Context.—

Transgender men and transmasculine persons experience a discordance between the female sex they were assigned at birth and their gender. They may choose to take hormone therapy and/or undergo surgery to masculinize the body. Understanding the common (and less common) histologic changes present in patients taking masculinizing hormones will empower pathologists to better serve this unique patient population.

Objective.—

To summarize histologic findings in surgical pathology specimens from persons taking masculinizing hormones as a part of gender transition.

Data Sources.—

A systematic review of the OVID Medline and PubMed databases was performed to identify all studies describing histologic findings in surgical pathology specimens from transgender men from January 1946 to January 2021.

Conclusions.—

Publication in this area has markedly increased in the last 2 decades. However, most of the studies identified were descriptive and case reports describing changes seen in specimens removed as a part of masculinizing surgical procedures. Benign histologic findings include stromal hyalinization and epithelial atrophy in the breast, polycystic ovarian syndrome–like changes in the ovary, and transitional cell metaplasia in the cervix. The most commonly reported neoplastic finding was adenocarcinoma of the breast, with rare cases of ovarian, endometrial, cervical, vaginal, pituitary, pancreatic, and cardiovascular neoplasia also reported. Ongoing research in this area is needed to better characterize the histologic findings in persons taking masculinizing hormones to provide a deeper understanding of the effect of these treatments on different tissues and facilitate better patient management.

Transgender men and transmasculine persons experience incongruence between their gender identity and their sex assigned at birth. Medical gender transition encompasses both hormonal and/or surgical treatments designed to masculinize. Hormone regimens typically consist of testosterone (transdermal, subcutaneous, or intramuscular) to facilitate body hair growth, muscle development, and body fat redistribution.1  Common masculinizing surgical procedures include breast/chest surgery (bilateral mastectomies, chest contouring), genital surgery (hysterectomy and bilateral salpingo-oophorectomy, metoidioplasty, phalloplasty), and nongenital/nonbreast surgical interventions (liposuction, lipofilling, and other plastic surgery procedures).1  Individuals may choose to undergo hormonal or surgical treatment, both, or neither process as a part of their gender transition.

Individuals using masculinizing hormones as a component of gender transition represent a unique population. Over the last several decades, there has been increasing understanding in the medical community of the necessity for specialized approaches to managing transgender and gender nonconforming patients. Within the pathology community, knowledge gaps remain regarding gender transition, changes associated with hormone therapy, and the appropriate language to use when discussing and reporting findings related to gender transition. Recently, Ahmad et al2  outlined transition affirming terminology to be used in anatomic pathology reports for specimens from transgender men. They highlighted the importance of using nongendered terms and of explicitly stating which anatomic sites are included in hysterectomy specimens as this is important for future cancer screening.2  Use of appropriate terminology is a necessary component of improving care for transgender men and transmasculine patients, but for the pathologist, an understanding of how specimens from transgender patients may differ histologically or pathologically from their cisgender counterparts is also vitally important.

To our knowledge, no comprehensive review of the literature describing the histologic changes and neoplastic findings in surgical pathology specimens from individuals taking masculinizing hormone therapy has been published to date. The objective of this review was to summarize the literature describing histologic changes and types of neoplasia identified in individuals taking masculinizing hormone therapy. A scoping review was chosen because this body of literature has not yet been comprehensively reviewed. Furthermore, heterology of study types and focus of study in the literature would be difficult to assess in a more precise systematic review. This review will provide both a reference for practicing pathologists and highlight gaps in the literature and targets for future research.

This review was conducted based on the guidelines of the Joanna Briggs Institute on conducting systematic scoping reviews.3  This review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses reporting guideline for systematic reviews. The review protocol was registered with the Open Science Framework on March 29, 2020 and can be found at https://osf.io/f7zyt (accessed May 5, 2021).

Literature Search

A search strategy was developed in consultation with a medical reference librarian. An electronic search was conducted in January 2021 and covered the PubMed and MEDLINE databases. The search strategy included both controlled vocabulary (National Library of Medicine's Medical Subject Headings) and keywords (transgender, transsexual, histology, anatomical pathology, surgical pathology). The search encompassed articles published from January 1, 1946 to January 20, 2021 (See Supplemental Digital Content for the full search strategy at https://meridian.allenpress.com/aplm in the June 2022 table of contents). The search strategy was designed to identify all studies which included descriptions of histopathologic findings from surgical specimens collected from transgender individuals. No filters were applied to limit the retrieval by study design or language.

