checklists specific to cohort and case-control studies to assess the methodological quality of the included studies.

Results

Five studies were included, 4 cohort studies and 1 case-control. The risk of transgender people developing cancer while on hormone therapy was identified by 2 studies and not identified in 3 studies.

Conclusion

Despite studies with large sample sizes and rigorous selection criteria, the literature does not present a consensus on the association between hormone therapy and the development of cancer in transgender people.

Palabras clave
Personas Transgénero; Neoplasias Malignas; Hormonal; Hormonoterapia; Revisión Sistemática

Study contributions

Main results

Five studies published between 2013 and 2021 were identified. The risk of developing cancer in transgender people undergoing hormone therapy was found in two studies, but there is no clear consensus for recommendations.

Implications for services

It contributes to comprehensive healthcare for transgender people. It supports more informed decision-making in the hormone therapy process and enhances the options available within the healthcare network for this population.

Perspectives

The review highlights the need for more randomized, long-term studies to assess the risks and benefits of hormone therapy in transgender people, in different subgroups, such as age, duration of use and types of hormones.

Palabras clave
Personas Transgénero; Neoplasias Malignas; Hormonal; Hormonoterapia; Revisión Sistemática

RESUMEN

Objetivo

Identificar las evidencias disponibles sobre el riesgo de desarrollar cáncer en personas transgénero que reciben tratamiento con hormonoterapia.

Métodos

Se trata de una revisión sistemática rápida en las bases de datos PubMed, Embase, Biblioteca Virtual en Salud, Cochrane Library y Epistemonikos. La selección y extracción de datos fueron realizadas por revisores independientes en la plataforma Rayyan. La extracción de datos fue llevada a cabo por tres revisores independientes. Utilizamos las listas de verificación del Instituto Joanna Briggs específicas para estudios de cohortes y casos y controles para evaluar la calidad metodológica de los estudios incluidos.

Resultados

Se incluyeron cinco estudios, de los cuales cuatro fueron estudios de cohortes y uno fue un estudio de caso y control. El riesgo de desarrollar cáncer en personas transgénero bajo hormonoterapia fue identificado en dos estudios y no identificado en tres estudios.

Conclusión

A pesar de la existencia de estudios con muestras grandes y criterios de selección rigurosos, la literatura no presenta un consenso sobre la asociación entre la hormonoterapia y el desarrollo de cáncer en individuos transgénero.

Palabras clave
Personas Transgénero; Neoplasias Malignas; Hormonal; Hormonoterapia; Revisión Sistemática

INTRODUCTION

The concept of transgender or gender nonconforming refers to individuals whose gender identity differs from that assigned at birth.¹1 Bradford NJ, Syed M. Transnormativity and transgender identity development: a master narrative approach. PsyArXiv [Internet]. 2018 Dec 1 [cited 2023 Jan 2]; 8(5-6):306-25. Available from: https://psycnet.apa.org/record/2019-00914-001., ²2 Muranksi S. The struggle with transnormativity: non-binary identity work, embodiment desires, and experience with gender dysphoria. Soc Sci Med [Internet]. 2023 May 3[cited 2024 Jan 20]; 327:115953. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0277953623003106?via%3Dihub. This divergence may lead to gender transition, which includes hormone therapy and gender affirming surgeries, aimed to align the body with the individual’s gender identity. Approximately 0.6% of the United States population identifies as transgender.³3 Flores AR, Herman JL, Gates GJ, Brown TNT. How many adults identify as transgender in the United States? [Internet]. Los Angeles: Williams Institute; 2016 Jun [cited 2024 Jan 20]. 26 p. Available from: https://williamsinstitute.law.ucla.edu/wp-content/uploads/Trans-Pop-Update-Jun-2022.pdf.
https://williamsinstitute.law.ucla.edu/w... In Brazil, about 2% of the population is transgender.⁴4 Spizzirri G, Eufrásio R, Lima MCP, Nunes HRC, Kreukels BPC, Steensma TD et al. Proportion of people identified as transgender and non-binary gender in Brazil. Sci Rep [Internet]. 2021 Jan 26 [cited 2024 Feb 22]; 2240. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249838/ doi:10.1038/s41598-021-81411-4.
https://www.ncbi.nlm.nih.gov/pmc/article...

