Testosterone Review: Uterine Lining Mostly Atrophic or Proliferative, 2.3% Hyperplasia; 35% Polycystic-Appearing Ovaries

Uterine and Ovarian Histopathology After Testosterone for Gender Affirmation: A Systematic Review

Systematic & evidence reviews Cross-sex hormones

Authors: Maris K. Toland, Kyra Bonasia, Jessica Bentz, Regina M. DelBaugh, Elaina J. Vitale, Paige N. Scudder, Ella A. Damiano
Journal: Transgender Health
Year: 2024
Source: https://doi.org/10.1089/trgh.2022.0207

Summary

Dartmouth doctors combined 17 published studies on what the womb and ovaries look like under the microscope after transmasculine people took testosterone and then had them removed. The womb lining was roughly half thin and inactive and half still growing, and a few (3%) showed signs of recent ovulation despite testosterone. About 2.3% had precancerous thickening of the lining and one person had a tiny cancer. No ovarian cancers were reported, though about a third had ovaries that looked polycystic (full of small cysts). The authors concluded testosterone does not raise precancer risk, and routine biopsies before surgery are not needed without other risk factors. This is useful descriptive data, but it cannot measure risk: there was no comparison group, the studies were small and often biased, average testosterone use was only about 2.5 years, and the cancer comparison was indirect.

Key findings

The review included 17 studies that observed patients (no trials), picked from 658 records, searched up to April 5, 2021.
Of 522 womb linings, 254 (49%) were thin and inactive, 243 (47%) were still growing and 16 (3%) showed recent ovulation, so testosterone does not reliably quiet the womb lining.
Twelve patients (2.3%) had precancerous thickening of the womb lining and one (0.2%) had it with a small spot of cancer; nine of these cases were in people who had no bleeding.
Among 410 patients (765 ovaries), 143 (35%) had ovaries that looked polycystic, 3 (0.7%) had harmless growths and no ovarian cancers were reported.
Signs of recent egg release were found in the ovaries of 5.6% of patients, which shows ovulation can continue on testosterone; the authors stress the need for contraception.
Other harmless findings included fibroids in 12.5%, womb-lining polyps in 7.3%, womb lining growing into the womb muscle in 2.7% and ovarian cysts linked to endometriosis in 1.2%.
Average testosterone use was about 30 months, and most studies were rated at moderate-to-high risk of being misleading.
The authors concluded testosterone does not raise the risk of precancer in the womb, and that a biopsy before surgery is not needed just because someone takes testosterone.

Abstract

PURPOSE: The objective of this systematic review was to evaluate the effects of testosterone on uterine and ovarian pathology in transmasculine patients at the time of gender-affirming surgery.

METHODS: Searches were conducted using MEDLINE, CINAHL with Full Text, Cochrane Library, Scopus, and Europe PMC for articles published before April 5, 2021, containing concepts of testosterone use, uterine histopathology, and transgender population. The initial search yielded a total of 658 abstracts. Studies were analyzed in full text if they reported one or more uterine or ovarian histopathological findings in a noncisgender population receiving testosterone for gender affirmation. Rayyan software was used for the abstract review.

RESULTS: This review was registered with PROSPERO. Twenty-eight full-text articles were reviewed, of which 17 met the inclusion criteria. Two reviewers performed data extraction and risk of bias assessment. Thirteen studies included endometrial histopathology results, representing 522 patients. Endometrial findings demonstrated that 254 patients (48.7%) were atrophic, 243 (46.6%) were proliferative, and 16 (3.0%) were secretory. Twelve patients (2.3%) had endometrial intraepithelial neoplasia (EIN), including one (0.2%) with focal adenocarcinoma. Eleven studies reported ovarian histopathology in 410 patients and 765 ovaries. A total of 143 (34.9%) patients had polycystic-appearing ovaries. Three (0.7%) patients had benign ovarian neoplasms. No ovarian malignancies were reported.

CONCLUSION: The endometrium was predominately found to be atrophic or proliferative, with low rates of EIN and carcinoma. No ovarian malignancy was observed. Based on this review, patients on testosterone do not have an increased risk of precancerous endometrial lesions due to unopposed hormones in the setting of amenorrhea.

Conclusion

The endometrium was predominately found to be atrophic or proliferative, with low rates of EIN and carcinoma. No ovarian malignancy was observed. Based on this review, patients on testosterone do not have an increased risk of precancerous endometrial lesions due to unopposed hormones in the setting of amenorrhea. (Full-text conclusion adds: a minority had secretory endometrium, supporting evidence that ovulation can occur on testosterone; benign lesions such as fibroids and endometriosis occur and symptoms should be evaluated as in cisgender patients.)

Methodological limitations

No comparison group: None of the data come from a matched group of people not on testosterone. The claim that testosterone does "not increase" precancer risk rests on comparing with rates from separate studies of women (1–7.9% in women before menopause with any bleeding pattern, or 0.4% in one group without bleeding), not on a direct comparison.
Short use of testosterone: People had taken testosterone for about 30 months on average (roughly 1–10 years where reported), far too short to judge cancer risk from decades of use. Two studies gave only ranges.
Simple head-counts: Results were just numbers added up across studies. There was no proper statistical combining, weighting by study size, check of how much studies disagreed, or measure of uncertainty.
Small, low-quality studies: All 17 studies only observed patients, most were rated at moderate-to-high risk of being misleading, samples were small, and the pathologists often knew the patients were on testosterone.
Things defined differently: Studies defined womb-lining stages, "polycystic" ovaries (from 6% to 80% across studies depending on the definition) and absent periods differently or not at all. So the combined percentages mix things that don't match, and two different systems for naming precancer were used.
Overlapping and mixed groups: Two studies shared many of the same patients, and three included some people not on testosterone whose results could not be separated out.
Only people who had surgery: Only people who had their womb or ovaries removed were studied. The results may not apply to people who keep their womb on long-term testosterone, the group for whom check-up advice matters most.
Key details missing: Bleeding patterns were reported in only nine studies, weight and other illnesses in few, race in two, and testosterone dose and blood levels were not analysed. So risk factors cannot be studied.
Out of date and English only: The search ended in April 2021 but the paper came out in 2024, and studies not in English were left out.
Narrow focus: The review only covers what tissue looks like under the microscope. It does not cover other reported effects of testosterone on the pelvis, such as pelvic pain, symptoms from thinning tissue or managing bleeding, so it should not be read as an overall safety check.

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Summary

Key findings

Abstract

Conclusion