We conducted an additional search to identify studies that may not have been captured in the PubMed and MEDLINE searches. For this search, we used SCOPUS to identify all studies referenced by studies identified in the initial electronic search (ie, backward search).

Study Selection

References were stored and reviewed using Covidence software for systematic reviews (Covidence, Melbourne, Australia). Title and abstracts were screened, and the full-text review of the potentially relevant articles was performed independently by 2 authors (A.A. and A.K.). Discrepancies in classification of individual studies between the 2 authors were resolved by discussion. Papers were included if (1) the study population was transgender individual/persons on masculinizing hormone therapy, (2) the study protocol included performing a biopsy procedure or resection of tissue, and (3) the study objective was specific/relevant to the workup of pathology specimens for transgender individuals. Papers were excluded if they did not include analysis of pathology specimens. At the level of the full-text review, papers that did not specifically discuss individuals on masculinizing hormone therapy were excluded. Papers were also excluded if the analysis of the specimens from transgender persons was pooled with other populations. Additional duplicate studies not removed by the Covidence software were also excluded. Interrater reliability was calculated using Cohen κ score as implemented by the Covidence software.

Data Extraction

Data extraction was performed by a single author using a pilot-tested collection form (A.A., A.K., or B.S.). We collected the following items: author, date of publication, country of study, organ system, aim or scope, number and characteristics of study participants (including age, gender, history of hormone treatment, indication for procedure), methods (including imaging modalities used, type of biopsy procedure or excision performed, staining techniques used, other ancillary tests performed), main results or findings, and implications for practice or research.

Literature Search

The database searches identified 3035 references including 341 duplicates. Three additional studies were identified through manual screening and peer suggestion. There were 2697 unique references after duplicates were removed (Figure 1). Two thousand four hundred and twenty-seven references were excluded in the title and abstract screen. Full-text review was performed on 270 articles. Of these, 190 were excluded (reasons for exclusion are provided in Figure 1). Eighty studies were included in the review (See Table 1).

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta Analyses diagram.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta Analyses diagram.

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Table 1

Characteristics of Included Studies

Characteristics of Included Studies
Characteristics of Included Studies

The Cohen κ score for the inclusion/exclusion of studies by the 2 authors involved in the screening process was 0.63 for the title and abstract screening and 0.74 for the full-text screening. There were 177 discrepancies out of 2697 (6.5%) titles and abstracts screened and 30 discrepancies of 270 (11.1%) full-text articles screened. These discrepancies were all resolved through discussion between the authors.

Characteristics of Included Studies

Basic characteristics of the 80 included studies are summarized in Table 2. The number of studies addressing surgical pathology specimens from patients taking masculinizing hormones for gender affirmation has increased over time with the largest increases since 2010 as follows: 1970 to 1979 (n = 4), 1980 to 1989 (n = 8), 1990 to 1999 (n = 8), 2000 to 2009 (n = 11), 2010 to 2019 (n = 38), and 2020 to 2021 (n = 11). Most of the published literature (n = 56) is in the form of descriptive studies, including case reports and case series. There are more studies addressing nonneoplastic than neoplastic findings (n = 52 versus n = 33). The most prevalent specimen types described in the identified studies are gynecologic excisions (n = 39) and breast tissue (n = 33). Reports of histologic changes or neoplasms in the cardiovascular system (n = 2), endocrine system (n = 1), gastrointestinal system (n = 7), and musculoskeletal system (n = 2) were also identified. The hormone regimens used by patients in the included studies have been collated in Table 3.

Table 2

Summary of Included Studies

Summary of Included Studies
Summary of Included Studies
Table 3

Summary of Hormone Regimes of Patients in Included Studies

Summary of Hormone Regimes of Patients in Included Studies
Summary of Hormone Regimes of Patients in Included Studies

The following sections will summarize the key findings and entities that have been described. The key benign findings are summarized in Table 4. The following discussion elaborates on the pathologic features seen in most of the common specimens to provide pathologists with an inventory of findings to be accounted for in their pathology reports.

Table 4

Key Benign Findings in Specimens From Persons on Masculinizing Hormone Therapy

Key Benign Findings in Specimens From Persons on Masculinizing Hormone Therapy
Key Benign Findings in Specimens From Persons on Masculinizing Hormone Therapy

Breast

Nonneoplastic Findings in the Breasts of Persons Taking Masculinizing Hormones

Sixteen studies describing the nonneoplastic findings in the breasts of persons taking masculinizing hormones were identified, including 6 case reports, 2 case series, 3 other descriptive studies, and 5 comparative studies.