The World Professional Association for Transgender Health emphasizes the need for individualized clinical care for transsexual, transgender, and gender-nonconforming individuals. In line with the association’s guidelines, which stress the importance of personalized care, studies have shown that gender-affirming surgery yields better outcomes when performed by multidisciplinary teams specialized in transgender healthcare.⁵5 Coleman E, Radix AE, Bouman WP, Brown GR, de Vries ALC, Deutsch MB et al. Standards of care for the health of transgender and gender diverse people, version 7. Int J Transgenderism [Internet]. 2021 Aug 27 [cited 2024 Feb 7]; 3:165-232. Available from: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English.pdf. doi:10.1080/15532739.2011.700873.

The National Policy for Comprehensive Health of Lesbians, Gays, Bisexuals, Transvestites and Transsexuals⁶6 Brasil. Ministério da Saúde. Política nacional de saúde integral de lésbicas, gays, bissexuais, travestis e transexuais [Internet]. 1º ed. Brasília, DF: Editora MS; 2013 Oct [cited 2024 Feb 28]. 32 p. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/politica_nacional_saude_lesbicas_gays.pdf.
https://bvsms.saude.gov.br/bvs/publicaco... and the guidelines for the transsexualization process in the Brazilian National Health System⁷7 Brasil. Ministério da Saúde. Gabinete do Ministro. Portaria nº 2.803, de 19 de novembro de 2013. Redefine e amplia o Processo Transexualizador no Sistema Único de Saúde (SUS). Diário Oficial da União, Brasília (DF), 19 nov 2013 [cited 2024 Feb 28]; Seção 1:225. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/gm/2013/prt2803_19_11_2013.html#:~:text=Redefine%20e%20amplia%20o%20Processo,%C3%9Anico%20de%20Sa%C3%BAde%20(SUS).&text=Considerando%20a%20necessidade%20de%20apoiar,Art.
https://bvsms.saude.gov.br/bvs/saudelegi... highlight the fundamental need to guarantee access to outpatient care for transgender individuals undergoing the transsexualization process. This underscores the importance of multidisciplinary work within the Brazilian National Health System.⁶6 Brasil. Ministério da Saúde. Política nacional de saúde integral de lésbicas, gays, bissexuais, travestis e transexuais [Internet]. 1º ed. Brasília, DF: Editora MS; 2013 Oct [cited 2024 Feb 28]. 32 p. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/politica_nacional_saude_lesbicas_gays.pdf.
https://bvsms.saude.gov.br/bvs/publicaco...

7 Brasil. Ministério da Saúde. Gabinete do Ministro. Portaria nº 2.803, de 19 de novembro de 2013. Redefine e amplia o Processo Transexualizador no Sistema Único de Saúde (SUS). Diário Oficial da União, Brasília (DF), 19 nov 2013 [cited 2024 Feb 28]; Seção 1:225. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/gm/2013/prt2803_19_11_2013.html#:~:text=Redefine%20e%20amplia%20o%20Processo,%C3%9Anico%20de%20Sa%C3%BAde%20(SUS).&text=Considerando%20a%20necessidade%20de%20apoiar,Art.
https://bvsms.saude.gov.br/bvs/saudelegi... - ⁸8 Brasil. Ministério da Saúde. Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde. Departamento de Ciência e Tecnologia. Serviço de produção de evidências para apoio à tomada de decisão: portifólio de produtos [Internet]. Brasília (DF): Ministério da Saúde; 2019 Dec [cited 2024 Feb 22]. 34 p. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/servico_producao_apoio_evidencias_tomada_decisao_portifolio_produtos.pdf.
https://bvsms.saude.gov.br/bvs/publicaco...

The number of services and health professionals capable of providing comprehensive health care for transgender people remains insufficient, which demonstrates a gap in healthcare for this population in the country. As of 2022, only 11 services in Brazil were accredited to provide specialized care within the transsexualization process. In 2023, an additional 10 services were accredited.⁹9 Brasil. Ministério da Saúde. Gabinete da Ministra. Portaria nº 404, de 28 de março de 2023. Habilita estabelecimento para realização do componente atenção especializada no processo transexualizador – modalidade ambulatorial. Diário Oficial da União, Brasília (DF), 15 mar. 2023 [cited 2024 Feb 28]; Seção 1:38. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/gm/2013/prt2803_19_11_2013.html#:~:text=Redefine%20e%20amplia%20o%20Processo,%C3%9Anico%20de%20Sa%C3%BAde%20(SUS).&text=Considerando%20a%20necessidade%20de%20apoiar,Art.
https://bvsms.saude.gov.br/bvs/saudelegi...

