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. 2017 Nov 1;313(5):E540-E551.
doi: 10.1152/ajpendo.00161.2017. Epub 2017 Aug 1.

Cross-sex Testosterone Therapy in Ovariectomized Mice: Addition of Low-Dose Estrogen Preserves Bone Architecture

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Free PMC article

Cross-sex Testosterone Therapy in Ovariectomized Mice: Addition of Low-Dose Estrogen Preserves Bone Architecture

Laura G Goetz et al. Am J Physiol Endocrinol Metab. .
Free PMC article

Abstract

Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here, we investigate the long-term effects of XHT on bone health using a murine model. Female mice underwent ovariectomy at either 6 or 10 wk and began weekly testosterone or vehicle injections. Dual-energy X-ray absorptiometry (DXA) was performed (20 wk) to measure bone mineral density (BMD), and microcomputed tomography was performed to compare femoral cortical and trabecular bone architecture. The 6-wk testosterone group had comparable BMD with controls by DXA but reduced bone volume fraction, trabecular number, and cortical area fraction and increased trabecular separation by microcomputed tomography. Ten-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone with effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-wk ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, including bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, trabecular thickness, and connectivity density) to estrogen therapy and were superior compared with mice treated with testosterone only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments with potential future clinical implications for treating transgender youth or men with estrogen deficiency.

Keywords: cross-sex hormone therapy; female-to-male; hormone therapy; osteoporosis; testosterone; transgender.

Figures

Fig. 1.
Fig. 1.
Early and late XHT testosterone and estradiol levels. Testosterone (A) and estradiol (B) levels are shown comparing early (6 wk: C6 vs. T6) and late (10 wk: C10 vs. T10) transition groups and controls. All groups were n = 5. Significance: *P = 0.05, **P = 0.02.
Fig. 2.
Fig. 2.
Early and late XHT DXA body composition. General body composition obtained by DXA is shown comparing early (6 wk: C6 vs. T6) and late (10 wk: C10 vs. T10) transition groups and controls. All groups were n = 5. A: total mass. B: total percent fat. C: total lean mass. D: total fat mass. No comparisons are significant.
Fig. 3.
Fig. 3.
Early and late XHT DXA bone. DXA results are shown comparing early (6 wk: C6 vs. T6) and late (10 wk: C10 vs. T10) OVX transition groups and controls. All groups were n = 5. A: femur bone mineral density. B: femur bone mineral content. C: spine bone mineral density. D: spine bone mineral content. E: total bone mineral density. F: total bone mineral content. Significance: *P = 0.03.
Fig. 4.
Fig. 4.
Early and late microCT trabecular. MicroCT results are shown comparing early (6 wk: C6 vs. T6) and late (10 wk: C10 vs. T10) transition groups and controls. All groups were n = 5. A: bone volume fraction. B: trabecular number. C: trabecular thickness. D: trabecular separation. E: connectivity density. Significance: *P = 0.05, **P = 0.04.
Fig. 5.
Fig. 5.
Early and late microCT cortical. MicroCT results are shown comparing early (6 wk: C6 vs. T6) and late (10 wk: C10 vs. T10) transition groups and controls. All groups were n = 5. A: total area. B: bone area. C: cortical area fraction. D: cortical thickness. E: medullary area. Significance: *P = 0.03, **P = 0.02, ***P = 0.01.
Fig. 6.
Fig. 6.
Combined testosterone + estrogen XHT testosterone and estradiol levels. Testosterone (A) and estradiol (B) levels are shown comparing the effects of combined testosterone and estradiol treatment after 6-wk OVX (T+E 6) with testosterone alone after 6-wk OVX (T6). T6 and E6 groups were n = 5, and T+E 6 was n = 6. Significance compared with T6 group: *P = 0.05, **P = 0.04.
Fig. 7.
Fig. 7.
Combined testosterone + estrogen XHT DXA body composition. DXA results are shown comparing the effects of combined testosterone and estrogen treatment after 6-wk OVX (T+E 6) with testosterone alone after 6-wk OVX (T6). T6 and E6 groups were n = 5, and T+E 6 was n = 6. A: total mass. B: total percent fat. C: total lean mass. D: total fat mass. Estrogen-only treatment after 6-wk OVX (E6) is provided as a reference to compare the effects of testosterone after OVX with standard care. There are no significant differences.
Fig. 8.
Fig. 8.
Combined testosterone + estrogen XHT DXA bone. DXA results are shown comparing the effects of combined testosterone and estrogen treatment after 6-wk OVX (T+E 6) with testosterone alone after 6-wk OVX (T6). T6 and E6 groups were n = 5, and T+E 6 was n = 6. A: spine bone mineral density. B: spine bone mineral content. C: femur bone mineral density. D: femur bone mineral content. E: total bone mineral density. F: total bone mineral content. Estrogen-only treatment after 6-wk OVX (E6) is provided as a reference to compare the effects of testosterone after OVX with standard care. Significance compared with T6 group: *P = 0.03, **P = 0.02, ***P = 0.01.
Fig. 9.
Fig. 9.
Combined testosterone + estrogen XHT microCT trabecular. MicroCT results are shown comparing the effects of combined testosterone and estrogen treatment after 6-wk OVX (T+E 6) with testosterone alone after 6-wk OVX (T6). T6 and E6 groups were n = 5, and T+E 6 was n = 6. A: bone volume fraction. B: trabecular number. C: trabecular thickness. D: trabecular separation. E: connectivity density. Estrogen-only treatment after 6-wk OVX (E6) is provided as a reference to compare the effects of testosterone after OVX with standard care. Significance compared with the T6 group: *P = 0.05, **P = 0.04, ***P = 0.03, ****P = 0.01.
Fig. 10.
Fig. 10.
Combined testosterone + estrogen XHT microCT cortical. MicroCT results are shown comparing the effects of combined testosterone and estrogen treatment after 6-wk OVX (T+E 6) with testosterone alone after 6-wk OVX (T6). T6 and E6 groups were n = 5, and T+E 6 was n = 6. A: total area. B: bone area. C: cortical area fraction. D: cortical thickness. E: medullary area. Estrogen-only treatment after 6-wk OVX (E6) is provided as a reference to compare the effects of testosterone after OVX with standard care. Significance compared with the T6 group: *P = 0.01.

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