Relatively few studies (4 of 16) described the gross features of benign breast tissue. Descriptions ranged from typical findings of nodular areas of adipose tissue intermixed with soft fibrous tissue,4  to firm, white hard tissue,5  with 1 report describing 2 patients with firm masses measuring up to 10 cm.6  Van Renterghem et al7  described the gross features of resected breast tissue from 344 transgender men; 3.2% showed less than 25% fibrous tissue, 5.5% had 25% to 49%, 16.0% had 50% to 75%, and 75.3% had more than 75% fibrous tissue.

Two studies described histologically unremarkable lobular units.8,9  The most commonly described histologic finding was an increase in fibrosis with a reduced number of variably atrophic acini with some resemblance to postmenopausal untreated breast or the fibrotic stage of gynecomastia.4,5,1016  Fibrosis and atrophy are often associated with masculinizing therapy but neither of these features showed a strong correlation with the duration of therapy. There are conflicting findings as to the frequency of these changes and whether they are more frequent in the breasts of individuals receiving masculinizing hormones. East et al17  found a frequency of 32.4% (22 of 68 cases) for what they describe as gynecomastoid change (atrophic duct epithelium and periductal hyalinization and fibrosis), citing a historic frequency of less than 1% in untreated patients. Torous and Schnitt16  found some degree of lobular atrophy in 73% (108 of 148) of cases, but prominent atrophy in only 42% (62 of 148), as well as predominantly fibrotic stroma in 45% (67 of 148) of cases and areas resembling the fibrous stage of gynecomastia in 41% (60 of 148). Baker et al15  note that all individuals who received 12 to 24 months of exogenous hormones showed predominantly fibrous stroma in their study of 367 transgender men.

Fibrocystic changes have also been observed with no difference in frequency identified between treated and untreated individuals in some studies.7,18  Baker et al15  described statistically significant reductions in frequency of cysts (P < .001), fibroadenomas (P = .03), pseudoangiomatous stromal hyperplasia (P < .001), columnar cell change (P < .01), papillomas (P = .02), and mild inflammation (P = .02) in individuals taking gender affirming testosterone. In another study comparing the breast tissue of untreated cisgender women with that of transgender men on testosterone therapy, the only histologic finding that was statistically different between the 2 groups was the presence of microcalcifications in 28% (8 of 29) of transgender men versus 0% of cisgender women (n = 10).19 

Neoplastic Findings in the Breasts of Persons Taking Masculinizing Hormones

Case reports are the primary source of evidence for neoplasia in persons receiving masculinizing hormones; 10 case reports, 3 case series, 2 other descriptive studies, 3 comparative studies, and 2 cohort studies were identified. Of 22 reported cases of breast carcinoma, 15 were confirmed as invasive carcinoma of no special type (including cases diagnosed as “ductal adenocarcinoma”),2029  2 cases were tubular carcinoma,30,31  1 case was a neuroendocrine carcinoma,54  and there were 4 cases in which the histologic type was not specified.15,24,30,33  Two cohort studies performed in the Netherlands found a lower incidence of breast adenocarcinoma in transgender men receiving testosterone than in untreated cisgender women.44,67 

Several studies have shown no observed increase in epithelial hyperplasia or malignancy in transgender men treated with hormones when compared with untreated transgender men or cisgender women.7,18,19,34  Baker et al15  found that 7 of 446 individuals in their study population had atypical ductal hyperplasia, as well as 2 of 446 with atypical lobular hyperplasia, 1 individual with ductal carcinoma in situ, and no cases of lobular carcinoma in situ. Eismann et al33  also described the same case of isolated high-grade ductal carcinoma in situ separately.15  Torous and Schnitt16  identified 5 cases of atypical hyperplasia in their cohort of 148 transgender men (3%; atypical ductal hyperplasia in 2; atypical lobular hyperplasia in 2; both in 1) and 1 case of high-grade ductal carcinoma in situ. In their 2021 study, Jacoby et al35  described 8.8% of their cases (17 of 169) containing high-risk lesions (5 complex fibroadenomas [2.6%]; 4 with atypical ductal hyperplasia [2.1%]; 3 with sclerosing adenosis [1.6%]; 3 intraductal papillomas [1.6%]; 1 with atypical lobular hyperplasia [0.5%]; 1 with lobular carcinoma in situ [0.5%]). In a recent comparative study, Hernandez et al34  showed significantly lower rates of neoplastic findings (atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ) in transmasculine individuals (n = 211 of whom 142 were taking hormone therapy) as compared with hormone-naive cisgender women (n = 273), with rates of 2.8% and 7%, respectively (P = .04).