Hormone therapy enhances secondary sexual characteristics to align with an individual’s gender identity. Transgender individuals may receive steroid hormones, prescribed by healthcare professionals, to reduce psychological distress and induce desired physical changes such as reduced skin oiliness, changes in body fat distribution, and hair growth/loss.¹⁰10 Wiepjes CM, Nota NM, Blok CJM et al. The Amsterdam cohort of gender dysphoria study (1972-2015): trends in prevalence, treatment, and regrets. J Sex Med [Internet]. 2018 Feb 17 [cited 2024 Jan 20];15:582-90. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609518300572. Gender-affirming hormone therapy may be administered in high doses over several decades³3 Flores AR, Herman JL, Gates GJ, Brown TNT. How many adults identify as transgender in the United States? [Internet]. Los Angeles: Williams Institute; 2016 Jun [cited 2024 Jan 20]. 26 p. Available from: https://williamsinstitute.law.ucla.edu/wp-content/uploads/Trans-Pop-Update-Jun-2022.pdf.
https://williamsinstitute.law.ucla.edu/w...

The potential cancer risk associated with hormonal therapy in transgender individuals is a significant concern.¹¹11 Braun H, Nash R, Tangpricha V, Brockman J, Ward K, Goodman M. Cancer in transgender people: evidence and methodological considerations. Epidemiol Ver [Internet]. 2017 Jan 1[cited 2023 Feb 28]; 39(1):93-107. Available from: https://academic.oup.com/epirev/article/39/1/93/3807302?login=false. This potential risk is often used as a justification for contraindicating or discontinuing hormone therapy. The use of hormones, especially estrogen, may influence the development of cancer cells, which increases the risk of certain types of cancer, such as breast cancer. It is important to note that the risk varies according to several factors, including the type of hormone, the dose and the duration of treatment. Other risk factors, such as family history and lifestyle habits, can also contribute to the development of the disease.

The benefits of hormone therapy for the mental health and well-being of transgender people are undeniable. Identifying cancer risks is crucial for guiding, shaping, and informing public health policies and raising awareness of the health issues affecting transgender individuals.

This rapid systematic review aims to identify the available evidence on the risk of developing cancer in transgender people undergoing hormonal therapy.

METHODS

This was a rapid review, following the steps outlined by the Cochrane Rapid Reviews Methods Grou^p1212 Garritty C, Gartlehner G, Kamel C, King VJ, Nussbaumer-Streit B, Stevens A, Hamel C, Affengruber L. Cochrane rapid reviews: interim guidance from the cochrane rapid reviews methods group [Internet]. Cochrane, Alberta: Cochrane; 2020 Mar [cited 2024 Jan 20]. Available from:http://methods.cochrane.org/sites/methods.cochrane.org.rapidreviews/files/uploads/cochrane_rr_-_guidance-23mar2020-v1.pdf.
http://methods.cochrane.org/sites/method... to investigate the risk of developing cancer in transgender people undergoing hormone therapy. The rapid review methodology aims to enhance the efficiency of conducting the review while seeking to minimize the impact on the study’s quality and bias.¹³13 Haby MM, Chapman E, Clark R, Barreto J, Reveiz L, Lavis JN. What are the best methodologies for rapid reviews of the research evidence for evidence-informed decision making in health policy and practice: a rapid review. Health Res Policy Syst [Internet]. 2016 Nov 25 [cited 2024 Jan 23];14(1):83. Available from: https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-016-0155-7. The research question of this review was constructed based on the PECOS framework (population, exposure, comparator, outcomes and type of study) (Box 1). This rapid review was focused on the question: What is the risk of cancer development in transgender individuals using hormone therapies?

Methodological shortcuts included limiting the review to studies published in Portuguese, English, or Spanish, and conducting a quality assessment by one reviewer, later verified by a second. The protocol was registered on the Zenodo.org repository before study selection began.

The literature search was performed in October 2023 across PubMed, Embase, Cochrane Library, the Virtual Health Library (VHL), and Epistemonikos, without date restrictions. The search strategies were based on controlled vocabularies, including Medical Subject Headings (MeSH) from PubMed, Emtree from Embase, and Health Sciences Descriptors (DeCS) from Virtual Health Library (VHL). Uncontrolled terms, such as keywords and synonyms, were also used in developing the strategies (Box 2).

