Tamoxifen transiently disrupts estrous cyclicity without altering long-term ovarian aging trajectories
- 1Oklahoma Medical Research Foundation
Abstract
The ovary is both one of the earliest organs to functionally age in the body, with declines emerging well before reproductive failure and contributing to systemic aging. Since ovarian function depends on tightly regulated hormonal and inflammatory cycles, even subtle disruptions can confound aging-related phenotypes. Tamoxifen-inducible Cre systems are widely used to study ovarian biology, however, tamoxifen is a selective estrogen receptor modulator capable of disturbing ovarian physiology. This introduces a critical and often overlooked concern that tamoxifen-based models may produce lasting effects that obscure true biological signals, particularly in ovarian aging studies. To address this, we tested the hypothesis that tamoxifen induces transient physiological disruption without altering long-term transcriptional outcomes. Female mice were treated with tamoxifen or vehicle at 3 months of age, and estrous cyclicity was monitored longitudinally by vaginal cytology at 3 days, 2 months, 3 months, 6 months, and 12 months post-induction. Ovaries were collected at young (6 months) and aged (12 months) time points for bulk RNA sequencing, followed by differential gene expression and pathway-level analyses. We found that tamoxifen treatment disrupted estrous cyclicity shortly after administration, confirming short term physiological effects. However, normal cycling was restored by 3 months post-treatment, indicating recovery of ovarian function. At the transcriptional level, minimal differences were observed between tamoxifen and vehicle treated groups at both young and aged time points. In contrast, aging-associated transcriptional programs were conserved across treatment conditions with shared alterations in pathways related to extracellular matrix remodeling, senescence, and cellular homeostasis. Together these findings demonstrated that while tamoxifen disturbs ovarian physiology in the short term, it does not produce lasting transcriptional effects or aging associated phenotypes. These results resolve a critical methodological concern and provide validation for the use of tamoxifen-inducible systems in ovarian research, supporting their application in studies of reproductive aging and systemic female health when proper controls are integrated into study design.
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BibTeX
@misc{badillo2026tamoxifen,
title = {{Tamoxifen transiently disrupts estrous cyclicity without altering long-term ovarian aging trajectories}},
author = {S. Badillo and E. Poljanska and S. Ray and H. H. Kilani and J. E. J. Cox and S. Ko and S. Biswas and D. M. Benbrook and M. B. Stout and S. R. Ocanas},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749251},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749251v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Tamoxifen transiently disrupts estrous cyclicity without altering long-term ovarian aging trajectories
AU - S. Badillo
AU - E. Poljanska
AU - S. Ray
AU - H. H. Kilani
AU - J. E. J. Cox
AU - S. Ko
AU - S. Biswas
AU - D. M. Benbrook
AU - M. B. Stout
AU - S. R. Ocanas
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749251
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749251v1
AB - The ovary is both one of the earliest organs to functionally age in the body, with declines emerging well before reproductive failure and contributing to systemic aging. Since ovarian function depends on tightly regulated hormonal and inflammatory cycles, even subtle disruptions can confound aging-related phenotypes. Tamoxifen-inducible Cre systems are widely used to study ovarian biology, however, tamoxifen is a selective estrogen receptor modulator capable of disturbing ovarian physiology. This introduces a critical and often overlooked concern that tamoxifen-based models may produce lasting effects that obscure true biological signals, particularly in ovarian aging studies. To address this, we tested the hypothesis that tamoxifen induces transient physiological disruption without altering long-term transcriptional outcomes. Female mice were treated with tamoxifen or vehicle at 3 months of age, and estrous cyclicity was monitored longitudinally by vaginal cytology at 3 days, 2 months, 3 months, 6 months, and 12 months post-induction. Ovaries were collected at young (6 months) and aged (12 months) time points for bulk RNA sequencing, followed by differential gene expression and pathway-level analyses. We found that tamoxifen treatment disrupted estrous cyclicity shortly after administration, confirming short term physiological effects. However, normal cycling was restored by 3 months post-treatment, indicating recovery of ovarian function. At the transcriptional level, minimal differences were observed between tamoxifen and vehicle treated groups at both young and aged time points. In contrast, aging-associated transcriptional programs were conserved across treatment conditions with shared alterations in pathways related to extracellular matrix remodeling, senescence, and cellular homeostasis. Together these findings demonstrated that while tamoxifen disturbs ovarian physiology in the short term, it does not produce lasting transcriptional effects or aging associated phenotypes. These results resolve a critical methodological concern and provide validation for the use of tamoxifen-inducible systems in ovarian research, supporting their application in studies of reproductive aging and systemic female health when proper controls are integrated into study design.
ER -