Pivo et al36  describe a case of a transgender man with a significant family history of breast cancer who underwent prophylactic mastectomies, a more extensive surgery than would be typical for gender affirming surgery. In this case, the patient had no atypical or malignant findings.36 

Ovary

Nonneoplastic Findings in the Ovaries of Persons Taking Masculinizing Hormones

There were 18 studies that described histologic changes in the ovary (3 case reports, 4 case series, 4 other descriptive studies, and 7 comparative studies). Ovaries from persons taking masculinizing hormones most frequently showed multicystic architecture with associated thickening of the tunica albuginea, stromal hyperplasia, and foci of luteinized cells.12,3744  One comparative study noted cystic architecture without increased fibrosis.45  Variable reports of cortical follicle distribution exist, from near normal with mostly primordial follicles44,4649  to increased atretic follicles.39,40  Divila et al50  reported surface epithelial hyperplasia in 3 of 12 patients and no increase in follicular atresia. Grimstad et al51  found no association between the duration of testosterone administration and the presence of cysts in the ovaries. In their studied group, 49.4% (42 of 85) of specimens showed follicular/simple cysts, 5.9% (5 of 85) were polycystic, and 38.8% (33 of 85) had no cysts.51  Corpora lutei have also been seen, indicating that ovulation has occurred in some ovaries.37,52  One study reported recent corpora lutei in 8 of 28 of the examined ovaries.52  Another study reported a single case with postovulatory changes including a hemorrhagic corpus luteum cyst.53 

Neoplastic Findings in the Ovaries of Persons Taking Masculinizing Hormones

Three case reports and 1 descriptive study describing 5 cases of ovarian neoplasms in persons taking masculinizing hormones were identified. Hage et al54  reported 2 cases, a papillary serous cystadenocarcinoma in a 45-year-old transgender man and a serous papillary borderline tumor in a 37-year-old transgender man. The second case report described a case of an androgen receptor–positive, well differentiated cystic endometrioid adenocarcinoma arising in the ovary and ipsilateral fallopian tube in a 46-year-old transgender man.55  Divila et al50  identified a 5-mm incidental Brenner tumor in their descriptive study. Millington et al56  report a case of a serous papillary borderline tumor (atypical proliferative serous tumor), grade IA by the International Federation of Gynecology and Obstetrics system, with associated negative omental biopsy specimens.

Fallopian Tubes

Three case series and 3 comparative studies assessed fallopian tubes for benign changes. Divila et al50  noted a paucity of secretory cells in the fallopian tubes of the 12 transgender men on masculinizing hormones they examined. In 1 comparative study, Dulohery et al57  described that the ampullae showed enlarged, irregularly shaped secretory cells with large, round nuclei and large accumulations of viscous mucus containing cellular debris in the lumen with an associated shift from secretory cell predominance to ciliated cell dominance 33.3% to 54.1% (±0.9) to 55.1% to 36.8% (±0.9). They also noted a decrease in protruding cells, but no change in peg cells, basal cells, or intraepithelial lymphocytes in the ampulla.57  In the isthmus, Dulohery et al57  found epithelial breakdown and partial to complete luminal closure and that glycogen production was decreased when compared with controls in all phases of the menstrual cycle. Patek et al58  noted a decrease in ciliated cells in the distal part of the tube by electron microscopy, but no changes were noted on light microscopy. The other 2 studies describing fallopian tubes did not identify any significant changes in persons treated with masculinizing hormones.45,52  Singh et al59  described a case showing a periadnexal epididymis-like structure. A similar Wolffian duct derivative was also described by Divila et al.50  As mentioned above, 1 case of endometroid adenocarcinoma with origin from the fallopian tube and ovary has also been reported.55 

Endometrium

Nonneoplastic Findings in the Endometrium of Persons Taking Masculinizing Hormones