The following inclusion criteria were considered: studies that analyzed the risk of developing cancer in transgender people undergoing hormone therapy, published in Portuguese, English, and Spanish without date restrictions; and study designs included systematic reviews, cohort studies, non-randomized and randomized clinical trials. Cross-sectional studies were not included due to the difficulty in establishing a causal relationship between exposure and outcome. Three reviewers independently screened titles and abstracts according to predefined criteria, aided by the Rayyan reference manager. Data extraction was conducted independently by three blinded reviewers and organized in an Excel spreadsheet under topics such as author, year, study type, intervention description, cancer type reported, target population characteristics, results, and study quality assessment. A narrative synthesis was performed due to methodological heterogeneity and outcome measure variability, which prevented a meta-analysis.

The methodological quality of the included studies was assessed using the Joanna Briggs Institute’s critical appraisal tools. Checklists were used for cohort and case-control studies. Quality assessments were conducted by one reviewer and verified by a second.

RESULTS

A total of 476 publications were identified in the electronic databases. Of these, 380 were screened by title and abstract after duplicate removal, with 359 excluded. A total of 21 publications were accessed for full-text eligibility, and 5 publications were ultimately included in this rapid review.

Figure 1 shows the flowchart of the review with the numbers of studies included and excluded at stage of the review. The full list of studies excluded after full-text reading, along with the reasons for exclusion, can be found in the review protocol (https://doi.org/10.17605/OSF.IO/F7DK8). Of the studies included for this review, 4 were cohort studies;¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319.

18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652.

19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259.- ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. 1 was a case-control study;²¹21 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493. 2 studies were published in 2013;¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319., ²¹21 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493. 1 was published in 2019;¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652. 1, in 2020; ¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259. and 1, in 2021, ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. with sample sizes ranging from 447 to 3,489 individuals (Table 1).

The outcomes analyzed in transgender people undergoing hormone therapy were diverse: 1 study analyzed the prevalence of cancer^;2121 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493. 2 studies analyzed the incidence of cancer;¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319.,¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652. and 2 studies, the rates of epithelial cell abnormalities and histopathological changes¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259.,²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. (Table 2).

Regarding cancer incidence, 2 Dutch cohort studies did not identify a significant increase in new cases of breast cancer in the transgender population.¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319., ¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652. The incidence rate of breast cancer in transgender women was lower than that of cisgender women, but within the expected range for cisgender men. The breast cancer incidence rate in transgender men was lower than expected for cisgender women but within the expected range for cisgender men. Breast cancer incidence in both transgender groups was comparable to that of male breast cancers.

Another study ¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652. identified a higher risk of breast cancer in transgender women compared to cisgender men. It also identified a lower risk in transgender men compared to cisgender women. Most of the tumors identified were of ductal origin with estrogen and progesterone receptors, and 8.3% were attributed to the protein responsible for the mammary cell growth. Another important finding was that breast cancer in transgender individuals was diagnosed at a younger age compared to cisgender women. The absolute risk of breast cancer in transgender people remained low; therefore, breast cancer screening should follow the guidelines for cisgender people. ¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652.

A study from Belgiu^m2121 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493. showed that the cancer rate in transgender individuals was similar to or lower than that of cisgender men and women in the control group – none of the transgender men developed cancer during the follow-up period. The transgender women in this study had undergone hormone therapy for an average of 7.7 years (ranging from 3 months to 35 years); of these, 42.5% had received oral estrogen. The majority of transgender women (65%) had undergone orchiectomy. Transgender men had been on testosterone replacement therapy for an average of 9.4 years (ranging from 3 months to 49 years), and 65% of these individuals had received intramuscular testosterone treatment using a mixture of testosterone esters. Among transgender men, 86% had undergone hysterectomy and/or oophorectomy. ²¹21 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493.

Two U.S. studies¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259., ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. on epithelial cells and histopathological changes also showed no increased risk of cancer in transgender people. One of them analyzed Pap smear results in a group of cisgender women and transgender men. No significant relationship was found between the duration of testosterone therapy and the presence of transitional metaplastic cells or small cells in the Pap smears of transgender patients. The difference in epithelial cell abnormality rates between the two cohorts was not statistically significant. ¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259.

A total of 447 surgical breast specimens from gender-confirming chest contouring surgeries were reviewed and histopathological findings were compared between transgender men and male-centered gender nonconforming individuals who did and did not receive testosterone therapy. Intramuscular testosterone was administered to 85.6% of the sample, followed by 7.9% who used transdermal testosterone gel or cream. The majority of individuals who had undergone hormone therapy for at least 12 months had moderate lobular atrophy (p-value<0.001). Atypical lesions were detected in 2.5% of individuals who had undergone hormone therapy. The study’s results indicated that hormone therapy did not lead to clinically significant changes in breast morphology (i.e., an increased frequency of atypical lesions or carcinoma), even after more than 12 months of use. ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9.

