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Testosterone treatment in transmen is associated with reduced hormone signaling in the mammary gland

ABSTRACT: Many transgender men receiving long-term testosterone replacement therapy (TRT) have high serum levels of testosterone, compared to the low levels seen in cisgender women. Compared to other sex hormones such as estrogen and progesterone, the effects of testosterone on the mammary gland have been relatively understudied. Comparison of mammary glands from transgender men on TRT and cisgender women can reveal the poorly understood consequences of testosterone expression on mammary gland biology and the long-term effects of TRT on patient health and disease outcomes. In this study, we performed single-cell RNA sequencing of breast tissues from cisgender women and transgender men on TRT. We identified that the donors on TRT had a decreased expression of genes downstream of estrogen signaling pathways in hormone receptor positive luminal epithelial, as well as a decrease in luteal phase gene activity in these donors. We confirmed this finding experimentally by showing reduced expression of progesterone receptor a/b, a prominent marker of estrogen signaling, in donors on TRT. Our results support the hypothesis that high levels of testosterone in transgender men on TRT suppresses hormone signaling in the breast through their impact on hormone receptor positive (HR+) mammary epithelial cells, with implications for TRT as an antagonist of estrogen receptor alpha (ER) signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283161 | GEO | 2026/01/14

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE283161_barcode.counts.lane1.rds.gz	Other
	GSE283161_barcode.counts.lane2.rds.gz	Other
	GSE283161_barcode.counts.lane3.rds.gz	Other
	GSE283161_breast_data.rds.gz	Other

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Project description:Goal of the experiment: To examine the effects of estrogen and testosterone on gene expression in the rat mesenteric arteries. Brief description of the experiment: A dramatic difference exists in the timing of development of cardiovascular disease in men vs. women. The primary candidates underlying the cause of gender differences in cardiovascular disease are the sex steroids, estrogen and testosterone. The effect of estrogen on the cardiovascular system has been expected to be protective but this concept has become controversial. The effect of testosterone on the cardiovascular system is considered to be deleterious. In spite of these concepts there is little data on the direct effects of estrogen and testosterone on gene expression in the vasculature. Since estrogen and testosterone exert many of their effects through genomic mechanisms, the DNA microarray is an excellent tool for assessing their effects in the vasculature. In this study, ovariectomized Sprague Dawley rats were treated for 4 days with vehicle (sesame oil), estradiol benzoate (0.15 mg/kg/day), or testosterone (1 mg/kg/day). The mesenteric arteries were obtained, total RNA was extracted, and CodeLink Uniset Rat I DNA microarrays (GE) were used to identify differential gene expression. Seven genes were identified as differentially expressed from the DNA microarray data and confirmed by real time RT-PCR. The expression of D site albumin promoter binding protein and fatty acid synthase were increased in response to both estrogen and testosterone. 3alpha-hydroxysteroid dehydrogenase, interleukin 4 receptor, JunB and c-Fos expression were increased by estrogen but not by testosterone. The aryl hydrocarbon nuclear translocator-like was reduced by testosterone. These data identify genes not previously known to be responsive to estrogen and testosterone in the vasculature. Keywords: hormone treatment, vasculature, gender differences Experimental factors: hormone treatment Keywords: hormone treatment

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Testosterone treatment in transmen is associated with reduced hormone signaling in the mammary gland

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