Nine descriptive studies and 5 comparative studies describing benign changes in the endometrium of persons taking masculinizing hormones were identified. The most common histologic finding was either proliferative endometrium (42%–64.9% in individual studies) or inactive/atrophic (8%–36.8% in individual studies).* One study described expanded stromal areas with decidua-like changes in 16 of 27 cases.38  Patek et al58  noted atypical proliferative endometrium in the uteruses of their transgender male patients with poorly developed mucosa and dense stroma and glands with numerous mitoses present. Grimstad et al61  measured the endometrial thickness in 82 cases and found a mean thickness of 2.0 ± 1.3 mm (95% CI, 1.7–2.3). The range of endometrial thickness was as follows: 35 subjects (42.7%) measuring 1 mm, 27 (32.9%) measuring 2 mm, 10 (12.2%) measuring 3 mm, 8 (9.8%) measuring 4 mm, and 2 (2.4%) measuring 7 mm; endometrial thickness did not correlate with duration of therapy.61  Grimstad et al61  also reported endometrial polyps or fibroids in 9 subjects (9.6%), adenomyosis in 7 (7.4%), complex hyperplasia without atypia in 1 (1.1%), and other benign pathology in 4 (4.3%). Another study found endometrial polyps present in 18% (5 of 27) of transgender men, noting that the polyps showed more proliferative features than adjacent endometrium and that polyps were found in persons with a higher body mass index.63  Divila et al50  observed endometrial hyperplasia in 4 of 12 uteruses in their series. One study noted no statistically significant difference (P = .09) in frequency of abnormal intrauterine bleeding as the indication for hysterectomy between cisgender women (537 of 850) and transgender men (16 of 33).64 

Neoplastic Findings in the Endometrium of Persons Taking Masculinizing Hormones

Three cases of endometrial adenocarcinoma were identified as follows: 2 reported as part of a descriptive study and 1 as a case report. The first was a transgender man with atypical endometrial hyperplasia and a small focus of adenocarcinoma.12  The second reported case was a Federation of Gynecology and Obstetrics grade II endometrioid endometrial adenocarcinoma, which had positive lymph nodes and parametrial involvement.65  The third case was reported as an adenomatous lesion fulfilling Hertig's criteria for “carcinoma in situ” in the 1986 study from Divila et al50  of the effect of exogenous testosterone on various tissues.

Myometrium

Three case series and 3 comparative studies discussing the effects of masculinizing hormones on the myometrium were identified. No cases of malignancy in the myometrium were identified. As with other organs, there is some variability in the reports of histologic findings in the myometrium. Some studies found no histologic difference between the myometrium of transgender men on testosterone and untreated cisgender women.8,12,52  However, Miller et al45  describe myometrium with increased mast cells and in a third of patients increased eosinophils as well. Of note, 1 study found that 85% (28 of 33) transgender men presented clinically with pain of presumed gynecologic origin compared with 22% (186 of 850) of cisgender controls (P = .001) and were less likely to have a histologic diagnosis, such as adenomyosis (7.1% versus 38.2%) or leiomyoma (17.9% versus 77.4%), to explain their pain.64  Grynberg et al12  found similar frequencies of adenomyosis (4.5%) and leiomyomata in (16.9%) in their population of 112 transgender men who underwent hysterectomy.

Cervix

Nonneoplastic Findings in the Cervixes of Persons Taking Masculinizing Hormones

Six descriptive studies and 4 comparative studies describing benign changes in the cervixes of persons taking masculinizing hormones for the purpose of gender transition were identified. The changes observed in the cervix were minimal in most cases, with 4 of 6 reporting atrophy.12,45,52  Singh et al59  describe 2 cases of transgender men who had undergone hysterectomy with prostate-like glands in cervical squamous epithelium, which they attribute to virilization of mesonephric duct remnants. Two other studies also described prostate-like glands located in the basal aspect of vaginal and exocervical epithelium at the junction with the lamina propria, which has been termed prostatic metaplasia.62,66  In 1 of these studies, hypertrophy within the metaplastic prostatic glands was also present.62  One case report describes a case of a patient testing positive for high-risk human papillomavirus but with no histopathologic changes on a biopsy specimen.67 

Six studies describe transitional cell metaplasia in 5 of 6, 13 of 28, 17 of 27, 7 of 7, 6 of 6, and 1 of 1 cases, which may be confused for a squamous intraepithelial lesion.38,52,62,66,68,69  However, immunohistochemical staining for p16 in cervixes with transitional cell metaplasia shows negative staining, which helps to differentiate it from the latter.38  One study also described collections of small cells at the surface of both atrophic cervical epithelium and epithelium with transitional metaplasia, which was seen on Papanicolau smears as well as histologic sections in 5 of 6 individuals.69 