Although the study population was small and young, with findings based on a limited sample, routine breast cancer screening of residual tissue following chest contouring surgery for transgender men and male-centered gender nonconforming individuals was considered important. ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. In addition to cancer, other morbidities such as venous thrombosis and/or pulmonary embolism, acute myocardial infarction, and cerebrovascular disease were tracked. Five percent of transgender women had venous thrombosis and/or pulmonary embolism. Transgender women had more myocardial infarctions than cisgender women in the control group (p-value 0.001), but the proportion was similar to that of men in the control group. The prevalence of cerebrovascular disease was higher in transgender women than in cisgender men in the control group (p-value 0.03). Rates of myocardial infarction and cardiovascular disease in transgender men were similar to those in cisgender individuals in the control group. The prevalence of type 2 diabetes was higher in both transgender men and women when compared to their respective controls.²¹21 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493.

DISCUSSION

This review included five studies and aimed to identify scientific evidence on the risk of cancer in transgender people undergoing hormone therapy. Two of these studies¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319., ¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259. indicated an overall increased risk of neoplasia in this group, while the others¹⁶16 Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Qureshi R, Mattis P, Lisy K, Mu P-F. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z (Editors). JBI Manual for Evidence Synthesis. JBI, 2020. Available from: https://synthesismanual.jbi.global.,¹⁸18 Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ [Internet]. 2019 Jan 1 [cited 2024 Feb 7]; 365:1652. Available from: https://www.bmj.com/content/365/bmj.l1652/ doi:10.1136/bmj.l1652., ²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. did not find this association. The studies included in this rapid systematic review presented robust methodologies with considerable population samples and well-defined inclusion and exclusion criteria. Breast cancer was the neoplasm most likely to develop in transgender individuals using hormone therapy.¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319., ¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259. It is noteworthy that the magnitude of this risk was not thoroughly evaluated in this review. Further research is needed to confirm and quantify this association.

Reliable epidemiological data remains scarce despite advances in studies in this field. Transgender people can develop cancer in organs related to the sex assigned at birth, as well as in newly formed organs.¹⁷17 Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med [Internet]. 2013 Dec 9 [cited 2024 Feb 22];10(12):3129-134. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1743609515302344 doi:10.1111/jsm.12319., ¹⁹19 Williams MPA, Kukkar V, Stemmer MN, Khurana KK. Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy. Cancer Cytopathol [Internet]. 2020 Mar 3 [cited 2024 Feb 20];128(7):491-498. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22259. doi:10.1002/cncy.22259.

The increased cancer risk in transgender people, compared with the cisgender population, is multifactorial. This includes the high prevalence of sexually transmitted infections, increased exposure to risk factors such as smoking and alcohol consumption, and lack of adequate access to cancer screening.¹¹11 Braun H, Nash R, Tangpricha V, Brockman J, Ward K, Goodman M. Cancer in transgender people: evidence and methodological considerations. Epidemiol Ver [Internet]. 2017 Jan 1[cited 2023 Feb 28]; 39(1):93-107. Available from: https://academic.oup.com/epirev/article/39/1/93/3807302?login=false. Several publications have identified cancer as a priority in studies on transgender people health and have recognized the importance of large-scale population-based studies.¹¹11 Braun H, Nash R, Tangpricha V, Brockman J, Ward K, Goodman M. Cancer in transgender people: evidence and methodological considerations. Epidemiol Ver [Internet]. 2017 Jan 1[cited 2023 Feb 28]; 39(1):93-107. Available from: https://academic.oup.com/epirev/article/39/1/93/3807302?login=false., ²¹21 Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol [Internet]. 2013 Sep 13 [cited 2024 Feb 23];169(4):471-8. Available from: https://academic.oup.com/ejendo/article-abstract/169/4/471/6661677?redirectedFrom=fulltext doi:10.1530/EJE-13-0493.