Neoplastic Findings in the Cervixes of Persons Taking Masculinizing Hormones

Six cases of cervical neoplasia in transgender men taking androgens were identified. Adkins et al67  reported a case of low-grade squamous intraepithelial lesion and a case of high-grade squamous intraepithelial lesion, each of which was associated with human papillomavirus infection and initially identified by Papanicolaou smear and confirmed on a biopsy specimen. One case of carcinoma in situ was diagnosed by a biopsy specimen and confirmed in the subsequent hysterectomy specimen.45  A second case of carcinoma in situ was diagnosed at hysterectomy for gender affirmation after a recent unremarkable pelvic examination with no visible transformation zone and normal Papanicolaou smear.8  Urban et al65  described a case of “adenoma malignum” (minimal deviation adenocarcinoma); the patient had a negative Papanicolaou smear 2 years previously. Beswick et al70  describe a case of locally advanced squamous carcinoma of the cervix with invasion of the bladder presenting after 2 years of abnormal vaginal bleeding in a patient who had been advised that he did not need cervical screening.

Vagina and Vulva

Nonneoplastic Findings in the Vagina of Persons Taking Masculinizing Hormones

Two studies by Baldassarre et al71,72  on the same patient group describing changes in the vaginal epithelium of persons taking long-term androgen for gender transition were identified. Vaginal epithelium from hysterectomy specimens from 16 transgender men were compared with those of 16 postmenopausal cis women and 16 premenopausal cis women.71,72  Epithelium was thinned, contained more layers of parabasal cells and less glycogen, had decreased Ki67 expression, and reduced estrogen receptor expression compared with the premenopausal or postmenopausal patients not taking testosterone.72 

Findings in the Corpus Spongiosum of Persons Taking Masculinizing Hormones

One comparative study was identified that described histologic changes to the corpus spongiosum in patients taking testosterone for gender affirmation.73  The transgender men presented with tethering of the clitoris after receiving exogenous androgens.73  Surgical intervention to relieve this tethering revealed chordae extending from the vestibular bulbs to the glans clitoris.73  Microscopically, the resected tissue showed irregularly shaped lacunae lined by endothelium and blood vessels with a longitudinal layer of smooth muscle surrounding them in an elastin-rich connective tissue stroma.73  These findings were interpreted as hypertrophied corpus spongiosum.73 

Neoplastic Findings in the Vagina and Vulva of Persons Taking Masculinizing Hormones

Two cases of neoplasia in the lower gynecologic tract were identified. One case was a vaginal squamous cell carcinoma in a 60-year-old transgender man who had undergone a hysterectomy and continued on testosterone therapy.74  The tumor was human papillomavirus DNA positive (genotype 16) by polymerase chain reaction.74  The second case was in a 41-year-old transgender man, with a history of well-controlled HIV and both cervical and rectal cancers, who presented with a suspicious labial lesion.35  Microscopic examination revealed a high-grade vulvar intraepithelial neoplasia associated with high-risk human papillomavirus.35 

Endocrine System

Pituitary Neoplasms in Persons Taking Masculinizing Hormones

One case report of a pituitary adenoma was identified.75  The patient was a 46-year-old transgender man who presented with sudden onset of severe headache, nausea, vomiting, and blurred vision.75  He had developed unexpectedly coarse facial features during the course of his hormonal therapy. Insulin-like growth factor type 1 was increased (311 ng/mL, reference level 75–220 ng/mL) and a biopsy specimen confirmed a pituitary adenoma with apoplexy.75  The timing of symptoms suggested the lesion was likely present before androgen therapy began and that the acromegalic features were initially assumed to be a part of the masculinization process.75 

Gastrointestinal System

Findings in the Livers of Persons Taking Masculinizing Hormones

Two studies from the late 1970s describing liver changes observed in persons taking oral methyltestosterone for the purpose of gender transition were identified. Paradinas et al76  describe livers of transgender men showing patchy thickening of liver cords, with accumulation of hepatocytes within the walls of hepatic veins, sinusoidal dilatation, and abundant cytoplasmic glycogen within the hepatocytes. Microcyst formation was seen in 3 of 11 cases.76  Severity of changes correlated with duration of treatment and these findings were also present in cisgender men taking androgens to treat impotence.76  The findings described by Paradinas et al76  are similar but less severe than those seen in peliosis hepatis, which is a rare hemorrhagic liver disorder classically showing larger blood-filled spaces and hemorrhage, associated with numerous etiologies including anabolic steroid use. A case of fulminant peliosis hepatis was described in a transgender man by Bird et al.77 

In addition, 3 cases of hepatocellular neoplasia have been reported in persons taking masculinizing hormones. The case reported by Bird et al77  had a concurrent hepatic adenoma. Paradinas et al76  also report 1 patient with a hepatic adenoma. This case was also reported separately by Westaby et al78  who described a 27-year-old transgender man who presented with a painful hypochondrial mass and mildly elevated liver enzymes. Microscopic examination of the resected 12 × 10 × 5.4-cm mass revealed hepatocyte cords and sinusoids arranged irregularly around blood vessels without portal tracts, and it was diagnosed as hepatic adenoma. Last, a case of hepatocellular carcinoma with clear cell changes was reported in a 17-year-old with a 14-month history of testosterone use for gender affirmation.79 

Findings in the Pancreas of Persons Taking Masculinizing Hormones

One case report of a mucinous cystic neoplasm of the pancreas in a transgender man taking androgens for gender affirmation was identified.80  The resection specimen showed completely excised mucinous cystic neoplasm with typical ovarian type stroma.80 

Findings in the Perianal Region of Persons Taking Masculinizing Hormones

Two cases of pathology in the perianal region were identified. Katz et al81  reported a case that was initially diagnosed clinically as condyloma accuminata, but in which the biopsy specimen showed fibroepithelial polyps with granulomatous inflammation, in a 21-year-old transgender man with a history of Crohn disease. Jacoby et al35  reported a case of high-grade perianal squamous intraepithelial neoplasia in the same 41-year-old transgender man with HIV and high-grade vulvar intraepithelial neoplasia described above.

Cardiovascular System

One case of an intramyocardial lipoma in a 21-year-old transgender man taking testosterone was identified.81  The mass occupied almost the entire free wall of the right atrium measuring 4 × 4 cm.82 

A second case report described a sudden death in 32-year-old transgender man52  who initially presented with chest pain (diagnosed as gastroesophageal reflux disease) and subsequent collapse 2 days later.52  At autopsy, the heart weighed 309 g and showed concentric myocardial hypertrophy of the left ventricle with greater than 90% stenosis of the left anterior descending artery and stenosis of approximately 50% in other coronary arteries.52  The microscopic examination showed coagulative necrosis and contraction band necrosis of both ventricles, without inflammatory response as well as myocardial fibrosis in the wall of the left ventricle and calcification of the septum and left ventricle, including the conduction system.52 

Musculoskeletal System

Two cases of nonneoplastic changes in the musculoskeletal system were identified. One case of biceps tendon rupture in a 42-year-old transgender man on testosterone was identified with nonspecific histiocytic inflammation, focal calcification, and degenerating wavy appearing collagen seen on the biopsy specimen.83  Vague et al84  describe histologic changes in the deltoid and trochanteric adipose of a transgender man on hormone therapy for 45 months. The biopsy specimen showed a decrease of trochanter and deltoid adipocyte number.84 

The study of transgender medicine and the effects of medical interventions on transgender men and transmasculine persons is a broad and expanding area of research. Within the pathology community there is great potential to add vital data to this blossoming field and support best practices in caring for individuals taking masculinizing hormones for the purpose of gender transition.

Several interesting findings are noted from our review, including solidification of the previously reported similarity between the ovaries of transgender men on testosterone and cisgender women with polycystic ovarian syndrome. Of note, some studies highlighted differences between the histologic features of the ovaries in these 2 patient groups. For example, Amirikia et al44  did not identify theca cell hyperplasia in their population of transgender men, which may correspond to differential findings between endogenous and exogenous hormone generation. Another noteworthy point is that 2 of the papers identified in our study describe histologic changes in the livers of patients taking methyltestosterone.76,78  This formulation of testosterone was previously used in masculinizing therapy, but is no longer used because of the hepatic side effects and current formulations do not result in the same changes.1 

The concept of sex/gender-associated neoplasms is touched on in some of the included studies, such as the case of a pancreatic mucinous cystic neoplasm reported by Foster et al.80  As there are many neoplasms where the reported incidence differs within the sex/gender binary, it would be interesting to pursue further research in this area. Such research would require knowledge of the gender history of patients when they have such neoplasms removed. Currently, gender history is not frequently included in the requisitions for specimens aside from those that are a part of specific gender affirming surgeries. This may be due both to individuals choosing not to disclose, or clinicians choosing not to include information on gender history on requisitions.