Estrogen and testosterone therapy in transgender people must be continuously monitored due to the relative risk of other morbidities, such as the development of cardiovascular diseases.²⁰20 Baker GM, Guzman-Arocho YD, Bret-Mounet VC, Torous VF, Schnitt, SJ, Tobias AM et al. Testosterone therapy and breast histopathological features in transgender individuals. Mod Pathol [Internet]. 2021 Sep 20 [cited 2023 Feb 28]; 34:85-94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825198/ doi:10.1038/s41379-020-00675-9. Doses and methods of administration may also vary during hormone replacement, which reinforces the need for close monitoring by healthcare teams for transgender people on hormone therapy.²²22 Iwamoto SJ, Grimstad F, Irwig MS, Rothman MS. Routine screening for transgender and gender diverse adults taking gender-affirming hormone therapy: a narrative review. J Gen Intern Med [Internet]. 2021 Feb 5 [cited 2024 Feb 7];36:1380-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131455/. doi:10.1007/s11606-021-06634-7.

Transgender people may present a distinct risk of developing chronic conditions and health conditions, as well as risk factors for these diseases and health conditions.²²22 Iwamoto SJ, Grimstad F, Irwig MS, Rothman MS. Routine screening for transgender and gender diverse adults taking gender-affirming hormone therapy: a narrative review. J Gen Intern Med [Internet]. 2021 Feb 5 [cited 2024 Feb 7];36:1380-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131455/. doi:10.1007/s11606-021-06634-7.Specific recommendations for transgender people regarding cancer and other comorbidities are necessary for better comprehensive health care. However, there are uncertainties about cancer screening protocols for transgender people.²²22 Iwamoto SJ, Grimstad F, Irwig MS, Rothman MS. Routine screening for transgender and gender diverse adults taking gender-affirming hormone therapy: a narrative review. J Gen Intern Med [Internet]. 2021 Feb 5 [cited 2024 Feb 7];36:1380-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131455/. doi:10.1007/s11606-021-06634-7.

The transsexualization process within the Brazilian National Health System is constantly marked by the lack of network coordination. Consequently, transgender people are often responsible for navigating their own therapeutic pathway, which frequently leads to seeking care in alternative spaces. These factors result in the abusive use of hormones, a lack of assistance from health professionals and treatment abandonment.

This situation worsens the health conditions of transgender people and contributes to the normalization of care neglect and the perpetuation of inequities. ²³23 Oliveira PRL, Galvão JR, Rocha KS, Santos AM. Itinerário terapêutico de pessoas transgênero: assistência despersonalizada e produtora de iniquidades. Physis [Internet]. 2022 Jul 6 [cited 2024 Jan 20];32(6):1-21. Available from: https://www.scielo.br/j/physis/a/NGWFCJ3STWFmJpnVRKLqp5J/ doi:10.1590/S0103-73312022320209.

One of the limitations of this rapid review was the unavailability of two systematic reviews due to lack of access to full texts and the exclusion of cross-sectional studies. Rapid reviews are conducted using some shortcuts to shorten the execution time and, therefore, no contact was made with the authors to request the full text and analyze bias. The exclusion of cross-sectional studies is justified by the difficulty in establishing causal relationships in this type of design.

The absence of a meta-analysis prevents a more accurate and robust analysis of data, which limits the ability to generate accurate estimates of the effects of hormone therapy on neoplasms. Although the studies included in this review were not set in the Brazilian context, the findings of this review may support the development of public policies regarding the follow-up of transgender people undergoing hormone therapy.

Few studies were included, and neither a systematic review nor a randomized clinical trial, which are considered the highest levels of scientific evidence, were included. The evidence retrieved showed that certain types of studies, such as randomized clinical trials, are still lacking to better answer the research question.

The main objective of this review was to investigate the risk of developing cancer in transgender individuals undergoing hormone therapy. Although the results of the included studies were heterogeneous, making it difficult to establish a definitive conclusion on the increased risk, the need for further research in this area is evident, especially in the Brazilian context. Given the specificities of the Brazilian transgender population and the existing knowledge gaps, future studies should deepen the investigation of risk factors, the most prevalent types of cancer, and the best practices for monitoring the health of this population. A potential association with an increased incidence of cancer should not be used at this time as a contraindication for hormone therapy, but should support the development of recommendations for the follow-up of the transgender population undergoing hormone therapy. This aims at population screening and early diagnosis of cancer.

ACKNOWLEDGMENTS

The authors express their gratitude to Patrícia de Campos Couto, Camille Cristine Gomes Togo, Izabela Fulone, and Keitty Regina Cordeiro de Andrade from the Coordenação-Geral de Evidências em Saúde, Secretaria de Ciência, Tecnologia e Inovação e do Complexo Econômico-Industrial da Saúde do Ministério da Saúde for their valuable review and contributions.

REFERENCES

Publication Dates

History