In most cases, it is not possible for the pathologist to infer gender history from the gross or histologic findings of neoplasms. However, characteristic changes, such as marked hyalinization of the breasts (See Figure 2, A and B), polycystic ovarian syndrome–like changes in the ovaries, and transitional cell metaplasia of the ectocervix (See Figure 3, A and B) are suggestive of exogenous masculinizing hormone use.

Figure 2

Breast tissue with fibrous stroma and atrophic lobules. Stromal fibrosis is particularly marked in B (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]).

Figure 3. Transitional cell metaplasia of the ectocervix, with a focus of prostatic metaplasia in B (hematoxylin-eosin, original magnifications ×100 [A] and ×200 [B]).

Figure 2

Breast tissue with fibrous stroma and atrophic lobules. Stromal fibrosis is particularly marked in B (hematoxylin-eosin, original magnifications ×20 [A] and ×40 [B]).

Figure 3. Transitional cell metaplasia of the ectocervix, with a focus of prostatic metaplasia in B (hematoxylin-eosin, original magnifications ×100 [A] and ×200 [B]).

Close modal

The reported nongenital neoplasia cases in this review, including the pituitary adenoma and intracardiac lipoma, did not seem to be related to the hormone administration and are likely just coincidental. Even the reports of breast, endometrial, and ovarian neoplasms were not particularly clustered in this subpopulation with higher incidences than that found in the general cisgender population. It has been postulated that pathophysiological mechanisms leading to endometrial hyperplasia and subsequent malignancies in patients taking exogenous androgens may be related to increased serum estrogen concentrations after conversion of androgens and insulin resistance.12  The changes, however, are relevant to pathology practice for the purposes of grossing, sampling for histologic examination, and increased awareness for reporting.

In the breast, the varied macroscopic findings, including detection of firm nodules and areas of fibrosis, could represent a pitfall with the formulation of a malignant gross impression. These areas would need to be sampled appropriately for microscopic examination. The observation of various neoplasms in the breast highlights the significance of proper sampling and microscopic examination of excised breast tissue from transgender men. Currently, there is no uniform grossing/sampling protocol for these specimens in the absence of preoperative concerning imaging studies. Whether they should be handled according to the gynecomastia or the cisgender women's breast reduction protocols has been a matter of some debate. As demonstrated by Hernandez et al34  in their recent comparative study, it is prudent to suggest the adoption of the cisgender women's reduction protocol.

There did not seem to be evidence from the current literature to suggest that androgen administration in this subpopulation altered the incidence of ovarian neoplasia. None of the reported ovarian tumors to date are expected to present a diagnostic challenge for the practicing pathologist. Following the routine institutional grossing protocols while being aware of the neoplastic possibilities should be adequate to deal with these cases in surgical pathology.

Still, many gaps in the literature describing the histologic findings in persons taking masculinizing hormones exist. There are few published studies from organ systems outside of the gynecologic tract and breast. This review also highlights the paucity of higher-level studies looking at the histologic changes in surgical pathology specimens from individuals receiving masculinizing hormones. Many of the papers identified are in the form of case reports, which limits the potential for synthesizing this data. Only 3 cohort studies mentioning histologic diagnoses were identified. More population-based studies in this area could give additional information on incidence of sex-related neoplasms. The increase in publications describing histologic findings from persons taking masculinizing hormones over the last decade highlights the increased interest in this area. To capture the evolution of data, a follow-up review in approximately 5 years may be warranted to follow up on the current review.

The primary limitation of this review is that the broad search terms used in the initial literature search may have resulted in studies using only keywords pertaining to specific procedures or findings being missed. On the other hand, the broad initial search strategy coupled with the backward search was very sensitive and enabled us to identify almost every study in this area. This is a strength of the review. Furthermore, the wide date range (January 1946 to January 2021) examined provides an overview of the evolution of these data and the increase in publications over time.

The data on the histologic findings in histologic specimens from transgender men and transmasculine persons taking masculinizing hormones are summarized, for the first time, in this review. The authors hope that this review can serve as both a reference for practicing pathologists, highlighting common benign histologic changes, as well as a springboard for future comparative and population-based studies as well as future reviews, so that we as the pathology community might better understand the complex effects of exogenous masculinizing hormones on all tissues of the body.

We would like to acknowledge the support of Melissa Upton, MD, of the University of Washington for her input and support in the initial phases of this project. We would also like to acknowledge the Canadian Medical Association reference librarians for their assistance with the literature search.

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References 8, 12, 40, 41, 45, 50, 52, 6062 .

Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the June 2022 table of contents.

The authors have no relevant financial interest in the products or companies described in this article.

Supplementary data